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Http://apps.fcc.gov/​ecfs/​. Follow the instructions for submitting comments. Mail. Parties who choose to file by paper must file an original and one copy of each filing.

Filings can be sent by commercial overnight courier, or by first-class or overnight U.S. Postal Service mail. All filings must be addressed to the Commission's Secretary, Office of the Secretary, Federal Communications Commission. Commercial overnight mail (other than U.S.

Postal Service Express Mail and Priority Mail) must be sent to 9050 Junction Drive, Annapolis Junction, MD 20701. U.S. Postal Service first-class, Express, and Priority mail must be addressed to 45 L Street NE, Washington, DC 20554. Effective March 19, 2020, and until further notice, the Commission no longer accepts any hand or messenger delivered filings.

This is a temporary measure taken to help protect the health and safety of individuals, and to mitigate the transmission of alcoholism treatment. See FCC Announces Closure of FCC Headquarters Open Window and Change in Hand-Delivery Policy, Public Notice, DA 20-304 (March 19, 2020). Https://www.fcc.gov/​document/​fcc-closes-headquarters-open-window-and-changes-hand-delivery-policy. People with Disabilities.

Contact the FCC to request reasonable accommodations (accessible format documents, sign language interpreters, CART, etc.) by email. FCC504@fcc.gov or phone. 202-418-0530 or TTY. 202-418-0432.

For detailed instructions for submitting comments and additional information on the rulemaking process, see the SUPPLEMENTARY INFORMATION section of this document. Start Further Info Michelle Sclater, Competition Policy Division, Wireline Competition Bureau, at (202) 418-0388, Michelle.Sclater@fcc.gov. End Further Info End Preamble Start Supplemental Information This is a summary of the Commission's further notice of proposed rulemaking (FNPRM) in WC Docket No. 18-336, adopted on April 22, 2021 and released on April 23, 2021.

The full text of the document is available at https://docs.fcc.gov/​public/​attachments/​FCC-21-47A1.pdf. To request materials in accessible formats for people with disabilities (e.g., braille, large print, electronic files, audio format, etc.) or to request reasonable accommodations (e.g., accessible format documents, sign language interpreters, CART, etc.), send an email to fcc504@fcc.gov or call the Consumer &. Governmental Affairs Bureau at (202) 418-0530 (voice) or (202) 418-0432 (TTY). Synopsis I.

Further Notice of Proposed Rulemaking A. Text-to-988 Can Save Lives 1. In this FNPRM, we tentatively conclude that text-to-988 functionality will greatly improve consumer access to the National Suicide Prevention Lifeline (Lifeline), particularly for at-risk populations, and thereby save lives. We seek comment on this tentative conclusion, and on the benefits of text messaging as a means to facilitate access to the critical mental health resources offered by the Lifeline generally.

2. We tentatively conclude that ensuring that Americans in crisis can text 988 is likely to save lives. In the 988 notice of proposed rulemaking, the Commission observed that “Americans, particularly younger Americans, increasingly rely on texting to communicate,” and sought comment on how to account for this fact in establishing 988 as a nationwide 3-digit code for the Lifeline. In response, numerous experts in mental health and other fields have submitted comments in this proceeding underscoring the importance of texting as a vital communications medium by which many individuals may wish to obtain crisis counseling.

Further, many of these commenters noted that texting is particularly important for “members of vulnerable communities such as young people, low-income individuals, members of the LGBTQ community, and individuals who are deaf and hard of hearing.” We seek comment on our tentative conclusion and the assertions of these commenters regarding the importance of texting as a means to access the lifesaving resources offered by the Lifeline. 3. Just as “Americans in crisis are in need of an easy-to-remember number to access the Lifeline's potentially life-saving resources” by telephone, in our preliminary view Americans have a similarly strong need for an easy-to-remember number to reach the Lifeline by text. Because stakeholders will widely advertise 988 as the telephone number for the Lifeline, we preliminarily believe that providing text access at the same number will generate synergies that enhance the value of efforts to promote 988.

Conversely, we fear that if text-to-988 is not available, Americans in crisis may be confused by efforts to promote 988 as the Lifeline's telephone number and mistakenly believe that they can reach the Lifeline by texting 988, putting lives at risk. We seek comment on this preliminary analysis. 4. As the Commission noted in the 988 Report and Order, young people are disproportionately at risk for mental health crises.

They are also more likely to be most comfortable communicating via text. According to the National Alliance on Mental Illness, “[n]early 95% of teens have access to smart phones and say that texting is the primary way that they connect.” For this reason, the International Council for Helplines describes the increasing use of “chat and text services. . .

For those who are in a mental health crisis,” pointing to a recent survey indicating that “75% of millennials prefer texting over talking.” According to Mental Health America, “[m]ultiple sources of data demonstrate youth prefer communicating by text rather than calls,” including a study finding that young people “were more likely to forgo psychological support than talk in person or over the phone.” As a result, Mental Health America argues, the “data strongly support[ ] the implementation of texting for providing resources to individuals experiencing suicidal ideation.” We seek comment on these views and whether adopting a text-to-988 mandate would provide particular benefits for young Americans. Are young people more inclined to seek help by text than by telephone, and if Start Printed Page 31405so, would making it easier to text the Lifeline save lives?. 5. In our preliminary view, facilitating Lifeline accessibility by text message to 988 is also likely to provide significant benefits to many other at-risk communities as well, further justifying our proposed mandate.

As the Commission explained in the 988 Report and Order, a broad range of American communities are disproportionately impacted by suicide, including Veterans, LGBTQ individuals, racial and ethnic minorities, and rural Americans. Many members of these affected communities may prefer to seek help through text messages. For example, Mental Health America reports that data they collect demonstrate that individuals “who identify as Black or African American are more likely to report that they would like to receive a phone number they can immediately call or text for help” than members of any other race or ethnicity. Do commenters agree with Mental Health America that making crisis counseling services available via text message “may mean the difference between accessing psychological support and forgoing it, especially among youth of color?.

€ Is Mental Health America correct that easy access to crisis services via text may be the difference between seeking and forgoing help for such groups, and if so would use of a 3-digit dialing code for the Lifeline make a significant difference in widespread understanding that such crisis services are available?. 6. Indeed, demographic evidence regarding usage of currently available non-governmental text and chat options indicate that texting is a particularly valuable means to obtain help, not only for young people, but also for many members of low income, minority, and other communities that are disproportionately impacted by mental health crises. Several commenters in this proceeding have pointed to the successes that private non-profit services like the Trevor Project have had in providing crisis counseling to at-risk communities through text messages, offering that their experiences demonstrate the need to provide text access to 988.

In addition, as one commenter to the 988 notice of proposed rulemaking argued, adding text access to 988 could allow the Lifeline and Veterans Crisis Line “to more efficiently route those in need to specialized services,” further leveraging the expertise of organizations like the Trevor Project, which provides mental health support and counseling specific to the needs of LGBTQ youth. We preliminarily agree with this assessment and believe that establishing text access to 988 will complement the important work already being done by these and other private sector organizations, and further facilitate access to the lifesaving resources offered by the Lifeline and Veterans Crisis Line. We seek comment on these views and on the benefits of text-to-988 for at-risk groups. Are there additional at-risk communities that may benefit from texting as an option to access the Lifeline?.

7. Likewise, we preliminarily believe that our tentative conclusion is further justified because implementing text-to-988 capability will provide substantial benefits for individuals with disabilities who uniquely rely on text-based media to communicate. As the Communications Equality Advocates and others note, texting is an indispensable means of communication for individuals with disabilities. These individuals have increasingly adopted widely available text messaging platforms such as those offered by CMRS providers and interconnected text messaging services in lieu of specialized legacy devices.

Further, texting may be the only means for such individuals to contact 988 directly and efficiently. Access to telecommunications for individuals with disabilities is a longstanding Commission priority and statutory obligation, and facilitating access to 988 for deaf and hard of hearing individuals is a particularly important policy objective in light of studies finding a significantly increased risk of suicide among deaf and hard of hearing people when compared to those without hearing loss. We seek comment on these views and whether our proposal would ease access to lifesaving counseling for individuals with disabilities. Do commenters agree with the Communications Equality Advocates that the ability for individuals normally using text for the bulk of their communications, including people with disabilities, to access trained mental health professionals using text-to-988 will be of “paramount importance”?.

Currently, how do people with disabilities reach the Lifeline?. How would texting grant access or enhance their ability to communicate with the Lifeline?. We seek comment on whether texting would be more accessible than the options currently available, including the Lifeline's online chat portal. 8.

We tentatively conclude that the potential lifesaving benefits of expanding access to suicide prevention and mental health crisis services for all Americans—and particularly the at-risk groups discussed above—justifies a text-to-988 mandate, and we seek comment on this view. The Commission's designation of 988 as the 3-digit telephone number for the Lifeline reflected its expectation that a simple, easy-to-remember, 3-digit dialing code for suicide prevention and mental health crisis counseling would “help increase the effectiveness of suicide prevention efforts, ease access to crisis services, reduce the stigma surrounding suicide and mental health conditions, and ultimately save lives.” We preliminarily believe that establishing text access to 988 will further advance these important objectives by providing mental health crisis counseling through a nationally available, easy-to-remember number that Americans will also associate with the telephonic Lifeline. Do commenters agree with the Communications Equality Advocates that individuals in crisis “are likely to first use their preferred, familiar mode of communication to reach out for help?. € We seek comment on this analysis, and on our proposed conclusion that a text-to-988 mandate is likely to offer substantial, lifesaving benefits to all Americans affected by mental health crises, particularly for many members of at-risk communities.

Is a text-to-988 mandate likely to have a significant impact on the likelihood of Americans considering suicide or in a mental health crisis to contact the Lifeline?. Would mandating text-to-988 amplify the benefits of promoting 988 as the telephone number for the Lifeline?. What are the costs or drawbacks to our proposal?. 9.

In our preliminary view, the Lifeline's soft launch of a texting capability is a significant changed circumstance that supports mandating text-to-988. When the Commission adopted the 988 Report and Order, the Lifeline was not capable of receiving or responding to text messages. The Commission, stating that it has no authority to require the Lifeline to develop texting capability, deferred “consideration of mandating text-to-988 at this time so that we could revisit the issue promptly should the Lifeline develop integrated texting.” Now, the Lifeline is capable of responding to texts sent to the Lifeline. The Lifeline's ability to respond to texts significantly strengthens the case for imposing a text-to-988 mandate on providers.

We seek comment on this evaluation. 10. We preliminarily expect many of the same lifesaving benefits from texting to 911 to accrue from texting to 988. In its comments in support of adopting a text-to-988 requirement, CTIA notes that text-to-911 functionality “has saved countless lives and enabled public safety to keep pace with the modern Start Printed Page 31406communications preferences of consumers.” Given the parallels between the Commission's efforts to promote text access to 911 and our proposals in this FNPRM, are there lessons learned in the context of establishing text-to-911 capability that would be instructive here?.

CTIA states that there are “significant technical and policy differences between the national 9-8-8 service that will be administered by the Lifeline and the local 9-1-1 services that are administered by thousands of PSAPs.” For example, unlike calls to 911, which carriers route to one of thousands of local PSAPs across the country based on the caller's geographic location, all calls to 988 are routed to a central toll free number, and are then directed within the Lifeline network to a local crisis center. How might these or other differences between the 911 and 988 networks affect our proposal to adopt a text-to-988 requirement?. B. Proposed Implementation of Text-to-988 1.

Scope of Text-to-988 Requirement 11. Text Formats. We seek comment on an appropriate scope of text messages that covered text providers must transmit to 988. At present, the Lifeline is capable of receiving text messages sent to the existing 10-digit number in “short message service” (SMS) format.

The Commission's Truth in Caller ID rules define the term `short message service' or SMS as “a wireless messaging service that enables users to send and receive short text messages, typically 160 characters or fewer, to or from mobile phones and can support a host of applications.” We recognize, however, that our federal partners may incorporate additional capabilities for receiving and responding to text messages in the future. We seek to adopt a forward-looking, flexible scope that can expand with the capabilities of the Lifeline without unnecessarily burdening covered text providers by requiring support of formats that the Lifeline is not yet capable of receiving. To that end, we propose (1) establishing a definition that sets the outer bound of text messages sent to 988 that covered text providers may be required to support. And (2) directing the Wireline Competition Bureau (Bureau) to identify text formats within the scope of that definition that the Lifeline can receive and thus covered text providers must support by routing to the 10-digit Lifeline number.

We seek comment on this proposal in detail below. 12. First, we propose to define the outer bound of text messages that covered text providers may be required to transmit to 988 based on the definition of “text message” that Congress enacted in 2018 in the context of Truth in Caller ID requirements. The term “text message” (i) means a message consisting of text, images, sounds, or other information that is transmitted to or from a device that is identified as the receiving or transmitting device by means of a 10-digit telephone number or N11 service code.

(ii) includes a [SMS] message and a multimedia message service (commonly referred to as `MMS') message. And (iii) does not include—(I) a real-time, two-way voice or video communication. Or (II) a message sent over an IP-enabled messaging service to another user of the same messaging service, except a message described in clause (ii). The Commission's Truth in Caller ID rules define MMS as “a wireless messaging service that is an extension of the SMS protocol and can deliver a variety of media, and enables users to send pictures, videos, and attachments over wireless messaging channels.” We seek comment on this proposed scope.

We believe this definition has several advantages—it incorporates multimedia messages. It is not limited to specific technologies. And it reflects a recent determination by Congress, albeit in a different policy context. For the purpose of our text-to-988 rules, we propose adding “or 988” to the phrase “10-digit telephone number or N11 service code” so that text messages from the Lifeline identified by the 3-digit code 988 are included within the scope of covered text providers' obligations, and we seek comment on this proposal.

We seek comment on whether using the Truth in Caller ID definition appropriately sets an outer bound that would achieve our goals of adopting a forward-looking, flexible scope that can expand with the capabilities of the Lifeline without unnecessarily burdening covered text providers. 13. We note that the Truth in Caller ID statutory definition of “text message” excludes “real-time, two-way voice or video communications,” as well as “messages sent over. .

. IP-enabled messaging services to another user of the same messaging service.” If we adopt the Truth in Caller ID definition, we seek comment on how we should interpret each of these two exclusions here. Is there any reason to adopt a different interpretation of the relevant exclusions in this context compared to the Truth in Caller ID context?. € Would adopting the Truth in Caller ID definition of “text message,” with the exclusions specified above, prevent us from possibly adding “next-generation” text messages to our requirements in the future?.

14. We also seek comment on alternative outer scopes of required texts. For instance, should we adopt the scope of our text-to-911 rules, which require providers to route “a message, consisting of text characters, sent to the short code `911' and intended to be delivered to a PSAP by a covered text provider, regardless of the text messaging platform used”?. In the Text-to-911 Second Report and Order, the Commission identified SMS and MMS messages as examples of text messages included within the scope of this proposed rule.

We seek comment on whether the Truth in Caller ID definition, the text-to-911 definition, or another definition offers the best model here. We note that the Truth in Caller ID model is newer than the text-to-911 definition, originates with Congress rather than the Commission, and unlike the text-to-911 definition explicitly includes images, sounds, and other non-textual information. On the other hand, the Commission developed the text-to-911 definition in a more analogous policy context than the Truth in Caller ID definition. Do these or other considerations suggest that one or the other model is superior?.

15. Should we ensure that any definition we adopt encompasses next-generation forms of text messaging, such as MMS, Rich Communications Services (RCS), and/or real-time text (RTT), and what modifications—if any—would we need to make to the definitions we are considering to ensure that such forms are within our proposed scope?. RCS has been described as a “successor protocol” to SMS, or as “next-generation” SMS. What are the fundamental differences between SMS, MMS, and RCS?.

How would the costs to implement SMS, MMS, and RCS differ?. The Commission has previously concluded that “messages sent over other IP-enabled messaging services that are not SMS or MMS—such as [RCS]—are excluded from” the Truth in Caller ID definition of text message “to the extent such messages are sent to other users of the same messaging service.” Would it be necessary to modify the Truth in Caller ID definition for our purposes to ensure that it includes RCS or other next-generation services?. 16. We also seek comment on whether we should ensure that our proposed outer bound definition of text message encompasses RTT.

Telecommunications for the Deaf and Hard of Hearing, Inc., et al. Have urged us to mandate the ability to reach 988 by RTT, noting that the Commission “has acknowledged the benefits of RTT in crisis situations such as `allow[ing] for interruption and reduc[ing] the risk of crossed messages Start Printed Page 31407because the. . .

Call taker is able to read the caller's message as it is being typed, rather than waiting until the caller presses the `send' key.” We seek comment on this assertion and other potential benefits and drawbacks of RTT to 988. We note that pursuant to the 2016 RTT Order, all wireless service providers are permitted to support RTT on their IP networks for purposes of 911 compliance (and for purposes of complying with the general accessibility requirements of Parts 6, 7, and 14 of the Commission's rules) as an alternative to supporting TTY communications over IP. In light of the deployment of such RTT capabilities in wireless IP networks, are there any impediments to wireless service providers routing RTT texts to the 988 number, in the event that Lifeline chooses to support RTT?. Do newer text messaging protocols like RTT and RCS represent a significant portion of the text messaging ecosystem, or are they likely to in the near future?.

Are consumers likely to expect the ability to use these kinds of platforms to send text messages to 988?. Do these texting solutions make texting more accessible for individuals with disabilities?. Are there other reasons to include, or exclude, these types of applications from our definition?. Are there any text message formats that we should specifically exclude from the definition we adopt?.

For example, in crafting the text-to-911 rules, the Commission chose to exclude from its requirements a variety of services, including “relay service. . . , mobile satellite service (MSS), and in-flight text messaging services,” as well as “text messages that originate from Wi-Fi only locations or that are transmitted from devices that cannot access the CMRS network.” Should we adopt any similar exclusions here?.

17. Second, we seek comment on how to structure our delegation to the Bureau to ensure that covered text providers support formats within the scope of the definition we adopt that the Lifeline can receive. We propose, as an initial matter, requiring covered text providers to support transmission of SMS messages to 988, since that is what the Lifeline can presently receive. We further propose directing the Bureau, after consultation with our federal partners at SAMHSA and the VA, to issue a Public Notice no less frequently than annually proposing and seeking comment on requiring covered text providers to transmit any new message formats to 988 that the Lifeline can receive and that are within the scope of the definition we adopt.

If the Bureau proposes requiring implementation of a new message format, we further propose directing the Bureau, after notice and comment, to issue a second Public Notice, requiring covered text providers to transmit the new message format to 988 by a fixed deadline that we specify unless the record demonstrates that implementation is not technically feasible. We seek comment on this proposal. Does it appropriately balance the need for expedient implementation with avoiding unduly burdening covered text providers with implementing formats that the Lifeline cannot receive?. Should we require the Bureau to issue a Public Notice more or less often than annually?.

Or is there another mechanism, such as one similar to the Commission's Text-to-911 PSAP registry, whereby PSAPs issue a valid request for texting service from covered text providers, that we should consider?. Is technical feasibility an appropriate standard for exclusion, or do commenters recommend a different standard?. Should we have a standard for exclusion by the Bureau at all?. If we do not have a standard for excluding certain technologies, is notice and comment necessary?.

What is an appropriate implementation deadline for us to specify after the Bureau issues its Public Notice requiring implementation?. For instance, would six months be sufficient?. Should we instead allow the Bureau flexibility to set an appropriate deadline?. Should we provide any further direction to the Bureau regarding the evaluation we propose to require?.

18. We also seek comment on structuring the scope of covered text messages differently. For instance, should we simply adopt a definition of “text message” and require covered text providers to support all such formats, regardless of whether the Lifeline can support that format presently?. Should we adopt a narrower definition of “text message” that conforms to what the Lifeline can support at present?.

While we appreciate the simplicity of either of these approaches compared to our proposal, how would commenters address our concern that the former is unnecessarily burdensome, and the latter is not adequately future-proofed?. 19. Covered Text Providers. We propose to apply our text-to-988 requirement to “covered text providers” as that term is defined in the text-to-911 rules, to “include[ ] all CMRS providers as well as all providers of interconnected text messaging services that enable consumers to send text messages to and receive text messages from all or substantially all text-capable U.S.

Telephone numbers, including through the use of applications downloaded or otherwise installed on mobile phones.” We note that the term “covered text provider” used in this notice of proposed rulemaking differs from the term “covered providers” used in the rules the Commission adopted in the 988 Order, which refers to all telecommunications carriers, interconnected VoIP providers, and one-way VoIP providers. We seek comment on this proposal, and on any alternative approaches to the scope of entities that must establish text-to-988 transmission capability. For example, if we can apply the definition of “text message” in the Truth in Caller ID rules to texting to 988, should we apply our text-to-988 rules to providers of “text messaging services,” as defined in section 227 of the Act and our Truth in Caller ID rules?. In that context, we define “text messaging service” as “a service that enables the transmission or receipt of a text message.” Is the Truth in Caller ID model preferable, for instance because it may incorporate a broader range of providers that support text messaging service, or is our proposal preferable, for instance because it is more specific?.

We also seek comment on other possible models and scopes of covered providers. Would using “CMRS providers” exclude services over certain spectrum bands or non-switched wireless services that transmit text messages to 988, and should we instead include “wireless carriers,” or a different term, in our definition of “covered text providers?. € 20. Interconnected Text Messaging Services.

In adopting the text-to-911 rules, the Commission observed that there are a variety of widely available text messaging services and platforms with different technological capabilities, including SMS, MMS, and “over-the-top” (OTT) applications delivered over internet protocol (IP)-based mobile data networks. As the Commission explained in the Text-to-911 Second Report and Order, “SMS requires use of an underlying carrier's SMS Center (SMSC) to send and receive messages from other users” while “[MMS]-based messaging makes use of the SMSC but also involves the use of different functional elements to enable transport of the message over IP networks.” A third category, OTT applications, may be offered by CMRS providers or third parties and allow consumers “to send text messages using SMS, MMS or directly via IP over a data connection to dedicated messaging servers and gateways.” These OTT services, which are often downloaded through mobile app stores, are increasingly popular with consumers and may be interconnected with the publicly Start Printed Page 31408switched telephone network (PSTN) or not. For purposes of the Commission's text-to-911 rules, interconnected text messaging applications enable consumers to “send text messages to all or substantially all text-capable U.S. Telephone numbers and receive text messages from the same,” while non-interconnected applications “only support communication with a defined set of users of compatible applications but do not support general communication with text-capable telephone numbers.” The Commission's text-to-911 rules include interconnected text messaging services but exclude non-interconnected applications because they do not provide the ability to communicate with text-capable U.S.

Telephone numbers. 21. As in the text-to-911 rules, we propose to apply our text-to-988 requirements to interconnected text messaging services, thereby excluding non-interconnected applications from the requirements. We seek comment on this approach.

This approach is also analogous to the Commission's decision in the 988 Report and Order to apply to “providers that access the [PSTN] on an interconnected basis to reach all Americans” and any “providers that access the [PSTN] on an interconnected basis to reach all Americans.” We note that the Commission's Truth in Caller ID rules provide an exemption for messages “sent over an IP-enabled messaging service to another user of the same messaging service, except [for an SMS or MMS message],” which similarly operates to exclude non-interconnected text messaging services. Since the services provided by the Lifeline require two-way communication and, by definition, non-interconnected text messaging applications cannot support two-way texting with “all or substantially all text-capable U.S. Telephone numbers,” we believe it is unlikely that these services would be technically capable of supporting text-to-988 functionality. We seek comment on this view.

Are there any tools available to the Commission to mitigate the potential for consumer confusion regarding the availability of text-to-988 across different text messaging platforms and technologies, particularly with respect to non-interconnected text messaging applications?. 2. Routing Texts to 988 22. We propose to require that covered text providers route covered 988 text messages to the Lifeline's current 10-digit number, 1-800-273-8255 (TALK), and we seek comment on this proposal.

This proposal is consistent with the Commission's decision for routing calls to 988 in the 988 Report and Order. In the 988 Report and Order, the Commission required “that service providers transmit all calls initiated by an end user dialing 988 to the current toll free access number for the Lifeline,” finding that a centralized routing solution will allow for faster implementation of the 988 3-digit dialing code, lower costs to maintain 988 routing, and provide continued easy access to Lifeline by callers with disabilities. We preliminarily believe that there are similar benefits to routing texts to 988 to a single, centralized number and seek comment on this view. 23.

There is support in the record thus far for routing to the Lifeline. CTIA supports directing texts sent to 988 to the Lifeline as a “central point for receiving such communications,” consistent with the Commission's mandate for routing 988 voice calls. Vibrant Emotional Health, the administrator of the Lifeline, argues in support of text-to-988 functionality integrated into the current Lifeline structure for routing voice and chat services, with oversight squarely within the role of the Lifeline's administrator. We seek comment on these assessments.

24. We anticipate that requiring covered text providers to route to a single destination provides SAMHSA and the VA with flexibility to develop their own routing solutions among the local crisis centers, including adding new crisis centers in the future, as compared to requiring covered text providers to implement additional updates or routing changes as more centers are added. Callers to 1-800-273-8255 (TALK) can reach the Veterans Crisis Line by pressing option 1 to connect with one of three linked call centers in New York, Georgia, or Kansas. For other calls, calls to the Lifeline from anywhere in the United States are routed to the closest certified local crisis center according to the caller's area code or, should the closest center be overwhelmed by call volume, experience a disruption of service, or if the call is placed from part of a state not covered by Lifeline's network, the system automatically routes calls to a backup center.

We seek comment on this preliminary analysis. Do the current obligations to route voice calls to 988 to the Lifeline 10-digit number offer any opportunities for streamlining implementation or reducing costs associated with routing texts to 988 to the same number?. 25. In the alternative, we seek comment on whether instead to follow a model more comparable to the text-to-911 architecture, whereby covered text providers route directly to a PSAP by requiring routing directly to a Lifeline local crisis center or to a Veterans Crisis Line crisis center.

We anticipate that this approach would be significantly more costly than centralized routing and seek comment on this preliminary view. Is it easier to route texts to a single number than to individual crisis centers?. As the Veterans Crisis Line is not currently set up for geographic distribution, would this architecture be appropriate for messages by Veterans or Service Members?. Are covered text providers able to leverage existing text-to-911 systems to reduce costs if required to route texts to 988 directly to local crisis centers?.

In the 988 Report and Order, the Commission recognized that some commenters expressed there may be benefits to routing voice calls to individual crisis centers, such as familiarity with a caller's area and potentially easier coordination with local emergency services, but ultimately concluded that the advantages associated with routing to a single number outweighed the benefits of localized routing. Does that rationale apply here?. Are there benefits to routing texts to the individual crisis centers that are unique to text messages, such as providing localized support to the public in the vicinity of the crisis center?. What are the costs or drawbacks to covered text providers to route texts to the Lifeline 10-digit number versus the local crisis centers?.

Which approach will lead to speedier implementation, and how should that impact our analysis?. Is there another alternative approach, other than centralized routing or routing by crisis center, that we should consider?. 26. Currently, Veterans and Service Members may dial the Lifeline to reach the Veterans Crisis Line via voice call, but the Lifeline texting service and the VA's short code texting service require contacting separate numbers.

How should we account for this distinction in evaluating what rules to adopt to ensure that Veterans, Service Members, and their families are able to reach the Veterans Crisis Line directly and promptly?. We seek comment on whether and how we can act to facilitate integration of the Veterans Crisis Line's separate short code-based texting service into text-to-988 routing. Are there specific actions that the Commission should take to allow users to text 988 and reach both the Lifeline and Veteran-specific assistance?. For instance, should we require covered text providers to provide an automated inquiry as to whether the texter is a Veteran or Service Member and route Start Printed Page 31409the text to either the existing Lifeline number or the existing short code for Veterans depending on the response?.

Alternatively, would it be feasible to immediately prompt individuals texting to 988 to reply with the number “1” or “Vet” to be routed to the Veterans Crisis Line, similar to the experience for voice callers?. Are other prompts preferable?. We seek comment on possible solutions to ensure that texts are routed to the proper counseling services via the Lifeline or the Veterans Crisis Line, including input on technical feasibility, ways to minimize consumer confusion, and implementation costs. Should other text or chat services be integrated into 988 text routing, and if so, how?.

27. We seek comment on whether we should require covered text providers to enable text-to-988 messages to include location information. As required by the National Suicide Hotline Designation Act of 2020, the Bureau will report to Congress on the costs and feasibility of providing location information with 988 calls on April 17, 2021. In our preliminary view, given that we have not adopted a location mandate in the context of calls to 988, we believe it would be premature to adopt a mandate here, and we seek comment on this view.

Does someone who sends a text message to 988 expect that their location will be transmitted to the Lifeline?. If consumers generally are aware that calls and texts to 911 include their location, would the same expectation apply to texts to 988?. Would including location information deter at-risk individuals from texting to 988?. We seek comment on any complications inherent in this plan and on ways for covered text providers to work with SAMHSA and the VA to limit misrouting of texts.

3. Implementation Timeframe for Text-to-988 28. Uniform Nationwide Deadline. We seek comment on an appropriate implementation timeframe for requiring covered text providers to support texting to 988 on a nationwide basis.

We preliminarily propose adopting a uniform nationwide deadline for implementation for all covered text providers and for all covered 988 text messages, as determined by the Bureau. In the 988 Report and Order, the Commission determined that the “rollout of 988 will be most effective if [it] set a single implementation deadline so that stakeholders can clearly and consistently communicate to the American public when 988 will be universally available.” We preliminarily believe that the same holds true here, and we seek comment on this view. Are there other benefits to a uniform nationwide implementation deadline?. What drawbacks, if any, exist?.

29. Although we propose adopting a uniform nationwide deadline, we seek comment on whether we should adopt any extensions or exemptions for certain classes of providers or categories of text messages. Should we adopt any extensions or exemptions for smaller, rural, or regional covered text providers?. If so, under what circumstances would such exemptions be appropriate?.

Are there unique technical considerations that necessitate different implementation timelines for certain covered text providers?. If so, what are they and why?. Are there any other considerations, such as any existing contractual obligations between our federal partners and other entities, that we should take into account in setting a deadline or deadlines?. 30.

Appropriate Deadline. We observe that CTIA and other commenters have previously argued that the Commission should not mandate text-to-988 before the Lifeline is capable of receiving and responding to texts, in part because the Lifeline's readiness to receive and respond to text messages is crucial to implementing text-to-988 successfully. We seek comment on this assertion. We also seek comment on CTIA's proposal to require covered text providers to “deliver text-to-988 to the Lifeline by July 16, 2022, or six months after the Lifeline demonstrates its readiness to accept text messages, whichever is later.” Is the Lifeline's pilot program sufficient to demonstrate that it is ready to accept text messages?.

If not, how should we determine that the Lifeline has demonstrated readiness to accept text messages, both from a technical and operational standpoint?. How should we take into account the capabilities of the Veterans Crisis Line in establishing a deadline?. Understanding that the Lifeline and Veterans Crisis Line successfully accepting and responding to text messages to 988 will require coordination between several stakeholders, we emphasize that the Commission will continue to coordinate closely with our federal partners, SAMHSA and the VA, in their efforts to enable crisis centers to respond to text messages to 988 and establish a reasonable implementation timeframe for text-to-988. We reiterate that the Commission does not wish to determine for SAMHSA how it allocates the Lifeline's resources, nor do we have the authority to require the Lifeline and its crisis centers to be capable of receiving and responding to text messages to 988.

31. We seek comment on whether the Commission should require all covered text providers to support text-to-988 by July 16, 2022, the same implementation deadline for telecommunications carriers, interconnected VoIP providers, and one-way VoIP providers to support voice calls to 988. Is this technically, economically and operationally feasible?. Are there benefits to requiring a uniform implementation timeline for all voice and text communications to 988?.

We observe that some covered text providers have already implemented voice calling to 988. For those providers, will requiring covered text providers to implement text-to-988 on the same timeline as voice calling to 988 create any efficiencies, such as reducing fixed costs?. Is there an expectation that once 988 is deployed nationwide for voice communications that texting to 988 will be similarly available?. Will a uniform implementation deadline discourage covered text providers from potentially supporting text to 988 before July 16, 2022?.

Are there other potential benefits or drawbacks to uniform implementation deadlines for providers supporting voice calling and texting to 988?. 32. Alternatively, we seek comment on whether we should separate the timeline for implementing text-to-988 from the implementation timeline for voice-to-988. Is a phased-in approach preferable?.

Would it be beneficial to consider balance of telecommunications activation needs and organizational response needs by SAMHSA and the VA?. Would it be less burdensome on providers working to implement 988 for voice calls in accordance with the 988 Report and Order?. Would a phased-in implementation timeline create consumer confusion regarding the availability of texting to 988?. If phased-in implementation deadlines would create consumer confusion, would requiring certain covered text providers to implement text-to-988 more quickly minimize consumer confusion?.

For example, if a covered text provider has already implemented voice calling to 988 and is advertising the availability of 988 to its customers, should the provider be required to implement text-to-988 before other covered text providers?. Are there other risks associated with a phased-in approach to an implementation timeline for voice and text communications to 988 as compared to uniform implementation timeline?. What, if any, phased-in deadlines should the Commission consider?. 33.

We also seek comment on whether we should we adopt the same timeline for all covered text providers, regardless of the text messaging technology they use. Are there other preparedness concerns that we should take into Start Printed Page 31410consideration when determining an implementation timeframe?. 4. Technical Considerations 34.

We seek comment on the specific technical considerations for covered text providers and equipment and software vendors—including those providers who are rural or small businesses—necessary to implement text-to-988. We propose to allow covered text providers to use any reliable method or methods (e.g., mobile-switched, IP-based) to support text routing and transmission to 988, similar to text-to-911 implementation. We seek comment on this proposal. 35.

Network Upgrades. We seek comment on possible upgrades covered text providers would have to make to their networks to support text-to-988 capability. Since we propose to allow covered text providers to use any reliable method or methods to support text routing and delivery to 988, are any necessary network hardware or software upgrades small in scope?. What specific components would require upgrading?.

Can the current solutions to enable text-to-911 capability be leveraged to support text-to-988, or are the implementation options for covered text providers to support text-to-988 significantly different?. CTIA notes “there are significant technical and policy differences between national 9-8-8 service that will be administered by the Lifeline and the local 9-1-1 services that are administered by thousands of PSAPs.” We seek comment on CTIA's view, especially with regard to any “significant” technical differences. Conversely, do commenters agree with Communications Equality Advocates that the costs to covered text providers for implementation of text-to-988 should be substantially lower than those associated with implementing text-to-911?. We seek further comment on the potential integration of text-to-988 solutions with existing systems, as well as other network considerations specific to covered text providers to support text-to-988.

36. We also seek comment on whether there are unique network considerations for different text messaging service technologies within the proposed outer bound scope of text-to-988 service that impact implementation. CTIA comments that its member companies are “optimistic about the technical feasibility of supporting text-to-988,” provided that implementation is consistent with existing capabilities of native SMS messaging. Do commenters agree?.

Are there fewer network upgrades necessary to support SMS-only texts to 988?. What specific network upgrades would be required should we obligate covered text providers to support other text messaging formats, such as MMS, RTT, or RCS?. Given that the Commission has recognized MMS as “an extension of the SMS protocol,” would support for MMS messaging be comparably feasible to support for SMS?. How does the evolution of texting services to new or future formats affect network upgrade options and implementation, and how should our rules account for such evolution?.

Would requiring support for certain text messaging formats be more feasible for covered text providers to implement than others?. 37. We specifically seek comment on the technical implementation capability and network upgrades necessary for interconnected text messaging service providers. Similar to the Commission's conclusion in the Text-to-911 proceeding, we anticipate that many interconnected text messaging service providers may choose to use a CMRS network-based solution to deliver texts to 988 and seek comment on this expectation.

Have there been developments in text-to-911 delivery by interconnected text messaging service providers that such providers can use in text-to-988 implementation?. In the text-to-911 context, the Commission's rules state. To the extent that CMRS providers offer Short Message Service (SMS), they shall allow access by any other covered text provider to the capabilities necessary for transmission of 911 text messages originating on such other covered text providers' application services. Covered text providers using the CMRS network to deliver 911 text messages must clearly inform consumers that, absent an SMS plan with the consumer's underlying CMRS provider, the covered text provider may be unable to deliver 911 text messages.

CMRS providers may migrate to other technologies and need not retain SMS networks solely for other covered text providers' 911 use, but must notify the affected covered text providers not less than 90 days before the migration is to occur. We seek comment on adopting this or a comparable requirement here. We recognize that text-to-911 network integration is necessary to facilitate a CMRS network-based solution, and we seek comment on whether the same integration is necessary for transmission of text-to-988 communications by other covered text providers using that solution. We seek comment on the relationship between CMRS providers and interconnected text messaging service providers to maintain support and capability for text-to-988 service based on the technical solutions available.

We emphasize that, as in the text-to-911 proceeding, even if we were to adopt a rule comparable to the text-to-911 rule above, we do not intend to establish an open-ended obligation for CMRS providers to maintain underlying SMS network support merely for the use of other providers. Further, similar to the Commission's position in the Text-to-911 Second Report and Order, if we adopt a rule comparable to the text-to-911 rule above, we propose concluding that it is the responsibility of the covered text provider using the CMRS-based solution to ensure that its text messaging service is technically compatible with the CMRS providers' SMS-based network and devices, and in conformance with any applicable technical standards. We seek comment on this proposal. Finally, as in the text-to-911 context, if we adopt a rule comparable to the text-to-911 rule above, we propose requiring CMRS providers to make any necessary specifications for accessing their SMS networks available to other covered text providers upon request, and to inform such covered text providers in advance of any changes to these specifications.

We seek comment on this proposal. 38. We also seek comment on specific technical considerations for covered text providers that are rural or regional providers, or small businesses. Are there unique impediments or challenges to implementation that these types of providers face that warrant further consideration?.

39. Equipment Upgrades. We seek comment on possible equipment or software upgrades required for covered text providers to implement text-to-988. What challenges will equipment (e.g., handsets, network infrastructure) and software vendors face with respect to the implementation and deployment of text-to-988?.

For example, are upgrades required for operating systems, firmware, or other software on mobile devices to support text-to-988 capability?. Are there upgrades necessary by vendors that are beyond the covered text providers' control that require additional coordination?. Will new standards need to be defined to ensure interoperability?. 40.

In the Text-to-911 proceeding, the Commission clarified that legacy devices that are incapable of sending texts via 3-digit codes are not subject to the text-to-911 requirements, provided the software for these devices cannot be upgraded over the air to allow text-to-911. If the device's text messaging software can be upgraded over the air to support a text to 911, however, then the Commission required the covered text provider to make the necessary software upgrade available. Should we include a Start Printed Page 31411similar exemption for legacy devices under any text-to-988 requirements we may adopt?. Have circumstances changed in the past seven years such that we should adopt a different approach here?.

5. Cost Recovery 41. Consistent with the Commission's decision in the 988 Report and Order, we propose to require that all covered text providers bear their own costs to implement text-to-988 capability to the Lifeline 10-digit number. As with call routing to 988, we do not anticipate any shared industry costs are necessary to implement text-to-988, in contrast to previous non-988 numbering proceedings where the Commission established a cost recovery mechanism.

As proposed, costs to support text-to-988 would be borne by each provider, specific to the solutions each has adopted to route texts to 988 ultimately to the Lifeline's current toll free access number, presently 1-800-273-8255 (TALK). We seek comment on this proposal. 42. We believe this approach promotes efficiency in implementation and avoids unnecessary administrative costs.

Section 251(e)(2) of the Act states that “[t]he cost of establishing telecommunications numbering administration arrangements and number portability shall be borne by all telecommunications carriers on a competitively neutral basis.” The Commission typically applies cost recovery mechanisms in situations involving some type of numbering administration arrangement, such as when the Commission hires a third party to develop a database for industry use, to ensure that the statutory cost neutrality requirements are met. Here, as with implementation of voice calls to 988, circumstances do not require establishment of a numbering administration arrangement as there will not be shared costs. Therefore, we believe the section 251(e)(2) requirements do not apply. Furthermore, even if section 251(e)(2) applies, we believe it is satisfied if we require each provider to bear its own costs because each provider's costs will be proportional to the size and quality of its network.

We seek comment on this analysis. 6. Bounce-Back Messages 43. We seek comment on whether and in what circumstances to require covered text providers to send automatic bounce-back messages where text-to-988 service is unavailable.

Throughout the ongoing roll-out of text-to-911 services across the U.S., the Commission has required covered text providers to send an automatic reply, or bounce-back, text message when a consumer attempts to send a text message to a PSAP by means of the 3-digit code “911” and the covered text provider cannot deliver the text because (1) the consumer is located in an area where text-to-911 is not available, or (2) the covered text provider either does not support text-to-911 generally or does not support it in the particular area at the time of the consumer's attempted text. Unlike in the text-to-911 context, where availability varies by geography and is based on whether the local PSAP can receive texts, our proposals herein would require covered text providers to support nationwide texting to the Lifeline via the 988 3-digit code on a uniform nationwide deadline. If we were to adopt our proposal, should we nonetheless require bounce-back messages?. If so, when and under what circumstances?.

Should we require covered text providers to make available bounce-back messages sooner than we require implementation of text-to-988?. Would requiring bounce-back messages be appropriate if we adopt a uniform nationwide deadline for text-to-988 capability later than July 16, 2022—the uniform nationwide deadline for covered providers to support calls to 988?. Would requiring bounce-back messages be appropriate if we adopt exemptions or extensions for some providers?. 44.

We seek comment on the potential benefits and costs of a bounce-back requirement. In the text-to-911 context, the Commission determined that “there is a clear benefit and present need for persons who attempt to send emergency text messages to know immediately if their text cannot be delivered to the proper authorities,” noting that feedback where text-to-911 is not available may be lifesaving by directing a person to seek out an alternative means of communicating with emergency services. Is that the case here as well?. Because some individuals with disabilities may rely exclusively on texting for communicating, are there unique benefits of a bounce-back requirement for these individuals?.

Since the Commission designated 988 as the 3-digit dialing code to access the Lifeline, efforts have been underway to educate the public about using this 3-digit code to reach help by telephone in times of mental health crisis, including its availability for routing voice calls to the Lifeline by July 16, 2022. In the absence of a bounce-back, might such advertising confuse the public about the availability of texting to 988?. Would an automated bounce-back help to prevent such confusion?. Are there other advantages to requiring covered text providers to send bounce-back messages for attempts to text 988 where service is unavailable?.

Are any providers included under the proposed “covered text providers” definition currently sending bounce-back messages to texts sent to 988?. 45. What are the costs of requiring a bounce-back message?. What work or upgrades would be necessary for text service providers to implement an automatic bounce-back reply?.

Given that covered text providers must provide a bounce-back in circumstances in which text-to-911 is unavailable, would adding a comparable bounce-back message for 988 be easier than if that existing infrastructure were not in place?. Would requiring text service providers to build bounce-back capabilities deter resources from more rapid deployment of text-to-988?. 46. We seek comment on how requiring bounce-back messages may impact the public's ability to seek help from the Lifeline in times of mental crisis.

What are the potential benefits to receiving an automatic bounce-back message when text-to-988 service is unavailable?. Are there any drawbacks to the public of requiring covered text providers to send bounce-back messages when text-to-988 is not available?. One commenter contends that if at-risk texters receive a bounce-back message regarding the unavailability of services, “the risks of disengagement and adverse outcomes increase.” Do commenters agree with the assessment that an automatic bounce-back message will negatively impact individuals seeking help during a crisis?. Would a bounce-back message have the effect of making the sender more discouraged, such that it that could increase, not decrease, the likelihood of suicide?.

Alternatively, if there is no automatic reply, and the sender is left wondering whether the Lifeline received the text message, would that uncertainty also increase sender's likelihood of suicide?. We seek comment on whether the benefits of receiving an automatic bounce-back message outweigh the potential risk of disengagement. 47. If we were to adopt a bounce-back requirement, we seek comment on the specific requirement we should adopt.

To align with the scope of the proposed outer bound text-to-988 capability requirements, we propose that if we were to adopt a bounce-back requirement, we would require all covered text providers to provide automatic bounce-back messages to text messages, as defined by our outer bound Start Printed Page 31412proposal herein, sent to 988 where text-to-988 service is unavailable. We seek comment on this approach. Are there unique considerations for different technologies within the outer bound scope of text message that we should consider under our bounce-back message proposal, including such impact on technical implementation or costs?. Should we consider requiring covered text providers to send automatic bounce-back messages in reply to messages outside the scope of the outer bound definition?.

Are there additional text or chat service providers that offer services beyond the proposed outer bound definition that we should include within the scope of our proposed bounce-back requirement?. Should we limit any bounce-back requirement to covered text providers, as proposed, or should the requirement sweep more broadly?. CTIA asserts that text-to-988 implementation should be consistent with existing SMS capabilities. Should any bounce-back requirement we may explore likewise remain consistent with SMS?.

Is sending a bounce-back message in response to texts to 988 feasible on legacy SMS systems?. We seek comment on the impact including other text or chat service providers, or other forms of messages, may have on the implementation costs, technical feasibility, and timeframe for our proposed bounce-back message requirements. 48. Should we adopt a bounce-back requirement, we seek comment on whether and how to expand on the circumstances in which a covered text provider must provide a bounce-back message due to unavailability of text-to-988.

In the text-to-911 context, when a customer is roaming away from his or her “home network” (i.e., the network of the customer's mobile carrier), the CMRS provider operating the customer's home network is nonetheless responsible for providing a bounce-back message when required. And the provider operating the network on which the customer is roaming must not impede the bounce-back response by the home network operator. We seek comment on adopting a similar requirement here. Additionally, we anticipate that there may be circumstances in which the Lifeline is unable to receive and respond to texts, including where demand may exceed its capacity to respond.

In instances amounting essentially to a “busy signal” for text delivery, are covered text providers capable of determining that the text cannot be delivered to 988?. Would covered text providers be able to determine if a text to 988 is undeliverable due to the Lifeline's inability, whether temporary or sustained, to receive and respond to the texts?. Or should we establish a mechanism whereby the Lifeline may inform providers of a temporary suspension of text-to-988 service, and should the bounce-back requirement apply until the suspension is lifted?. Lastly, we seek comment on considerations, either within the control of the covered text provider or the Lifeline's administrators, in which a message from an individual in crisis attempting to reach 988 may not be delivered, and therefore may benefit from receipt of a bounce-back message directing the individual to contact 988 by alternative means.

Are there additional circumstances where we should require covered text providers to send bounce-back messages in response to 988 texts?. 49. If we were to adopt a bounce-back requirement, we propose to adopt the same exceptions to our bounce-back notification requirement for text-to-988 as currently exist for the Commission's text-to-911 rules. If we adopt that same approach, a covered text provider would not be required to provide an automatic bounce-back message when.

(1) Transmission of the text message is not controlled by the provider. (2) a consumer is attempting to text 988, through a text messaging application that requires CMRS service, from a non-service initialized handset. (3) the text-to-988 message cannot be delivered due to a failure in the Lifeline's routing network that has not been reported to the provider. Or (4) a consumer is attempting to text 988 through a device that is incapable of sending texts via 3-digit codes, provided that the software for the device cannot be upgraded over the air to allow text-to-988.

We seek comment on this approach. Are there other situations where a covered text provider should not be required to send bounce-back messages to consumers attempting to text to 988?. Furthermore, we seek comment on the circumstances in which the provider of a pre-installed or downloaded interconnected text application would be considered to have “control” over the transmission of text messages for the purposes of any requirements we adopt. If a user or third party modifies or manipulates the application after it is installed or downloaded so that it no longer supports bounce-back messaging, should the application provider be presumed not to have control?.

50. If we adopt a bounce-back requirement, should we specify or provide guidance regarding the content of the bounce-back message, and if so, what should we specify or encourage?. Similar to automatic messages sent in response to undeliverable texts to 911, we propose that any bounce-back messages to consumers attempting to text 988 would not require all covered text providers to use identical wording for their automatic responses. Rather, if we were to adopt a bounce-back requirement, we propose that a covered text provider would be deemed to have met its obligation so long as the bounce-back message to 988 includes, at a minimum, two essential points of information.

(1) That text-to-988 is not available. And (2) identify other means to reach the Lifeline, such as by telephone. We seek comment on this approach and on alternatives. We seek comment on what role our federal partners and non-governmental mental health organizations could play in developing best practices regarding the content of messages.

7. Role of the Substance Abuse and Mental Health Services Administration and the Department of Veterans Affairs 51. Although the Commission has an important role to play in expanding access to crisis counseling through its implementation of 988, SAMHSA and the VA are ultimately responsible for ensuring the continued success of these lifesaving resources. As such, we propose to direct the Bureau to continue to coordinate the implementation of 988 with SAMHSA and the VA, including any issues pertaining to the delivery of text messages to 988.

52. We seek comment on this proposal. How we can best support the work of our federal partners in administering the Lifeline and Veterans Crisis Line?. We recognize that many commenters have stressed the importance of ensuring adequate funding and staffing for the Lifeline and the Veterans Crisis Line over the course of this proceeding.

Although these issues are beyond our jurisdiction, are there unique considerations pertaining to staffing, funding, or the availability of other resources at the Lifeline or Veterans Crisis Line that we should be aware of as we consider adopting rules to require the delivery of text messages to 988?. How should we account for the possibility that text-to-988 may be popular and increase demands on the Lifeline and Veterans Crisis Line?. What resources will be needed for the Lifeline and Veterans Crisis Line to ensure that text-to-988 is a success?. How should we account for our federal partners' budget cycles?.

We are cognizant of the potential burdens our proposals may impose upon our federal partners, Start Printed Page 31413including personnel, equipment, and resource allocation, and we seek comment on the impact the possible implementation solutions may have on SAMHSA and the VA when supporting text-to-988 service. To that end, we intend to coordinate with SAMHSA and the VA, and we encourage other industry stakeholders in the wireless and texting service industry to coordinate with these agencies as well. Assuming that our adoption of rules implementing text-to-988 capability will require expenditure of additional resources by SAMHSA and the VA, are there ways that we can structure our rules to minimize the burden on our federal partners?. Are there any steps we should take to deter misuse of text-to-988, so as to limit the unnecessary expenditure of resources by our federal partners?.

Are there any solutions that have been employed in other contexts, such as text-to-911, that we or others should adapt here to deter misuse of text-to-988?. 53. In addition, we encourage SAMHSA and the VA to coordinate with outside organizations that have expertise in providing crisis counseling via text message as they develop the infrastructure to receive and respond to text messages which may one day be delivered to the Lifeline and Veterans Crisis Line via 988. Many commenters in this proceeding have urged collaboration between private entities like the Trevor Project and federal agencies providing similar services.

We therefore seek comment on how to facilitate such coordination across federal agencies and the private sector, as we work towards our shared goal of ensuring that all Americans have ready access to mental health counseling and support services. C. Legal Authority 54. We propose concluding that we have the authority to adopt the rules proposed and for which we seek comment in this further notice of proposed rulemaking under Title III of the Act and the Twenty-First Century Communications and Video Accessibility Act (CVAA).

We seek comment on these and any other sources of authority available to us. In particular, we seek comment on whether, and if so, to what extent, our numbering authority under section 251(e) of the Act provides an additional source of authority for the rules proposed and for which we seek comment in this further notice of proposed rulemaking. Finally, we also seek comment on whether we should employ our ancillary authority. We note that, in our preliminary review, the National Suicide Hotline Designation Act of 2020 does not provide additional support for—nor does it hinder—the actions proposed in this further notice of proposed rulemaking.

We seek comment on these views. 55. The rules we propose and for which we seek comment in this further notice of proposed rulemaking are analogous to those the Commission has adopted to facilitate text-to-911 communications, which relied, in part, on the Commission's Title III authority over wireless carriers, including sections 301, 303, 307, 309, and 316. We propose concluding that, with respect to CMRS providers, Title III provides us with appropriate authority to require wireless carriers to support text-to-988 service and to require delivery of a bounce-back message to consumers in cases where delivery of a text to 988 cannot be completed.

As the Supreme Court has long recognized, Title III grants the Commission a “comprehensive mandate” regarding regulation of spectrum usage, and courts have routinely found that Title III provides the Commission with “broad authority to manage spectrum. . . In the public interest.” As we explain, we believe the rules we propose in this further notice of proposed rulemaking are likely to have significant public interest benefits.

And, the Commission has previously found that its Title III licensing authority supported adoption of a similar set of obligations in the text-to-911 context. Therefore, we believe that with respect to CMRS providers, Title III provides sufficient authority here. We note that, following the release of the Text-to-911 Order, the Commission released a Declaratory Ruling classifying SMS and MMS services as “information services” under the Act. However, as the Commission explicitly noted in the Declaratory Ruling, this determination “does not affect the general applicability of the spectrum allocation and licensing provisions of Title III and the Commission's rules” to SMS and MMS services, nor does it affect the specific application of sections 301, 303, 307, 309, and 316 to the Commission's text-to-911 rules.

We seek comment on this analysis. 56. With respect to interconnected text messaging service providers, we propose to find that the CVAA provides us with authority to adopt the proposals in this further notice of proposed rulemaking, as some commenters in this proceeding suggest. Congress enacted the CVAA to increase the accessibility of modern communications technologies to people with disabilities, including access related to emergency services, and the Commission relied, in part, on this authority when it adopted similar text-to-911 requirements.

The CVAA provides the Commission with authority to “achiev[e] equal access to emergency services by individuals with disabilities, as a part of the migration to a national internet protocol-enabled emergency network.” In particular, the CVAA granted the Commission the authority to adopt regulations to implement recommendations proposed by the Emergency Access Advisory Committee established by the CVAA, which concern access to 911 and NG911 services, and to adopt “other regulations” as are necessary to achieve reliable, interoperable communication that ensures access by persons with disabilities to an IP-enabled emergency services network. We tentatively conclude that the CVAA provides authority for our proposals because access to 988 is similar to 911 access for the purposes of our CVAA authority. We seek comment on this tentative conclusion. Do commenters agree that access to the Lifeline or Veterans Crisis Line through 988 constitute “access to emergency services” under the CVAA?.

Do commenters agree that text-to-988 is necessary to achieve reliable, interoperable communication that ensures access by persons with disabilities to an IP-enabled emergency services network?. More generally, does the CVAA provide us with authority to adopt the rules proposed in this further notice of proposed rulemaking?. 57. We seek comment on any other sources of authority available to the Commission to adopt the proposals detailed in this further notice of proposed rulemaking.

In particular, we seek comment on whether our section 251(e) authority over numbering provides authority to require support for text-to-988 service. Section 251(e)(1) of the Act grants us “exclusive jurisdiction over those portions of the North American Numbering Plan that pertain to the United States” and provides that numbers must be made “available on an equitable basis.” This provision gives the Commission “authority to set policy with respect to all facets of numbering administration in the United States.” The Commission found in the 988 Report and Order that section 251(e) provides us with the ability to regulate interconnected and one-way VoIP providers that make use of numbering resources when they connect with the PSTN. We seek comment on whether our numbering authority provides an additional, independent basis to adopt rules with respect to CMRS providers Start Printed Page 31414and interconnected text messaging services. 58.

We also seek comment on the Commission's authority to mandate location information with text-to-988 service. Section 222 of the Communications Act, as amended, provides strong legal protections for customer proprietary network information (CPNI), including geolocation information. Section 222(d) provides exceptions to allow CPNI and call location data to be shared for “emergency services.” We seek comment on whether this could encompass the transmission of geolocation information with 988 calls. Should we choose to require covered text providers to include location information with texts to 988, does section 222 authorize the disclosure of location information with texts to 988?.

Are there other privacy concerns that we should consider with regard to texts to 988?. 59. Finally, we seek comment on whether exercise of our ancillary authority would be necessary or appropriate to support any of our proposed rules. The Commission relied in part on ancillary authority to apply the bounce-back notification requirement to providers of interconnected text messaging services when it adopted text-to-911 requirements.

Would a similar finding be appropriate with respect to any aspect of our text-to-988 rules?. D. Benefits and Costs of Text-to-988 60. We expect to find that the benefits of requiring service providers to support text-to-988 service will exceed the costs of implementation.

We seek comment on this proposal, and any specific data regarding both the benefits of facilitating access to the Lifeline via texts to 988 and on the costs or burdens implementation of text-to-988 may impose upon covered text providers. 61. Suicide causes shock, anguish, grief, and guilt among victims' families and friends. Suicide attempts exact a similarly heavy toll on the community and the victim.

The long-lasting damage from mental distress and suicide can extend deep into communities. As outlined above, we preliminarily believe that enabling text-to-988 service will improve access to lifesaving resources for individuals contemplating suicide or experiencing mental health crises, especially for members of at-risk communities such as young people, LGBTQ, people of color, and individuals with disabilities, thereby saving lives. By expanding access to counseling, text-to-988 may help break the cycle of pain, suffering, and suicide. We seek comment generally on these and other important benefits that may follow from increased access to mental health resources via texting to 988.

62. We further seek comment on ways to quantify these benefits. Of course, the benefits to individuals who the Lifeline or Veterans Crisis Line places on a path to recovery, much less to their families and friends, cannot be reduced to dollars and cents. That being said, even if text-to-988 service could annually place just one-per-one-thousand suicide victims on a path to long-term recovery, the economic gain would be $19.2 million in any single year, for a present-value of $78.7 million over five years and $134.9 million over ten years.

In estimating benefits, we focus on teens and individuals with disabilities, as individuals in these groups are more likely to use a text-to-988 capability. Based on the most recent CDC data from 2015-2019, 11,283 youth (ages 15-19) and an estimated 13,101 individuals who are deaf, hard of hearing, deafblind or speech disabled committed suicide (using an estimated incidence among adults of 6%), or an average of more than 2,000 per year for each group. To calculate the estimated benefits for a single year, we multiply the annual average by 0.1% and the VSL (2,000 * 0.001 * $9.6 million = $19.2 million). We discount over five years and ten years at a 7% discount rate.

We seek comment on this analysis. 63. Our proposed analysis does not examine certain categories of benefits. For example, we have not estimated the cost savings from medical expenses and loss-of-work avoided through reduced suicides and suicide attempts.

We also have not estimated the cost savings of reduced burdens on PSAPs, police, ambulance, and fire and rescue services, which currently respond to some 911 texts that will be routed to the Lifeline, where they will be more effectively and efficiently de-escalated or otherwise resolved. Moreover, we have not examined the benefits of text-to-988 usage by every demographic group. For example, smartphone ownership and suicide are particularly common in younger age groups. According to the Common Sense Census.

Media Use by Tweens and Teens, 2019, 53% of children have their own smartphone by age 11, and 69% have one at age 12. Currently, our estimated benefits analysis looks at youth ages 15-19. To accurately estimate these benefits, we seek comment on how broadly we should define youth who may text to 988. Relatedly, there is the possibility that adults without hearing or speech disabilities may rely exclusively on text-to-988 for added privacy or convenience, meriting inclusion in our benefit estimates.

We also seek comment on ways to better assess the long-term impact of text-to-988 service. Without longitudinal studies evaluating the long-term effectiveness of suicide call centers, we cannot pinpoint how many suicides text-to-988 will prevent in the long run. Available survey-based studies, however, reveal call centers can substantially reduce suicides during the initial call and follow-up periods. We seek comment on the types and magnitudes of these and other benefits not covered in this further notice of proposed rulemaking, as well as any overlooked categories of costs.

64. In the Text-to-911 proceeding, the Commission estimated that the total cost for covered providers to implement text-to-911 service amounted to less than $21 million. The costs of nationwide deployment of text-to-911 fell into three categories. CMRS and PSAP system cost components.

Interconnected text providers' software upgrades. And bounce-back messaging application alterations and server platform modifications. Assuming that all or most of the software and equipment necessary to receive and transmit 911 texts will again be needed to deploy text-to-988, we expect that the implementation costs for text-to-988 service will be comparable to the costs for text-to-911 service. Using cost estimates from the Text-to-911 proceeding as a model, we estimate it will cost $19,024,916 for CMRS providers to implement text-to-988, $613,275 for interconnected text messaging service providers to implement text-to-988, and $7,310,340 for Lifeline to route texts to local crisis centers.

We convert the estimate for CMRS providers to implement text-to-911 service to 2021 dollars by multiplying by a Consumer Price Index (CPI) factor of 1.16, then discounting over five years at a 7% discount rate. Similarly, we convert the estimate for interconnected text messaging providers to implement text-to-911 service into 2021 dollars by using a CPI factor of 1.105. To soberly assess Lifeline capability, we assume that 100% of Lifeline call centers may require SMS upgrades and thus multiply PSAP software estimates by 2.22. To estimate the costs to equip the more than 180 Lifeline crisis centers, we calculate an average cost based on an estimated per PSAP cost of $40,613 (=($263,277,595 + $12,891,283)/6,800), for a total of $7,310,340 (=180 * $40,613).

Therefore, we preliminarily estimate that total costs for implementing text-to-988 will be approximately $27 million. We seek Start Printed Page 31415comment on this analysis, including our preliminary assumption that text-to-911 software and equipment can be leveraged for texting to 988. Do commenters agree with CTIA that there are “significant technical and policy differences” between 988 and 911 service, and if so, how might those differences impact our evaluation?. Furthermore, we seek comment on whether cost estimates for PSAPs from the Text-to-911 proceeding reflect an appropriate estimate for costs to the Lifeline or Veterans Crisis Line.

Are there other costs borne by the Lifeline or Veterans Crisis Line needed to implement text-to-988 service?. 65. We preliminarily assume that some costs may be streamlined or reduced due to the previous implementation of text-to-911, which may be leveraged to facilitate text-to-988 capability and seek comment on this assumption. As a result, we anticipate that costs for covered text providers to implement text-to-988 may be less than what we estimate above and seek comment on this finding.

We further seek comment on what extent covered text providers may rely upon existing text-to-911 services and how to quantify the costs needed to upgrade such systems to support text-to-988. 66. Deterring suicide has benefits that simply cannot be reduced to numbers—saving lives has value beyond measure. While recognizing this fact, to illustrate how the benefits of our proposal relate to the more aptly quantified costs, we attempt to estimate the quantifiable value of suicide prevention using a measure of collective willingness to pay.

We propose calculating that the level of suicide prevention needed to generate benefits exceeding our preliminary estimate of $27 million in text-to-988 costs is a total of four suicides avoided over five years. Specifically, the level of teen suicide prevention needed to generate benefits exceeding $27 million is one per 2,821, and the level of suicide prevention among individuals with disabilities to generate benefits exceeding $27 million is one per 3,275. Even assuming that text-to-988 prevented no suicides in its inaugural year as the service rolled out but prevented one suicide in each of the ensuing four years, measured in terms of the public's willingness to pay for that mortality reduction, the present value of the benefit would be $30.39 million, more than three million dollars greater than the total cost. The present value would be an uneven stream of payments of $9.6 million ($0 in Year 1 + $9.6 million per year in Year 2 through Year 5) at a 7% discount rate.

We seek comment on our analysis. 67. Using break-even points and highly attainable suicide reductions that are well below those suggested by survey studies, we estimate that the benefits of text-to-988 will far exceed the costs. Pooling teenagers and individuals with disabilities, we estimate that text-to-988 would need to prevent one suicide out of every six thousand in order to break-even in the first five years of deployment.

Slightly raising the bar to preventing one suicide per one thousand, we further estimate that the more than $157.5 million estimated benefit from modestly reducing suicides in two vulnerable populations far exceeds the text-to-988 deployment costs of $19.6 million incurred by CMRS and interconnected text providers. Even if sizable Lifeline deployment costs are added, increasing estimated total cost to nearly $27 million, the estimated benefits of text-to-988 remain greater by a multiple of nearly six. Over ten years, the benefits rise to $269.8 million, exceeding costs by a multiple of nearly ten. We seek comment on these estimates.

We also seek comment on the methods and underlying benefits and costs estimates, including those submitted by third parties, used to arrive at our overall proposed conclusion. II. Initial Regulatory Flexibility Analysis 1. As required by the Regulatory Flexibility Act of 1980, as amended (RFA), the Commission has prepared this Initial Regulatory Flexibility Analysis (IRFA) of the possible significant economic impact on small entities by the policies and rules proposed in this Implementation of the National Suicide Hotline Improvement Act of 2018 further notice of proposed rulemaking (FNPRM).

The Commission requests written public comments on this IRFA. Comments must be identified as responses to the IRFA and must be filed by the deadlines for comments provided on the first page of the further notice of proposed rulemaking. The Commission will send a copy of the further notice of proposed rulemaking, including this IRFA, to the Chief Counsel for Advocacy of the Small Business Administration (SBA). In addition, the further notice of proposed rulemaking and IRFA (or summaries thereof) will be published in the Federal Register.

A. Need for, and Objectives of, the Proposed Rules 2. In this FNPRM, the Commission proposes and seeks comment on requiring CMRS providers and providers of interconnected text messaging services that enable consumers to send text messages to, and receive text messages from, the PSTN (covered text providers) to enable delivery of text messages to 988. The Commission proposes to require that covered text providers route 988 text messages to the National Suicide Prevention Lifeline's (Lifeline) 10-digit number, currently 1-800-273-8255 (TALK).

The Commission believes these proposed rules will expand the availability of mental health and crisis counseling resources to Americans who suffer from depressive or suicidal thoughts, by allowing individuals in crisis to reach the Lifeline by texting 988. B. Legal Basis 3. The legal basis for any action that may be taken pursuant to this FNPRM is contained in sections 201, 251, 301, 303, 307, 309, and 316 of the Communications Act of 1934, as amended, 47 U.S.C.

201, 251, 301, 303, 307, 309, 316. C. Description and Estimate of the Number of Small Entities to Which the Proposed Rules Will Apply 4. The RFA directs agencies to provide a description of, and where feasible, an estimate of the number of small entities that may be affected by the proposed rules and by the rule revisions on which the Notice seeks comment, if adopted.

The RFA generally defines the term “small entity” as having the same meaning as the terms “small business,” “small organization,” and “small governmental jurisdiction.” In addition, the term “small business” has the same meaning as the term “small-business concern” under the Small Business Act. A “small-business concern” is one which. (1) Is independently owned and operated. (2) is not dominant in its field of operation.

And (3) satisfies any additional criteria established by the SBA. 5. Small Businesses, Small Organizations, Small Governmental Jurisdictions. Our actions, over time, may affect small entities that are not easily categorized at present.

We therefore describe here, at the outset, three broad groups of small entities that could be directly affected herein. First, while there are industry specific size standards for small businesses that are used in the regulatory flexibility analysis, according to data from the Small Business Administration's (SBA) Office of Advocacy, in general a small business is an independent business having fewer than 500 employees. These types of small businesses represent 99.9% of all businesses in the United Start Printed Page 31416States, which translates to 30.7 million businesses. 6.

Next, the type of small entity described as a “small organization” is generally “any not-for-profit enterprise which is independently owned and operated and is not dominant in its field.” The Internal Revenue Service (IRS) uses a revenue benchmark of $50,000 or less to delineate its annual electronic filing requirements for small exempt organizations. Nationwide, for tax year 2018, there were approximately 571,709 small exempt organizations in the U.S. Reporting revenues of $50,000 or less according to the registration and tax data for exempt organizations available from the IRS. 7.

Finally, the small entity described as a “small governmental jurisdiction” is defined generally as “governments of cities, counties, towns, townships, villages, school districts, or special districts, with a population of less than fifty thousand.” U.S. Census Bureau data from the 2017 Census of Governments indicate that there were 90,075 local governmental jurisdictions consisting of general purpose governments and special purpose governments in the United States. Of this number there were 36,931 general purpose governments (county, municipal and town or township) with populations of less than 50,000 and 12,040 special purpose governments—independent school districts with enrollment populations of less than 50,000. Accordingly, based on the 2017 U.S.

Census of Governments data, we estimate that at least 48,971 entities fall into the category of “small governmental jurisdictions.” 8. Wired Telecommunications Carriers. The U.S. Census Bureau defines this industry as “establishments primarily engaged in operating and/or providing access to transmission facilities and infrastructure that they own and/or lease for the transmission of voice, data, text, sound, and video using wired communications networks.

Transmission facilities may be based on a single technology or a combination of technologies. Establishments in this industry use the wired telecommunications network facilities that they operate to provide a variety of services, such as wired telephony services, including VoIP services, wired (cable) audio and video programming distribution, and wired broadband internet services. By exception, establishments providing satellite television distribution services using facilities and infrastructure that they operate are included in this industry.” The SBA has developed a small business size standard for Wired Telecommunications Carriers, which consists of all such companies having 1,500 or fewer employees. U.S.

Census Bureau data for 2012 show that there were 3,117 firms that operated that year. Of this total, 3,083 operated with fewer than 1,000 employees. Thus, under this size standard, the majority of firms in this industry can be considered small. 9.

Local Exchange Carriers (LECs). Neither the Commission nor the SBA has developed a size standard for small businesses specifically applicable to local exchange services. The closest applicable NAICS Code category is Wired Telecommunications Carriers. Under the applicable SBA size standard, such a business is small if it has 1,500 or fewer employees.

U.S. Census Bureau data for 2012 show that there were 3,117 firms that operated for the entire year. Of that total, 3,083 operated with fewer than 1,000 employees. Thus under this category and the associated size standard, the Commission estimates that the majority of local exchange carriers are small entities.

10. Incumbent LECs. Neither the Commission nor the SBA has developed a small business size standard specifically for incumbent local exchange services. The closest applicable NAICS Code category is Wired Telecommunications Carriers.

Under the applicable SBA size standard, such a business is small if it has 1,500 or fewer employees. U.S. Census Bureau data for 2012 indicate that 3,117 firms operated the entire year. Of this total, 3,083 operated with fewer than 1,000 employees.

Consequently, the Commission estimates that most providers of incumbent local exchange service are small businesses that may be affected by our actions. According to Commission data, one thousand three hundred and seven (1,307) Incumbent Local Exchange Carriers reported that they were incumbent local exchange service providers. Of this total, an estimated 1,006 have 1,500 or fewer employees. Thus, using the SBA's size standard the majority of incumbent LECs can be considered small entities.

11. Competitive Local Exchange Carriers (Competitive LECs). Competitive Access Providers (CAPs), Shared-Tenant Service Providers, and Other Local Service Providers. Neither the Commission nor the SBA has developed a small business size standard specifically for these service providers.

The appropriate NAICS Code category is Wired Telecommunications Carriers and under that size standard, such a business is small if it has 1,500 or fewer employees. U.S. Census Bureau data for 2012 indicate that 3,117 firms operated during that year. Of that number, 3,083 operated with fewer than 1,000 employees.

Based on these data, the Commission concludes that the majority of Competitive LECS, CAPs, Shared-Tenant Service Providers, and Other Local Service Providers, are small entities. According to Commission data, 1,442 carriers reported that they were engaged in the provision of either competitive local exchange services or competitive access provider services. Of these 1,442 carriers, an estimated 1,256 have 1,500 or fewer employees. In addition, 17 carriers have reported that they are Shared-Tenant Service Providers, and all 17 are estimated to have 1,500 or fewer employees.

Also, 72 carriers have reported that they are Other Local Service Providers. Of this total, 70 have 1,500 or fewer employees. Consequently, based on internally researched FCC data, the Commission estimates that most providers of competitive local exchange service, competitive access providers, Shared-Tenant Service Providers, and Other Local Service Providers are small entities. 12.

We have included small incumbent LECs in this present RFA analysis. As noted above, a “small business” under the RFA is one that, inter alia, meets the pertinent small business size standard (e.g., a telephone communications business having 1,500 or fewer employees), and “is not dominant in its field of operation.” The SBA's Office of Advocacy contends that, for RFA purposes, small incumbent LECs are not dominant in their field of operation because any such dominance is not “national” in scope. We have therefore included small incumbent LECs in this RFA analysis, although we emphasize that this RFA action has no effect on Commission analyses and determinations in other, non-RFA contexts. 13.

Interexchange Carriers (IXCs). Neither the Commission nor the SBA has developed a small business size standard specifically for Interexchange Carriers. The closest applicable NAICS Code category is Wired Telecommunications Carriers. The applicable size standard under SBA rules is that such a business is small if it has 1,500 or fewer employees.

U.S. Census Bureau data for 2012 indicate that 3,117 firms operated for the entire year. Of that number, 3,083 operated with fewer than 1,000 employees. According to internally developed Commission data, 359 companies reported that their primary telecommunications service activity was the provision of interexchange services.

Of this total, an estimated 317 have 1,500 or fewer employees. Start Printed Page 31417Consequently, the Commission estimates that the majority of interexchange service providers are small entities. 14. Local Resellers.

The SBA has not developed a small business size standard specifically for Local Resellers. The SBA category of Telecommunications Resellers is the closest NAICs code category for local resellers. The Telecommunications Resellers industry comprises establishments engaged in purchasing access and network capacity from owners and operators of telecommunications networks and reselling wired and wireless telecommunications services (except satellite) to businesses and households. Establishments in this industry resell telecommunications.

They do not operate transmission facilities and infrastructure. Mobile virtual network operators (MVNOs) are included in this industry. Under the SBA's size standard, such a business is small if it has 1,500 or fewer employees. U.S.

Census Bureau data from 2012 show that 1,341 firms provided resale services during that year. Of that number, all operated with fewer than 1,000 employees. Thus, under this category and the associated small business size standard, the majority of these resellers can be considered small entities. According to Commission data, 213 carriers have reported that they are engaged in the provision of local resale services.

Of these, an estimated 211 have 1,500 or fewer employees and two have more than 1,500 employees. Consequently, the Commission estimates that the majority of local resellers are small entities. 15. Toll Resellers.

The Commission has not developed a definition for Toll Resellers. The closest NAICS Code Category is Telecommunications Resellers. The Telecommunications Resellers industry comprises establishments engaged in purchasing access and network capacity from owners and operators of telecommunications networks and reselling wired and wireless telecommunications services (except satellite) to businesses and households. Establishments in this industry resell telecommunications.

They do not operate transmission facilities and infrastructure. MVNOs are included in this industry. The SBA has developed a small business size standard for the category of Telecommunications Resellers. Under that size standard, such a business is small if it has 1,500 or fewer employees.

2012 U.S. Census Bureau data show that 1,341 firms provided resale services during that year. Of that number, 1,341 operated with fewer than 1,000 employees. Thus, under this category and the associated small business size standard, the majority of these resellers can be considered small entities.

According to Commission data, 881 carriers have reported that they are engaged in the provision of toll resale services. Of this total, an estimated 857 have 1,500 or fewer employees. Consequently, the Commission estimates that the majority of toll resellers are small entities. 16.

Other Toll Carriers. Neither the Commission nor the SBA has developed a definition for small businesses specifically applicable to Other Toll Carriers. This category includes toll carriers that do not fall within the categories of interexchange carriers, operator service providers, prepaid calling card providers, satellite service carriers, or toll resellers. The closest applicable size standard under SBA rules is for Wired Telecommunications Carriers.

The applicable SBA size standard consists of all such companies having 1,500 or fewer employees. U.S. Census Bureau data for 2012 indicates that 3,117 firms operated during that year. Of that number, 3,083 operated with fewer than 1,000 employees.

Thus, under this category and the associated small business size standard, the majority of Other Toll Carriers can be considered small. According to internally developed Commission data, 284 companies reported that their primary telecommunications service activity was the provision of other toll carriage. Of these, an estimated 279 have 1,500 or fewer employees. Consequently, the Commission estimates that most Other Toll Carriers are small entities.

17. Prepaid Calling Card Providers. Neither the Commission nor the SBA has developed a small business definition specifically for prepaid calling card providers. The most appropriate NAICS code-based category for defining prepaid calling card providers is Telecommunications Resellers.

This industry comprises establishments engaged in purchasing access and network capacity from owners and operators of telecommunications networks and reselling wired and wireless telecommunications services (except satellite) to businesses and households. Establishments in this industry resell telecommunications. They do not operate transmission facilities and infrastructure. Mobile virtual networks operators (MVNOs) are included in this industry.

Under the applicable SBA size standard, such a business is small if it has 1,500 or fewer employees. U.S. Census Bureau data for 2012 show that 1,341 firms provided resale services during that year. Of that number, 1,341 operated with fewer than 1,000 employees.

Thus, under this category and the associated small business size standard, the majority of these prepaid calling card providers can be considered small entities. According to the Commission's Form 499 Filer Database, 86 active companies reported that they were engaged in the provision of prepaid calling cards. The Commission does not have data regarding how many of these companies have 1,500 or fewer employees, however, the Commission estimates that the majority of the 86 active prepaid calling card providers that may be affected by these rules are likely small entities. 18.

Wireless Telecommunications Carriers (except Satellite). Neither the SBA nor the Commission has developed a size standard specifically applicable to Wireless Carriers and Service Providers. The closest applicable is Wireless Telecommunications Carriers (except Satellite), which the SBA small business size standard is such a business is small if it 1,500 persons or less. For this industry, U.S.

Census Bureau data for 2012 show that there were 967 firms that operated for the entire year. Of this total, 955 firms had employment of 999 or fewer employees and 12 had employment of 1000 employees or more. Thus under this category and the associated size standard, the Commission estimates that the majority of Wireless Carriers and Service Providers are small entities. 19.

According to internally developed Commission data for all classes of Wireless Service Providers, there are 970 carriers that reported they were engaged in the provision of wireless services. Of this total, an estimated 815 have 1,500 or fewer employees, and 155 have more than 1,500 employees. Thus, using available data, we estimate that the majority of Wireless Carriers and Service Providers can be considered small. 20.

Cable and Other Subscription Programming. The U.S. Census Bureau defines this industry as establishments primarily engaged in operating studios and facilities for the broadcasting of programs on a subscription or fee basis. The broadcast programming is typically narrowcast in nature (e.g., limited format, such as news, sports, education, or youth-oriented).

These establishments produce programming in their own facilities or acquire programming from external sources. The programming material is usually delivered to a third party, such as cable systems or direct-to-home satellite Start Printed Page 31418systems, for transmission to viewers.” The SBA size standard for this industry establishes as small any company in this category with annual receipts less than $41.5 million. Based on U.S. Census Bureau data for 2012, 367 firms operated for the entire year.

Of that number, 319 firms operated with annual receipts of less than $25 million a year and 48 firms operated with annual receipts of $25 million or more. Based on this data, the Commission estimates that a majority of firms in this industry are small. 21. Cable Companies and Systems (Rate Regulation).

The Commission has also developed its own small business size standards, for the purpose of cable rate regulation. Under the Commission's rules, a “small cable company” is one serving 400,000 or fewer subscribers nationwide. Industry data indicate that there are 4,600 active cable systems in the United States. Of this total, all but five cable operators nationwide are small under the 400,000-subscriber size standard.

In addition, under the Commission's rate regulation rules, a “small system” is a cable system serving 15,000 or fewer subscribers. Commission records show 4,600 cable systems nationwide. Of this total, 3,900 cable systems have fewer than 15,000 subscribers, and 700 systems have 15,000 or more subscribers, based on the same records. Thus, under this standard as well, we estimate that most cable systems are small entities.

22. Cable System Operators (Telecom Act Standard). The Communications Act of 1934, as amended, also contains a size standard for small cable system operators, which is “a cable operator that, directly or through an affiliate, serves in the aggregate fewer than one percent of all subscribers in the United States and is not affiliated with any entity or entities whose gross annual revenues in the aggregate exceed $250,000,000.” As of 2019, there were approximately 48,646,056 basic cable video subscribers in the United States. Accordingly, an operator serving fewer than 486,460 subscribers shall be deemed a small operator if its annual revenues, when combined with the total annual revenues of all its affiliates, do not exceed $250 million in the aggregate.

Based on available data, we find that all but five cable operators are small entities under this size standard. We note that the Commission neither requests nor collects information on whether cable system operators are affiliated with entities whose gross annual revenues exceed $250 million. Therefore, we are unable at this time to estimate with greater precision the number of cable system operators that would qualify as small cable operators under the definition in the Communications Act. 23.

All Other Telecommunications. The “All Other Telecommunications” category is comprised of establishments primarily engaged in providing specialized telecommunications services, such as satellite tracking, communications telemetry, and radar station operation. This industry also includes establishments primarily engaged in providing satellite terminal stations and associated facilities connected with one or more terrestrial systems and capable of transmitting telecommunications to, and receiving telecommunications from, satellite systems. Establishments providing internet services or voice over internet protocol (VoIP) services via client-supplied telecommunications connections are also included in this industry.

The SBA has developed a small business size standard for “All Other Telecommunications”, which consists of all such firms with annual receipts of $35 million or less. For this category, U.S. Census Bureau data for 2012 show that there were 1,442 firms that operated for the entire year. Of those firms, a total of 1,400 had annual receipts less than $25 million and 15 firms had annual receipts of $25 million to $49,999,999.

Thus, the Commission estimates that the majority of “All Other Telecommunications” firms potentially affected by our action can be considered small. 24. Radio and Television Broadcasting and Wireless Communications Equipment Manufacturing. This industry comprises establishments primarily engaged in manufacturing radio and television broadcast and wireless communications equipment.

Examples of products made by these establishments are. Transmitting and receiving antennas, cable television equipment, GPS equipment, pagers, cellular phones, mobile communications equipment, and radio and television studio and broadcasting equipment. The SBA has established a small business size standard for this industry of 1,250 or fewer employees. U.S.

Census Bureau data for 2012 show that 841 establishments operated in this industry in that year. Of that number, 828 establishments operated with fewer than 1,000 employees, 7 establishments operated with between 1,000 and 2,499 employees and 6 establishments operated with 2,500 or more employees. Based on this data, we conclude that a majority of manufacturers in this industry are small. 25.

Semiconductor and Related Device Manufacturing. This industry comprises establishments primarily engaged in manufacturing semiconductors and related solid state devices. Examples of products made by these establishments are integrated circuits, memory chips, microprocessors, diodes, transistors, solar cells and other optoelectronic devices. The SBA has developed a small business size standard for Semiconductor and Related Device Manufacturing, which consists of all such companies having 1,250 or fewer employees.

U.S. Census Bureau data for 2012 show that there were 862 establishments that operated that year. Of this total, 843 operated with fewer than 1,000 employees. Thus, under this size standard, the majority of firms in this industry can be considered small.

26. Software Publishers. This industry comprises establishments primarily engaged in computer software publishing or publishing and reproduction. Establishments in this industry carry out operations necessary for producing and distributing computer software, such as designing, providing documentation, assisting in installation, and providing support services to software purchasers.

These establishments may design, develop, and publish, or publish only. The SBA has established a size standard for this industry of annual receipts of $41.5 million or less per year. U.S. Census data for 2012 indicates that 5,079 firms operated for the entire year.

Of that number 4,691 firms had annual receipts of less than $25 million and 166 firms had annual receipts of $25,000,000 to $49,999,999. Based on this data, we conclude that a majority of firms in this industry are small. 27. Internet Service Providers (Broadband).

Broadband internet service providers include wired (e.g., cable, DSL) and VoIP service providers using their own operated wired telecommunications infrastructure fall in the category of Wired Telecommunication Carriers. Wired Telecommunications Carriers are comprised of establishments primarily engaged in operating and/or providing access to transmission facilities and infrastructure that they own and/or lease for the transmission of voice, data, text, sound, and video using wired telecommunications networks. Transmission facilities may be based on a single technology or a combination of technologies. The SBA size standard for this category classifies a business as small if it has 1,500 or fewer employees.

U.S. Census Bureau data for 2012 show that there were 3,117 firms that operated Start Printed Page 31419that year. Of this total, 3,083 operated with fewer than 1,000 employees. Consequently, under this size standard the majority of firms in this industry can be considered small.

28. Internet Service Providers (Non-Broadband). Internet access service providers such as Dial-up internet service providers, VoIP service providers using client-supplied telecommunications connections and internet service providers using client-supplied telecommunications connections (e.g., dial-up ISPs) fall in the category of All Other Telecommunications. The SBA has developed a small business size standard for All Other Telecommunications which consists of all such firms with gross annual receipts of $35 million or less.

For this category, U.S. Census Bureau data for 2012 show that there were 1,442 firms that operated for the entire year. Of these firms, a total of 1,400 had gross annual receipts of less than $25 million. Consequently, under this size standard a majority of firms in this industry can be considered small.

29. All Other Information Services. The U.S. Census Bureau has determined that this category “comprises establishments primarily engaged in providing other information services (except news syndicates, libraries, archives, internet publishing and broadcasting, and Web search portals).” The SBA has developed a small business size standard for this category, which consists of all such firms with annual receipts of $30 million or less.

U.S. Census Bureau data for 2012 show that there were 512 firms that operated for the entire year. Of those firms, a total of 498 had annual receipts less than $25 million and 7 firms had annual receipts of $25 million to $49, 999,999. Consequently, we estimate that the majority of these firms are small entities that may be affected by our action.

D. Description of Projected Reporting, Recordkeeping, and Other Compliance Requirements for Small Entities 30. The FNPRM proposes and seeks comment on rules to require covered text providers to support text messaging to 988. It tentatively concludes that text-to-988 functionality will greatly improve consumer access to the Lifeline, particularly for at-risk populations, and thereby save lives.

The proposed rules would require CMRS providers and interconnected text messaging service providers to route texts sent to 988 to the 10-digit Lifeline number, presently 1-800-273-8255 (TALK). The FNPRM proposes (1) establishing a definition that sets the outer bound of text messages sent to 988 that covered text providers may be required to support. And (2) directing the Wireline Competition Bureau (Bureau) to identify text formats within the scope of that definition that the Lifeline can receive and thus covered text providers must support by routing to the 10-digit Lifeline number. The FNPRM seeks comment on this proposal.

The Commission preliminarily believes that applying the same rules equally to all entities in this context is necessary to alleviate potential consumer confusion from adopting different rules for different covered text providers. The Commission proposes that the costs and/or administrative burdens associated with the rules will not unduly burden small entities. E. Steps Taken To Minimize the Significant Economic Impact on Small Entities, and Significant Alternatives Considered 31.

The RFA requires an agency to describe any significant alternatives that it has considered in reaching its proposed approach, which may include the following four alternatives (among others). (1) The establishment of differing compliance or reporting requirements or timetables that take into account the resources available to small entities. (2) the clarification, consolidation, or simplification of compliance and reporting requirements under the rules for such small entities. (3) the use of performance rather than design standards.

And (4) an exemption from coverage of the rule, or any part thereof, for such small entities. 32. In the FNPRM, the Commission seeks comment from all entities, including small entities, regarding the impact of these proposed rules on small entities. The Commission seeks comment on the impact, cost or otherwise, that requiring text messaging to 988 capability will impose on regional and rural carriers and small businesses.

The Commission also seeks comment on whether to adopt any exemptions for small businesses and if so, under what circumstances. The Commission asks and will consider alternatives to the proposals and on alternative ways of implementing the proposals. F. Federal Rules That May Duplicate, Overlap, or Conflict With the Proposed Rules 33.

None. III. Procedural Matters 34. Ex Parte Rules.

This proceeding shall be treated as a “permit-but-disclose” proceeding in accordance with the Commission's ex parte rules. Persons making ex parte presentations must file a copy of any written presentation or a memorandum summarizing any oral presentation within two business days after the presentation (unless a different deadline applicable to the Sunshine period applies). Persons making oral ex parte presentations are reminded that memoranda summarizing the presentation must (1) list all persons attending or otherwise participating in the meeting at which the ex parte presentation was made, and (2) summarize all data presented and arguments made during the presentation. If the presentation consisted in whole or in part of the presentation of data or arguments already reflected in the presenter's written comments, memoranda or other filings in the proceeding, the presenter may provide citations to such data or arguments in his or her prior comments, memoranda, or other filings (specifying the relevant page and/or paragraph numbers where such data or arguments can be found) in lieu of summarizing them in the memorandum.

Documents shown or given to Commission staff during ex parte meetings are deemed to be written ex parte presentations and must be filed consistent with Rule 1.1206(b). In proceedings governed by Rule 1.49(f) or for which the Commission has made available a method of electronic filing, written ex parte presentations and memoranda summarizing oral ex parte presentations, and all attachments thereto, must be filed through the electronic comment filing system available for that proceeding, and must be filed in their native format (e.g., .doc, .xml, .ppt, searchable .pdf). Participants in this proceeding should familiarize themselves with the Commission's ex parte rules. 35.

Initial Regulatory Flexibility Analysis. Pursuant to the Regulatory Flexibility Act (RFA), the Commission has prepared an Initial Regulatory Flexibility Analysis (IRFA) of the possible significant economic impact on small entities of the policies and actions considered in this FNPRM. Written public comments are requested on this IRFA. Comments must be identified as responses to the IRFA and must be filed by the deadlines for comments on the FNPRM.

The Commission's Consumer and Governmental Affairs Bureau, Reference Information Center, will send a copy of the FNPRM, including the IRFA, to the Chief Counsel for Advocacy of the Small Business Administration.Start Printed Page 31420 36. Comment Filing Procedures. Pursuant to §§ 1.415 and 1.419 of the Commission's rules, 47 CFR 1.415, 1.419, interested parties may file comments and reply comments on or before the dates indicated on the first page of this document. Comments may be filed using the Commission's Electronic Comment Filing System (ECFS).

See Electronic Filing of Documents in Rulemaking Proceedings, 63 FR 24121 (1998). Electronic Filers. Comments may be filed electronically using the internet by accessing ECFS. Https://www.fcc.gov/​ecfs/​.

Paper Filers. Parties who choose to file by paper must file an original and one copy of each filing. Filings can be sent by commercial overnight courier, or by first-class or overnight U.S. Postal Service mail.

All filings must be addressed to the Commission's Secretary, Office of the Secretary, Federal Communications Commission. Commercial overnight mail (other than U.S. Postal Service Express Mail and Priority Mail) must be sent to 9050 Junction Drive, Annapolis Junction, MD 20701. U.S.

Postal Service first-class, Express, and Priority mail must be addressed to 45 L Street NE, Washington, DC 20554. Effective March 19, 2020, and until further notice, the Commission no longer accepts any hand or messenger delivered filings. This is a temporary measure taken to help protect the health and safety of individuals, and to mitigate the transmission of alcoholism treatment. See FCC Announces Closure of FCC Headquarters Open Window and Change in Hand-Delivery Policy, Public Notice, 35 FCC Rcd 2788 (OS 2020), https://www.fcc.gov/​document/​fcc-closes-headquarters-open-window-and-changes-hand-delivery-policy.

37. People with Disabilities. To request materials in accessible formats for people with disabilities (braille, large print, electronic files, audio format), send an email to fcc504@fcc.gov or call the Consumer &. Governmental Affairs Bureau at (202) 418-0530 (voice).

38. Paperwork Reduction Act of 1995 Analysis. This document may contain proposed new or modified information collection requirements. The Commission, as part of its continuing effort to reduce paperwork burdens, invites the general public and the Office of Management and Budget (OMB) to comment on the information collection requirements contained in this document, as required by the Paperwork Reduction Act of 1995, Public Law 104-13.

In addition, pursuant to the Small Business Paperwork Relief Act of 2002, Public Law 107-198, we seek specific comment on how we might further reduce the information collection burden for small business concerns with fewer than 25 employees. 39. Contact Person. For further information about this rulemaking proceeding, please contact Michelle Sclater, Competition Policy Division, Wireline Competition Bureau, at (202) 418-0388 or michelle.sclater@fcc.gov.

IV. Ordering Clauses 40. It is ordered, pursuant to sections 201, 251, 301, 303, 307, 309, and 316 of the Communications Act of 1934, as amended, 47 U.S.C. 201, 251, 301, 303, 307, 309, 316, that the FNPRM in WC Docket No.

18-336 is adopted. 41. It is further ordered that the Petition for Reconsideration filed by Communications Equality Advocates is granted in part to the extent described herein. 42.

It is further ordered that the Commission's Consumer and Governmental Affairs Bureau, Reference Information Center, shall send a copy of this FNPRM, including the Initial Regulatory Flexibility Analysis, to the Chief Counsel for Advocacy of the Small Business Administration. Start List of Subjects Communications common carriersTelecommunicationsTelephone End List of Subjects Start Signature Federal Communications Commission. Marlene Dortch, Secretary. End Signature Proposed Rules For the reasons discussed in the preamble, the Federal Communications Commission proposes to amend 47 CFR part 52 as follows.

Start Part End Part Start Amendment Part1. The authority citation for part 52 is revised to read as follows. End Amendment Part Start Authority 47 U.S.C. 151, 152, 153, 154, 155, 201-205, 207-209, 218, 225-227, 251-252, 271, 301, 303, 307, 309, 316, 332, unless otherwise noted.

End Authority Start Amendment Part2. Add § 52.201 to subpart E to read as follows. End Amendment Part Texting to the National Suicide Prevention and Mental Health Crisis Hotline. (a) Support for 988 text message service.

Beginning [[DATE]], all covered text providers must have the capability to route a covered 988 text message to the current toll free access number for the National Suicide Prevention Lifeline, presently 1-800-273-8255 (TALK). (b) Definitions. For purposes of this section. 988 text message.

(i) Means a message consisting of text, images, sounds, or other information that is transmitted to or from a device that is identified as the receiving or transmitting device by means of a 10-digit telephone number, N11 service code, or 988. (ii) Includes a SMS message and a MMS message. And (iii) Does not include— (A) A real-time, two-way voice or video communication. Or (B) A message sent over an IP-enabled messaging service to another user of the same messaging service, except a message described in paragraph (b)(2) of this section.

Covered 988 text message means a 988 text message in SMS format and any other format that the Wireline Competition Bureau has determined must be supported by covered text providers. Covered text provider shall mean all Commercial Mobile Radio Services (CMRS) providers and providers of interconnected text messaging services that enable consumers to send text messages to and receive text messages from all or substantially all text-capable U.S. Telephone numbers, including through the use of applications downloaded or otherwise installed on mobile phones. Multimedia message service (MMS) shall have the same definition as the term in § 64.1600(k) of the Commission's rules.

Short message service (SMS) shall have the same definition as the term in § 64.1600(m) of the Commission's rules. End Supplemental Information [FR Doc. 2021-09855 Filed 6-9-21. 4:15 pm]BILLING CODE 6712-01-PFarmer Mike Nolan is only cultivating a fraction of 1 acre this year, as opposed to past years when he’s cultivated up to 7 acres.

(Photo by Lucas Brady Woods/KSJD) Mike Nolan said his farm in the Mancos Valley, with the bluffs of Mesa Verde National Park in the distance, has changed because of the drought. (Photo by Lucas Brady Woods/KSJD) Mike Nolan has been a farmer for about 18 years.“I don’t like gardening,” he said. €œI like farming in the sense of like, I like tractors. I like equipment.

I like big harvests.”His farm is in the Mancos Valley at the base of southwest Colorado’s snow-capped San Juan Mountains and across from the bluffs of Mesa Verde National Park. In a normal season, Nolan grows up to 7 acres of vegetable crops, anything from turnips to squash to tomatoes.This season, though, he’s had to cut down to less than a single acre.“These fields should be cultivated and prepped and looking good, but they’re covered in grass and thistle and stuff like that,” Nolan said as he pointed at one of his fields.That’s because Nolan’s farm and all of his neighbor’s farms in the Four Corners region are experiencing extreme drought conditions, or worse. And that’s limiting irrigation water supplies the region’s farmers rely on to grow hay, wine grapes and fruit trees, and to fill livestock watering ponds. Nearby McPhee Reservoir is fed by the Dolores River, and farmers across southwestern Colorado and the Ute Mountain Ute tribe’s farming operation rely on it.

The river is expected to have its fourth-lowest runoff on record this year.Alfalfa growers ideally need 30 inches of irrigation water per acre, per season, for their crops. This season, some farmers in the county are only getting a fraction of an inch from their reservoirs. As a result, farmers have to adjust, by selling cattle, limiting acreage or shutting down completely. And some of the sacrifices they’re forced to make can be really hard on their mental health, Nolan said.

€œSometimes you look in the mirror and you’re like, ‘Should I be doing this?. €™â€ Nolan said. €œâ€˜Like, does this make any sense?. €™ That stuff just builds.

And it’s in seasons like this, it can crack. And that’s the scary part.”Nolan is not the only one noticing the mental health effects that drought is having on farmers.According to data compiled by Celebrating Healthy Communities, a Colorado-based suicide-prevention group, farmers and agricultural workers are the second-highest at-risk population in Montezuma County, where Nolan farms.

What is antabuse prescribed for

€‚For the what is antabuse prescribed for podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts.This Focus Issue on arrhythmias opens with a Fast Track clinical research article entitled ‘Catheter ablation vs. Thoracoscopic surgical ablation in long-standing persistent atrial fibrillation. CASA-AF randomized controlled trial’ by Shouvik Haldar what is antabuse prescribed for from the Royal Brompton &. Harefield NHS Foundation Trust in London, UK, and colleagues. Recent prevalence estimates suggest that at least 33 million persons are affected by atrial fibrillation (AF).1 Catheter ablation is increasingly offered to relieve AF-related symptoms, based on evidence what is antabuse prescribed for illustrating its efficacy compared with antiarrhythmic drug therapy.

There is less evidence supporting AF ablation in persistent AF, although small studies suggest better maintenance of sinus rhythm.2 The authors of the current study note that thoracoscopic surgical ablation has shown promising efficacy in AF.3 This multicentre randomized controlled trial tested whether surgical ablation was superior to catheter ablation as the first interventional strategy in de novo long-standing persistent atrial fibrillation. The authors randomized 120 patients to surgical or catheter ablation. All patients underwent what is antabuse prescribed for implantable loop recorder insertion. Primary outcome was freedom from AF/atrial tachycardia ≥30 s without antiarrhythmic drugs at 12 months. The rate of the primary outcome was what is antabuse prescribed for similar (26% in patients treated by surgical ablation vs.

28% in those treated by catheter ablation). The rates of procedure-related serious adverse events within 30 days of intervention were also similar in the two groups (15% vs. 10%, respectively) what is antabuse prescribed for. Surgical ablation was more expensive and provided fewer quality-adjusted life years (QALYs) compared with catheter ablation (Figure 1).3 Figure 1Left panel. Schematic representation of what is antabuse prescribed for lesions’ placement in catheter and surgical ablation.

Most lesions were performed by radiofrequency ablation (thin red or blue lines) but the left atrial appendage (LAA) was occluded with a clip (thick red line) and the ligament of Marshall (LoM) was dissected (dashed green line). Middle panel what is antabuse prescribed for. Kaplan–Meier survival plots illustrating freedom from AF/AT (left) and clinical success (right) of both treatments. Right panel. Graphical representation of symptom what is antabuse prescribed for improvement (EHRA score reduction), QALYs gained, and the total costs associated with both treatments at 12 months.

(from Haldar S, Khan HR, Boyalla V, Kralj-Hans I, Jones S, Lord J, Onyimadu O, Satishkumar A, Bahrami T, De Souza A, Clague JR, Francis DP, Hussain W, Jarman JW, Jones DH, Chen Z, Mediratta N, Hyde J, Lewis M, Mohiaddin R, Salukhe TV, Murphy C, Kelly J, Khattar RS, Toff WD, Markides V, McCready J, Gupta D, Wong T. On behalf of what is antabuse prescribed for the CASA-AF Investigators. Catheter ablation vs. Thoracoscopic surgical ablation in long-standing persistent atrial fibrillation. CASA-AF randomized controlled what is antabuse prescribed for trial.

See pages 4471--4480.)Figure 1Left panel. Schematic representation of lesions’ placement in catheter and surgical ablation what is antabuse prescribed for. Most lesions were performed by radiofrequency ablation (thin red or blue lines) but the left atrial appendage (LAA) was occluded with a clip (thick red line) and the ligament of Marshall (LoM) was dissected (dashed green line). Middle panel what is antabuse prescribed for. Kaplan–Meier survival plots illustrating freedom from AF/AT (left) and clinical success (right) of both treatments.

Right panel. Graphical representation of what is antabuse prescribed for symptom improvement (EHRA score reduction), QALYs gained, and the total costs associated with both treatments at 12 months. (from Haldar S, Khan HR, Boyalla V, Kralj-Hans I, Jones S, Lord J, Onyimadu O, Satishkumar A, Bahrami T, De Souza A, Clague JR, Francis DP, Hussain W, Jarman JW, Jones DH, Chen Z, Mediratta N, Hyde J, Lewis M, Mohiaddin R, Salukhe TV, Murphy C, Kelly J, Khattar RS, Toff WD, Markides V, McCready J, Gupta D, Wong T. On behalf of the CASA-AF Investigators what is antabuse prescribed for. Catheter ablation vs.

Thoracoscopic surgical ablation in long-standing persistent atrial fibrillation. CASA-AF randomized controlled what is antabuse prescribed for trial. See pages 4471--4480.)The authors conclude that thoracoscopic surgical ablation is not superior to catheter ablation in treating long-standing persistent AF. The manuscript is accompanied what is antabuse prescribed for by an Editorial by Lucas Boersma from the St Antonius Hospital in Nieuwegein, the Netherlands.4 Boersma notes that from the current study it would appear that surgical ablation in its present form is not ready to become first-line therapy, given the fact that catheter ablation is easier and readily available, just as efficacious, safe, less invasive, and cheaper. Nevertheless, he believes that with novel tools, stronger energy sources, and enhanced imaging of individual AF pathophysiology, many different combinations will have to be tested in sufficiently large trials to come up with a strategy that always wins.Accumulating evidence shows that AF is associated with increased risk of dementia.5–7 Catheter ablation for AF prolongs the duration of sinus rhythm, thereby improving quality of life, and might theoretically reduce the risk of dementia.

In a clinical research manuscript what is antabuse prescribed for entitled ‘The risk of dementia after catheter ablation for atrial fibrillation. A nationwide cohort study’, Daehoon Kim from the Yonsei University College of Medicine in Seoul, Republic of Korea and colleagues investigated the association of catheter ablation for AF with the occurrence of dementia.8 Using the Korean National Health Insurance Service database, about 200000 adults with AF treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between 1 January 2005 and 31 December 2015, the authors studied ∼9000 patients undergoing ablation and ∼18 000 patients managed with medical therapy. The time-at-risk was counted from the first medical therapy, and ablation was analysed as a time-varying exposure. Propensity score matching was used to correct for what is antabuse prescribed for differences between the groups. During a median follow-up of 52 months, compared with patients with medical therapy, ablated patients showed significantly lower incidence and risk of overall dementia [8.1 and 5.6 per 1000 person-years, respectively.

Hazard ratio (HR) 0.73] what is antabuse prescribed for. The associations between ablation and dementia risk were consistently observed after additionally censoring for incident stroke (HR 0.76) (Figure 2).8 Ablation was associated with lower risks of dementia subtypes including Alzheimer’s disease and vascular dementia. Figure 2Association between catheter ablation and dementia in AF. (from Kim D, Yang P-S, Sung J-H, Jang E, Yu what is antabuse prescribed for HT, Kim T-H, Uhm J-S, Kim J-Y, Pak H-N, Lee M-H, Lip GYH, Joung B. Less dementia after catheter ablation for atrial fibrillation.

A nationwide what is antabuse prescribed for cohort study. See pages 4483--4493.)Figure 2Association between catheter ablation and dementia in AF. (from Kim D, Yang P-S, Sung J-H, Jang E, Yu HT, Kim T-H, Uhm J-S, Kim J-Y, Pak H-N, Lee M-H, Lip GYH, Joung what is antabuse prescribed for B. Less dementia after catheter ablation for atrial fibrillation. A nationwide cohort study.

See pages 4483--4493.)The authors conclude that in this nationwide cohort of AF patients treated with catheter what is antabuse prescribed for ablation or medical therapy, ablation was associated with decreased dementia risk. This relationship was evident after censoring for stroke and adjusting for clinical confounders. The manuscript what is antabuse prescribed for is accompanied by an Editorial by A. John Camm from the University of Oxford in the UK.9 The author notes that the study does provide more evidence leading us a step closer to discovering whether AF provokes dementia, and that it is not a chance association. However, it provides only limited circumstantial evidence that the rhythm itself is responsible for the cognitive impairment and that eliminating the arrhythmia by left atrial ablation will delay or reduce the likelihood of dementia.

The author concludes that we may be closer to the answer, but we are not at what is antabuse prescribed for the finishing post yet.Anticoagulation is an established approach to prevent intravascular clot formation. Unfortunately, whenever we inhibit platelets and/or the coagulation cascade, we not only reduce the risk of thrombosis formation, but also increase the risk of bleeding. Although compared with vitamin K antagonists (VKAs), novel oral anticoagulants or NOACs are an important step forward, this is still no free lunch, in particular in patients with AF undergoing what is antabuse prescribed for coronary stent implantation.10,11 In a clinical research article entitled ‘Edoxaban in atrial fibrillation patients with percutaneous coronary intervention by acute or chronic coronary syndrome presentation. A pre-specified analysis of the ENTRUST-AF PCI trial’, Pascal Vranckx from Hasselt University in Belgium, and colleagues present a pre-specified subanalysis of the ENTRUST-AF PCI trial in which patients with AF were randomly assigned 1:1 to an edoxaban- or VKA-based strategy following percutaneous coronary intervention (PCI). Participants received edoxaban 60 mg once daily plus a P2Y12 inhibitor for 12 months, or a VKA combined what is antabuse prescribed for with a P2Y12 inhibitor and aspirin 100 mg (for 1–12 months).

In this study, randomization was stratified by acute coronary syndrome (ACS. N = 777) vs. Chronic coronary syndrome what is antabuse prescribed for (CCS. N = 729).12 The primary bleeding endpoint at 12 months occurred in 15% vs. 20% among ACS patients (HR 0.73, P = 0.063), what is antabuse prescribed for and in 19.0% vs.

20% among CCS patients (HR 0.94, P = 0.708) with edoxaban- and VKA-based therapy, respectively (P for interaction = 0.27). The main secondary endpoint (composite of cardiovascular death, myocardial infarction, stroke, systemic embolic events, or definite stent thrombosis) among ACS patients was 8.5% vs. 7.2% (HR 1.16), compared with what is antabuse prescribed for 4.4% vs. 4.9% (HR 0.91) among CCS patients with edoxaban- and VKA-based therapy, respectively (P for interaction = 0.5573).Vranckx et al. Conclude that in patients with AF who underwent PCI, the edoxaban-based regimen, as compared with the VKA-based regimen, provides consistent safety and similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation what is antabuse prescribed for.

This manuscript is accompanied by an Editorial by Renato Lopes from the Duke University School of Medicine in Durham, North Carolina, USA, and Alexander Fanaroff from the University of Pennsylvania in Philadelphia, USA.13 The authors note that for now, in the 12 months after PCI, the current evidence is clear that patients with AF should be treated with an NOAC plus a P2Y12 inhibitor, regardless of indication for PCI.Cardiac death is the most common cause of death in Europe. Approximately half of those deaths occur because of sudden out-of-hospital cardiac what is antabuse prescribed for arrest (OOHCA). Recent articles have shown that outcomes of witnessed cardiac arrest have improved due to greater emphasis on resuscitation training, increased density of automatic external defibrillators, better organization of emergency medical systems, and improved post-resuscitation care. There has also been reassuring information about the quality of life and functional outcomes after successful resuscitation from OOHCA. However, it is still unusual to see >10% of the victims leaving the hospital alive.14,15 In a clinical research article entitled ‘A practical risk what is antabuse prescribed for score for early prediction of neurological outcome after out-of-hospital cardiac arrest.

MIRACLE2’, Nilesh Pareek from King’s College Hospital NHS Foundation Trust in London, UK, and colleagues sought to develop a practical risk score to predict poor neurological outcome after OOHCA.16 From May 2012 to December 2017, a total of 1055 patients had OOHCA in their region, of whom 373 patients were included in the King’s Out of Hospital Cardiac Arrest Registry (KOCAR). The authors performed prediction modelling with what is antabuse prescribed for multivariable logistic regression to identify predictors of the primary outcome to derive a risk score. This was externally validated in two independent cohorts comprising 473 patients. The primary outcome was poor neurological function at 6-month follow-up (Cerebral Performance Category 3–5). Seven independent what is antabuse prescribed for predictors of outcome were identified.

Missed (unwitnessed) arrest, Initial non-shockable rhythm, non-Reactivity of pupils, Age (60–80 years, 1 point. >80 years, 3 points), Changing intra-arrest rhythms, Low pH what is antabuse prescribed for <7.20, and Epinephrine administration (2 points).The MIRACLE2 score had an area under the receiver operating characteristic curve (AUC) of 0.90 in the development cohort and 0.84/0.91 in the validation cohort. The MIRACLE2 score had significantly superior discrimination to the OHCA and CAHP models and equivalent performance to the TTM score.The authors conclude that the MIRACLE2 is a practical risk score for early accurate prediction of poor neurological outcome after OOHCA, which has been developed for simplicity of use on hospital admission. The manuscript is accompanied by an Editorial by Christopher Granger from the Duke University Medical Center in Durham, North Carolina, USA and Carolina Malta Hansen from the University of Copenhagen, Denmark.17 The authors note that for now, the MIRACLE2 score is an effective tool for assessing longer term outcome for patients with cardiac arrest presenting to hospitals which provide primary what is antabuse prescribed for PCI for acute myocardial infarction. However, they propose that it should not be used as the sole factor to decide who should have aggressive care withheld.

It can be included as one of several parameters to identify the unusual patient who may have such a low chance of good recovery at presentation that limiting care may be appropriate. The greatest need now what is antabuse prescribed for is to develop tools to predict futile care for those with persistent coma several days after arrest.The issue is accompanied by Discussion Forum contributions. In a contribution entitled ‘Biomarkers in inherited arrhythmias. Opportunities for validation and collaboration’, Robert Hamilton from the Hospital for Sick what is antabuse prescribed for Children in Toronto, Canada, and colleagues comment on the recent publication ‘A highly specific biomarker for Brugada syndrome. Also too good to be true?.

€™ by Arthur Wilde and Elisabeth Lodder from the Academic University Medical Center in Amsterdam, the Netherlands.18,19 Wilde et al. Respond in a separate comment.20In another what is antabuse prescribed for Discussion Forum contribution entitled ‘Is the clinical benefit of primary prevention implantable cardioverter-defibrillator overestimated?. The role of sudden cardiac death to total mortality ratio’, Marcello Disertori from the Santa Chiara Hospital in Trento, Italy, and colleagues comment on the recent publication ‘Clinical effectiveness of primary prevention implantable cardioverter-defibrillators. Results of the EU-CERT-ICD controlled multicentre cohort study’ by Markus Zabel from the German Center for Cardiovascular Research in Göttingen, Germany, and colleagues.21,22 Zabel and colleagues respond in a separate comment.23The editors hope that this issue of the European Heart Journal what is antabuse prescribed for will be of interest of its readers.With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. References1Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL.

2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European what is antabuse prescribed for Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J 2020;41:doi. 10.1093/eurheartj/ehaa612.2Kirchhof P, Calkins H. Catheter ablation in patients with persistent what is antabuse prescribed for atrial fibrillation. Eur Heart J 2017;38:20–26.3Haldar S, Khan HR, Boyalla V, Kralj-Hans I, Jones S, Lord J, Onyimadu O, Satishkumar A, Bahrami T, De Souza A, Clague JR, Francis DP, Hussain W, Jarman JW, Jones DG, Chen Z, Mediratta N, Hyde J, Lewis M, Mohiaddin R, Salukhe TV, Murphy C, Kelly J, Khattar RS, Toff WD, Markides V, McCready J, Gupta D, Wong T.

Catheter ablation what is antabuse prescribed for vs. Thoracoscopic surgical ablation in long-standing persistent atrial fibrillation. CASA-AF randomized controlled trial. Eur Heart what is antabuse prescribed for J 2020;41:4471–4481.4Boersma LVA. Surgical or catheter ablation for longstanding persistent atrial fibrillation.

A game of what is antabuse prescribed for rock paper scissors?. Eur Heart J 2020;41:4481–4482.5Kühne M, Krisai P, Conen D, Osswald S. The heart–brain connection what is antabuse prescribed for. Further establishing the relationship between atrial fibrillation and dementia?. Eur Heart J 2019;40:2324–2326.6Kim D, Yang PS, Yu HT, Kim TH, Jang E, Sung JH, Pak HN, Lee MY, Lee MH, Lip GYH, Joung B.

Risk of dementia what is antabuse prescribed for in stroke-free patients diagnosed with atrial fibrillation. Data from a population-based cohort. Eur Heart J 2019;40:2313–2323.7Friberg L, Andersson T, Rosenqvist M what is antabuse prescribed for. Less dementia and stroke in low-risk patients with atrial fibrillation taking oral anticoagulation. Eur Heart J 2019;40:2327–2335.8Kim D, Yang PS, Sung JH, Jang E, Yu HT, Kim TH, Uhm JS, Kim JY, Pak HN, Lee MH, Lip GYH, Joung B.

Less dementia after catheter ablation for atrial fibrillation what is antabuse prescribed for. A nationwide cohort study. Eur Heart what is antabuse prescribed for J 2020;41:4483–4493.9Camm AJ. Does ablation of atrial fibrillation reduce the likelihood of dementia?. A step closer but not yet there.

Eur Heart J 2020;41:4494–4496.10Gargiulo G, Goette A, Tijssen what is antabuse prescribed for J, Eckardt L, Lewalter T, Vranckx P, Valgimigli M. Safety and efficacy outcomes of double vs. Triple antithrombotic therapy in patients with atrial fibrillation what is antabuse prescribed for following percutaneous coronary intervention. A systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials. Eur Heart J 2019;40:3757–3767.11Golwala HB, Cannon CP, Steg PG, Doros G, Qamar A, Ellis SG, Oldgren J, what is antabuse prescribed for Ten Berg JM, Kimura T, Hohnloser SH, Lip GYH, Bhatt DL.

Safety and efficacy of dual vs. Triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention. A systematic review and meta-analysis of what is antabuse prescribed for randomized clinical trials. Eur Heart J 2018;39:1726–1735.12Vranckx P, Valgimigli M, Eckardt L, Lewalter T, Unikas R, Marin F, Schiele F, Laeis P, Reimitz PE, Smolnik R, Zierhut W, Tijssen J, Goette A. Edoxaban in atrial fibrillation patients what is antabuse prescribed for with percutaneous coronary intervention by acute or chronic coronary syndrome presentation.

A pre-specified analysis of the ENTRUST-AF PCI trial. Eur Heart J 2020;41:4497–4504.13Fanaroff AC, Lopes RD. Antithrombotic therapy for patients with atrial fibrillation what is antabuse prescribed for undergoing percutaneous coronary intervention. Balance best with double antithrombotic therapy. Eur Heart what is antabuse prescribed for J 2020;41:4505–4507.14Wellens HJ.

Out-of-hospital cardiac arrest. The need for continuing education what is antabuse prescribed for. Eur Heart J 2017;38:1674–1675.15Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe. Epidemiological update what is antabuse prescribed for 2016.

Eur Heart J 2016;37:3232–3245.16Pareek N, Kordis P, Beckley-Hoelscher N, Pimenta D, Kocjancic ST, Jazbec A, Nevett J, Fothergill R, Kalra S, Lockie T, Shah AM, Byrne J, Noc M, MacCarthy P. A practical what is antabuse prescribed for risk score for early prediction of neurological outcome after out-of-hospital cardiac arrest. MIRACLE2. Eur Heart J 2020;41:4508–4517.17Granger CB, Hansen CM. Predicting outcome in cardiac what is antabuse prescribed for arrest.

Some progress, but more work needed. Eur Heart J 2020;41:4518–4520.18Hamilton RM, Chatterjee D, Saguner AM what is antabuse prescribed for. Biomarkers in inherited arrhythmias. Opportunities for what is antabuse prescribed for validation and collaboration. Eur Heart J 2020;41:4521–4522.19Wilde AAM, Lodder EM.

A highly specific biomarker for Brugada syndrome. Also too what is antabuse prescribed for good to be true?. Eur Heart J 2020;41:2891–2893.20Wilde AAM Lodder EM. Biomarkers in what is antabuse prescribed for inherited arrhythmias. Necessity for validation and collaboration.

Eur Heart J 2020;41:4523–4524.21Disertori M, Masè M, Nollo G. Is the clinical what is antabuse prescribed for benefit of primary prevention implantable cardioverter-defibrillator overestimated?. The role of sudden cardiac death to total mortality ratio. Eur Heart J 2020;41:4525–4526.22Zabel M, Willems R, what is antabuse prescribed for Lubinski A, Bauer A, Brugada J, Conen D, Flevari P, Hasenfuß G, Svetlosak M, Huikuri HV, Malik M, Pavlović N, Schmidt G, Sritharan R, Schlögl S, Szavits-Nossan J, Traykov V, Tuinenburg AE, Willich SN, Harden M, Friede T, Svendsen JH, Sticherling C, Merkely B. Clinical effectiveness of primary prevention implantable cardioverter-defibrillators.

Results of the EU-CERT-ICD controlled what is antabuse prescribed for multicentre cohort study. Eur Heart J 2020;41:3437–3447.23Zabel M, Friede T, Huikuri H, Malik M, Willems R. Role of the proportion of sudden cardiac death to mortality for clinical effectiveness of primary prevention ICDs. Eur Heart J what is antabuse prescribed for 2020;41:4527–4528. Published on behalf of the European Society of Cardiology.

All rights what is antabuse prescribed for reserved. © The Author(s) 2020. For permissions, please email. Journals.permissions@oup.com.Mark Nicholls focuses what is antabuse prescribed for on the work of George H. Hitchings and Gertrude B.

Elion and their what is antabuse prescribed for award—with Sir James W. Black—of the Nobel Prize in Physiology or Medicine 1988 ‘for their discoveries of important principles for drug treatment’George H. Hitchings and Gertrude B what is antabuse prescribed for. Elion were children of the Great Depression, experiencing hardship and seeing family wealth dissolve during the economic collapse of the USA in the 1930s. Both were also influenced in their choice of career by personal grief.

With Elion, it was the death of her beloved grandfather what is antabuse prescribed for. For Hitchings, it was the passing of his father when he was 12 years.That choice of a career in science and medicine ultimately brought them together in the same laboratory, where their discoveries changed the approach to drug development. Hitchings and Elion diverged from the historical trial-and-error approach of drug development towards what became termed as what is antabuse prescribed for rational drug design and designed new molecules with specific molecular structures. They used the technique to create compounds that would interfere with the natural production of deoxyribonucleic acid (DNA) in cells and interrupt cell growth.Together, Black, Elion, and Hitchings received the 1988 Nobel Prize in Physiology or Medicine for ‘their discoveries of important principles for drug treatment’.Black realized the pharmacotherapeutic potential of receptor-blocking drugs and in 1964 developed the first clinically useful beta-receptor-blocking drug, propranolol, which became widely used in the treatment of coronary heart disease and hypertension.Elion and Hitchings demonstrated differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria, and antabuse. On the basis of such differences, a series of drugs were developed that block nucleic acid synthesis in cancer cells and noxious organisms without damaging the normal human cells.It was this that caught the attention of the Nobel committee, noting that the research work carried out by Black, Elion, and Hitchings had a more fundamental significance.While previous drug development had been built on chemical modification of natural products.

They introduced a more rational approach what is antabuse prescribed for based on the understanding of basic biochemical and physiological processes.Over the years, the research philosophy of Hitchings and Elion has formed the basis for development of new drugs against a variety of diseases. These included. Thioguanine and 6-mercaptopurine against what is antabuse prescribed for leukaemia. Pyrimethamine against malaria. Azathioprine which prevents rejection of transplanted organs what is antabuse prescribed for.

And allopurinol used in the treatment of gout.An important discovery was that the chemotherapeutic effects of pyrimethamine and trimethoprim were markedly enhanced by sulfonamides and a successful application of their research ideas is exemplified by acyclovir, the first effective drug in the treatment of herpes antabuse s. Acyclovir was described by Elion and co-workers in 1977 and a decade later an application of these led to the development of azidothymidine and was used in the treatment of AIDS.Having first collaborated in the mid-1940s, when Elion joined Hitchings’ lab at Wellcome Research Laboratories in Tuckahoe, NY, USA, their original research looked for differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria, and antabuse, which could be utilized to develop drugs that selectively block the growth of cancer cells and of noxious organisms.Hitchings assigned Elion to investigate the purines, including adenine and guanine, and their role in nucleic acid metabolism in cells. They soon discovered that what is antabuse prescribed for bacterial cells required certain purines in order to make DNA.They reasoned that if they could prevent these purines from being incorporated along the metabolic pathway that leads to DNA synthesis, then they could stop the production of DNA, thereby stop cell growth. They set to work on compounds that did just this by locking up the metabolic enzymes necessary for purine incorporation.Born into a family of shipbuilders in Hoquiam, WA, USA, on 18 April 1905, Hitchings recalled ‘a warm and loving home environment’, where a high standard of ethics prevailed, together with a ‘thirst for knowledge’.But in his Nobel biography, he also reflected on the impact of his father’s death, adding. €˜The deep impression made by this event turned my thoughts toward medicine’.He entered the University of Washington as a premedical student in 1923 majoring in chemistry, earned a degree cum laude in 1927 and a master’s degree in 1928 before going to Harvard to achieve his PhD in biochemistry in 1933.He married Beverly Reimer, but his family suffered a ‘nine-year period of impermanence, both financial and intellectual’ during the Depression, with Hitchings holding a series of temporary appointments—including at Harvard, working on analytical methods used in the physiological studies of purines.He points to his career taking a significant what is antabuse prescribed for step forward in 1942 when he joined the Wellcome Research Laboratories as head and sole member of the Biochemistry Department with the freedom to develop his own programme of research.

Elvira Falco was the first permanent member of his staff followed by Gertrude Elion in 1944 and Peter Russell in 1947. €˜It was always stimulating to work with Elion’, added Hitchings. €˜She is intelligent, hard-working and ambitious what is antabuse prescribed for. She became my first assistant, and as I was promoted, she succeeded to the position just left’.Initially conducting antiviral work, they began to send compounds to the Sloan Kettering Institute to be screened for activity. Among the first few compounds submitted was 2,6-diaminopurine, which proved active and later produced several notable remissions in acute leukaemia.In 1967, he became Vice President in Charge what is antabuse prescribed for of Research of Burroughs Wellcome and when the Wellcome Laboratory moved to Research Triangle Park in NC, USA, he and Elion moved with it.

He became Scientist Emeritus in 1976 (until 1994) and also served as Adjunct Professor of Pharmacology and of Experimental Medicine from 1970 to 1985 at Duke University as well as pursuing his interests in philanthropy with roles with The Burroughs Wellcome Fund.Maintaining a lasting interest in innovative methods in drug design, he said. €˜I look back with what is antabuse prescribed for pride at our contributions to this field. Our research was untargeted, and the line of inquiry we had begun in the 1940s yielded new drug therapies for malaria (pyrimethamine), leukaemia (6-mercaptopurine and thioguanine), gout (allopurinol), organ transplantation (azathioprine) and bacterial s (cotrimoxazole (trimethoprim A). The new knowledge contributed by our studies pointed the way for investigations that led to major antiviral drugs for herpes s (acyclovir) and AIDS (zidovudine). My greatest satisfaction has come from knowing that our what is antabuse prescribed for efforts helped to save lives and relieve suffering’.George H.

Hitchings died on 27 February 1998, in Chapel Hill, NC, USA, aged 92 years. A few years earlier, in what is antabuse prescribed for 1991, renowned transplant surgeon Professor Sir Roy Calne, also an acclaimed artist, sketched George Hitchings in charcoal, with the image now part of the Wellcome Collection.Gertrude B. Elion, often known as Trudy, was born in New York City on 23 January 1918, the daughter of a dentist who had arrived in the USA from Lithuania and her mother, who was a Polish immigrant. Image 3Front cover of Wellcome News, Special Nobel Prize Issue, 1988, showing Hitchings and Elion. Credit.

Wellcome Collection. CC BY.Image 3Front cover of Wellcome News, Special Nobel Prize Issue, 1988, showing Hitchings and Elion. Credit. Wellcome Collection. CC BY.Recalling growing up in the Bronx as ‘a child with an insatiable thirst for knowledge’, she said.

€˜When it came time at the end of my high school career to choose a major in which to specialise, I was in a quandary. One of the deciding factors may have been that my grandfather, whom I loved dearly, died of cancer when I was 15. I was highly motivated to do something that might eventually lead to a cure for this terrible disease’.Entering Hunter College in 1933, she majored in science and then went to New York University in 1939 as the only female in her graduate chemistry class, obtaining her Master of Science degree in chemistry in 1941, having also worked part-time as a doctor’s receptionist to help pay her expenses.During World War II, she was offered a number of positions in research laboratories but the one which intrigued her most was as assistant to Hitchings at Burroughs Wellcome, where she ‘never felt constrained to remain strictly in chemistry, but was able to broaden my horizons into biochemistry, pharmacology, immunology, and eventually virology’.In 1967, she was appointed Head of the Department of Experimental Therapy and a position she held until retirement in 1983 in a department colleagues sometimes termed a ‘mini-institute’ as it contained sections of chemistry, enzymology, pharmacology, immunology, and virology, as well as a tissue culture laboratory. €˜This made it possible to co-ordinate our work and cooperate in a manner that was extremely useful for development of new drugs’, she said.Associated with the National Cancer Institute in many capacities and president of the American Association for Cancer Research (1983–84), she was a member of the American Chemical Society, the Royal Society of Chemistry, the Transplantation Society, the American Society of Biological Chemists, and a Fellow of the New York Academy of Sciences, among many others.After retiring as Department Head, she remained at Burroughs Wellcome (which later became Glaxo Wellcome plc and merged with SmithKlineBeecham in 2000 to create GlaxoSmithKline) as a Scientist Emeritus and Consultant and also became a Research Professor of Medicine and Pharmacology at Duke University.An avid photographer and traveller with interests in opera and ballet, Elion never married after her fiancé Leonard Canter became ill and died in 1941 of bacterial endocarditis.Upon her death aged 81 years on 21 February 1999 at Chapel Hill, NC, USA, wide-ranging tributes were paid to her work. €˜Robert A.

Ingram, Chief Executive of Glaxo Wellcome at the time, said. €˜For oncologists, her work is equivalent to the development of written language, the invention of gunpowder, the lunar landing - all those events that cause mankind to forever alter its view of what’s possible’.Of Hitchings, Ingram said. €˜He revolutionized the world of drug exploration and design’.George H. Hitchings and Gertrude B. Elion legacy—Professor Curt PetersonProfessor Curt Peterson, Professor Emeritus in the Department of Biomedical and Clinical Sciences at Linköping University, Sweden, outlined the role of Gertrude Elion with George Hitchings in pioneering rational drug development.He knew Trudy Elion, having met her at conferences several times both before and after her Nobel prize, and she also visited his laboratory at the Karolinska Institute for scientific contact, where his team was studying the pharmacokinetics and pharmacodynamics of 6-mercaptopurine and azathioprine used in childhood leukaemia and autoimmune diseases such as inflammatory bowel disease.Professor Peterson said.

€˜She was special among Nobel prize winners in two respects. She had no higher education and she worked in a pharmaceutical company. She was originally employed by George Hitchings at Burroughs Wellcome and their approach was different in that they focused on the role of purines and pyrimidines in cell growth. Previously anticancer drugs were developed by a trial and error approach’.He explained that when George Hitchings and Gertrude Elion started their collaboration during World War II at the Wellcome Research laboratories, drug development had so far been focused on substances of natural origin.‘An antimetabolite theory had been presented to explain the action of sulphonamides on bacteria suggesting that the sulphonamides interfered with the utilization of a nutrient necessary for bacterial growth’, he said.‘At that time the structure and function of nucleic acids was only rudimentarily known, but Hitchings and Elion predicted that nucleic acid bases are important for the growth of rapidly dividing cells like cancer cells and bacteria. They started to synthesize and explore the effects of purine analogues in a bacterial model.

Thereby they pioneered rational drug development’.Professor Peterson said that at the start of the 1950s, Dr Elion focused on 6-mercaptopurine and after some animal toxicology studies, clinical trials were started at the Sloan Kettering Memorial Institute in NY, USA.‘It was found that 6-mercaptopurine induced complete remissions in children with acute leukaemia and the drug is still a cornerstone in the treatment of childhood leukaemia’.He said that a close analogue, azathioprine, proved superior to 6-mercaptopurine to prevent rejection of transplanted kidneys in dogs, with azathioprine now being an important drug in the treatment of autoimmune diseases such as inflammatory bowel disease. Further studies led to the development of allopurinol used in gout and acyclovir for the treatment of viral s.Conflict of interest. None declared. Published on behalf of the European Society of Cardiology. All rights reserved.

© The Author(s) 2020. For permissions, please email. Journals.permissions@oup.com..

€‚For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts.This Focus Issue on arrhythmias opens with can you get antabuse without a prescription a Fast Track clinical research article entitled ‘Catheter ablation vs. Thoracoscopic surgical ablation in long-standing persistent atrial fibrillation. CASA-AF randomized controlled trial’ by Shouvik can you get antabuse without a prescription Haldar from the Royal Brompton &. Harefield NHS Foundation Trust in London, UK, and colleagues.

Recent prevalence estimates suggest that at least 33 million persons are affected by atrial fibrillation (AF).1 Catheter ablation is increasingly offered to relieve can you get antabuse without a prescription AF-related symptoms, based on evidence illustrating its efficacy compared with antiarrhythmic drug therapy. There is less evidence supporting AF ablation in persistent AF, although small studies suggest better maintenance of sinus rhythm.2 The authors of the current study note that thoracoscopic surgical ablation has shown promising efficacy in AF.3 This multicentre randomized controlled trial tested whether surgical ablation was superior to catheter ablation as the first interventional strategy in de novo long-standing persistent atrial fibrillation. The authors randomized 120 patients to surgical or catheter ablation. All patients underwent implantable loop recorder can you get antabuse without a prescription insertion.

Primary outcome was freedom from AF/atrial tachycardia ≥30 s without antiarrhythmic drugs at 12 months. The rate of the primary outcome was similar (26% in patients treated by surgical ablation can you get antabuse without a prescription vs. 28% in those treated by catheter ablation). The rates of procedure-related serious adverse events within 30 days of intervention were also similar in the two groups (15% vs.

10%, respectively) can you get antabuse without a prescription. Surgical ablation was more expensive and provided fewer quality-adjusted life years (QALYs) compared with catheter ablation (Figure 1).3 Figure 1Left panel. Schematic representation can you get antabuse without a prescription of lesions’ placement in catheter and surgical ablation. Most lesions were performed by radiofrequency ablation (thin red or blue lines) but the left atrial appendage (LAA) was occluded with a clip (thick red line) and the ligament of Marshall (LoM) was dissected (dashed green line).

Middle panel can you get antabuse without a prescription. Kaplan–Meier survival plots illustrating freedom from AF/AT (left) and clinical success (right) of both treatments. Right panel. Graphical representation of symptom improvement (EHRA score reduction), QALYs gained, and can you get antabuse without a prescription the total costs associated with both treatments at 12 months.

(from Haldar S, Khan HR, Boyalla V, Kralj-Hans I, Jones S, Lord J, Onyimadu O, Satishkumar A, Bahrami T, De Souza A, Clague JR, Francis DP, Hussain W, Jarman JW, Jones DH, Chen Z, Mediratta N, Hyde J, Lewis M, Mohiaddin R, Salukhe TV, Murphy C, Kelly J, Khattar RS, Toff WD, Markides V, McCready J, Gupta D, Wong T. On behalf of the CASA-AF Investigators can you get antabuse without a prescription. Catheter ablation vs. Thoracoscopic surgical ablation in long-standing persistent atrial fibrillation.

CASA-AF randomized controlled trial can you get antabuse without a prescription. See pages 4471--4480.)Figure 1Left panel. Schematic representation of lesions’ placement in catheter and can you get antabuse without a prescription surgical ablation. Most lesions were performed by radiofrequency ablation (thin red or blue lines) but the left atrial appendage (LAA) was occluded with a clip (thick red line) and the ligament of Marshall (LoM) was dissected (dashed green line).

Middle panel can you get antabuse without a prescription. Kaplan–Meier survival plots illustrating freedom from AF/AT (left) and clinical success (right) of both treatments. Right panel. Graphical representation of symptom improvement (EHRA score reduction), QALYs gained, and can you get antabuse without a prescription the total costs associated with both treatments at 12 months.

(from Haldar S, Khan HR, Boyalla V, Kralj-Hans I, Jones S, Lord J, Onyimadu O, Satishkumar A, Bahrami T, De Souza A, Clague JR, Francis DP, Hussain W, Jarman JW, Jones DH, Chen Z, Mediratta N, Hyde J, Lewis M, Mohiaddin R, Salukhe TV, Murphy C, Kelly J, Khattar RS, Toff WD, Markides V, McCready J, Gupta D, Wong T. On behalf of the CASA-AF Investigators can you get antabuse without a prescription. Catheter ablation vs. Thoracoscopic surgical ablation in long-standing persistent atrial fibrillation.

CASA-AF randomized controlled can you get antabuse without a prescription trial. See pages 4471--4480.)The authors conclude that thoracoscopic surgical ablation is not superior to catheter ablation in treating long-standing persistent AF. The manuscript is accompanied by an Editorial by Lucas Boersma from the St Antonius Hospital in Nieuwegein, the Netherlands.4 Boersma notes that from the current study it would appear that surgical ablation in its present form is not ready to become first-line therapy, given the fact that catheter ablation is easier and readily available, just as efficacious, safe, less invasive, and can you get antabuse without a prescription cheaper. Nevertheless, he believes that with novel tools, stronger energy sources, and enhanced imaging of individual AF pathophysiology, many different combinations will have to be tested in sufficiently large trials to come up with a strategy that always wins.Accumulating evidence shows that AF is associated with increased risk of dementia.5–7 Catheter ablation for AF prolongs the duration of sinus rhythm, thereby improving quality of life, and might theoretically reduce the risk of dementia.

In a clinical research manuscript entitled ‘The can you get antabuse without a prescription risk of dementia after catheter ablation for atrial fibrillation. A nationwide cohort study’, Daehoon Kim from the Yonsei University College of Medicine in Seoul, Republic of Korea and colleagues investigated the association of catheter ablation for AF with the occurrence of dementia.8 Using the Korean National Health Insurance Service database, about 200000 adults with AF treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between 1 January 2005 and 31 December 2015, the authors studied ∼9000 patients undergoing ablation and ∼18 000 patients managed with medical therapy. The time-at-risk was counted from the first medical therapy, and ablation was analysed as a time-varying exposure. Propensity score matching was can you get antabuse without a prescription used to correct for differences between the groups.

During a median follow-up of 52 months, compared with patients with medical therapy, ablated patients showed significantly lower incidence and risk of overall dementia [8.1 and 5.6 per 1000 person-years, respectively. Hazard ratio (HR) can you get antabuse without a prescription 0.73]. The associations between ablation and dementia risk were consistently observed after additionally censoring for incident stroke (HR 0.76) (Figure 2).8 Ablation was associated with lower risks of dementia subtypes including Alzheimer’s disease and vascular dementia. Figure 2Association between catheter ablation and dementia in AF.

(from Kim D, Yang P-S, Sung J-H, Jang E, Yu HT, Kim T-H, Uhm J-S, can you get antabuse without a prescription Kim J-Y, Pak H-N, Lee M-H, Lip GYH, Joung B. Less dementia after catheter ablation for atrial fibrillation. A nationwide cohort study can you get antabuse without a prescription. See pages 4483--4493.)Figure 2Association between catheter ablation and dementia in AF.

(from Kim D, Yang P-S, Sung J-H, Jang E, Yu HT, Kim T-H, Uhm J-S, Kim J-Y, Pak H-N, Lee M-H, can you get antabuse without a prescription Lip GYH, Joung B. Less dementia after catheter ablation for atrial fibrillation. A nationwide cohort study. See pages 4483--4493.)The authors conclude that in this nationwide cohort of AF patients treated can you get antabuse without a prescription with catheter ablation or medical therapy, ablation was associated with decreased dementia risk.

This relationship was evident after censoring for stroke and adjusting for clinical confounders. The manuscript can you get antabuse without a prescription is accompanied by an Editorial by A. John Camm from the University of Oxford in the UK.9 The author notes that the study does provide more evidence leading us a step closer to discovering whether AF provokes dementia, and that it is not a chance association. However, it provides only limited circumstantial evidence that the rhythm itself is responsible for the cognitive impairment and that eliminating the arrhythmia by left atrial ablation will delay or reduce the likelihood of dementia.

The author can you get antabuse without a prescription concludes that we may be closer to the answer, but we are not at the finishing post yet.Anticoagulation is an established approach to prevent intravascular clot formation. Unfortunately, whenever we inhibit platelets and/or the coagulation cascade, we not only reduce the risk of thrombosis formation, but also increase the risk of bleeding. Although compared with vitamin K antagonists (VKAs), novel oral anticoagulants or NOACs are an important step forward, this is still no free lunch, in particular in patients with AF undergoing coronary stent can you get antabuse without a prescription implantation.10,11 In a clinical research article entitled ‘Edoxaban in atrial fibrillation patients with percutaneous coronary intervention by acute or chronic coronary syndrome presentation. A pre-specified analysis of the ENTRUST-AF PCI trial’, Pascal Vranckx from Hasselt University in Belgium, and colleagues present a pre-specified subanalysis of the ENTRUST-AF PCI trial in which patients with AF were randomly assigned 1:1 to an edoxaban- or VKA-based strategy following percutaneous coronary intervention (PCI).

Participants received edoxaban 60 mg once daily plus a P2Y12 inhibitor for 12 months, or a VKA can you get antabuse without a prescription combined with a P2Y12 inhibitor and aspirin 100 mg (for 1–12 months). In this study, randomization was stratified by acute coronary syndrome (ACS. N = 777) vs. Chronic coronary syndrome (CCS can you get antabuse without a prescription.

N = 729).12 The primary bleeding endpoint at 12 months occurred in 15% vs. 20% among ACS patients (HR 0.73, can you get antabuse without a prescription P = 0.063), and in 19.0% vs. 20% among CCS patients (HR 0.94, P = 0.708) with edoxaban- and VKA-based therapy, respectively (P for interaction = 0.27). The main secondary endpoint (composite of cardiovascular death, myocardial infarction, stroke, systemic embolic events, or definite stent thrombosis) among ACS patients was 8.5% vs.

7.2% (HR 1.16), compared with 4.4% can you get antabuse without a prescription vs. 4.9% (HR 0.91) among CCS patients with edoxaban- and VKA-based therapy, respectively (P for interaction = 0.5573).Vranckx et al. Conclude that in patients with AF who underwent PCI, the edoxaban-based regimen, as compared with the VKA-based regimen, provides consistent safety and can you get antabuse without a prescription similar efficacy for ischaemic events in patients with AF regardless of their clinical presentation. This manuscript is accompanied by an Editorial by Renato Lopes from the Duke University School of Medicine in Durham, North Carolina, USA, and Alexander Fanaroff from the University of Pennsylvania in Philadelphia, USA.13 The authors note that for now, in the 12 months after PCI, the current evidence is clear that patients with AF should be treated with an NOAC plus a P2Y12 inhibitor, regardless of indication for PCI.Cardiac death is the most common cause of death in Europe.

Approximately half can you get antabuse without a prescription of those deaths occur because of sudden out-of-hospital cardiac arrest (OOHCA). Recent articles have shown that outcomes of witnessed cardiac arrest have improved due to greater emphasis on resuscitation training, increased density of automatic external defibrillators, better organization of emergency medical systems, and improved post-resuscitation care. There has also been reassuring information about the quality of life and functional outcomes after successful resuscitation from OOHCA. However, it is still unusual to see >10% of the victims leaving the hospital alive.14,15 In a clinical research article entitled ‘A practical risk score can you get antabuse without a prescription for early prediction of neurological outcome after out-of-hospital cardiac arrest.

MIRACLE2’, Nilesh Pareek from King’s College Hospital NHS Foundation Trust in London, UK, and colleagues sought to develop a practical risk score to predict poor neurological outcome after OOHCA.16 From May 2012 to December 2017, a total of 1055 patients had OOHCA in their region, of whom 373 patients were included in the King’s Out of Hospital Cardiac Arrest Registry (KOCAR). The authors can you get antabuse without a prescription performed prediction modelling with multivariable logistic regression to identify predictors of the primary outcome to derive a risk score. This was externally validated in two independent cohorts comprising 473 patients. The primary outcome was poor neurological function at 6-month follow-up (Cerebral Performance Category 3–5).

Seven independent can you get antabuse without a prescription predictors of outcome were identified. Missed (unwitnessed) arrest, Initial non-shockable rhythm, non-Reactivity of pupils, Age (60–80 years, 1 point. >80 years, 3 points), Changing intra-arrest rhythms, Low pH can you get antabuse without a prescription <7.20, and Epinephrine administration (2 points).The MIRACLE2 score had an area under the receiver operating characteristic curve (AUC) of 0.90 in the development cohort and 0.84/0.91 in the validation cohort. The MIRACLE2 score had significantly superior discrimination to the OHCA and CAHP models and equivalent performance to the TTM score.The authors conclude that the MIRACLE2 is a practical risk score for early accurate prediction of poor neurological outcome after OOHCA, which has been developed for simplicity of use on hospital admission.

The manuscript is accompanied by an Editorial by Christopher Granger from the Duke University Medical Center in Durham, North Carolina, USA and Carolina Malta Hansen from the University of Copenhagen, Denmark.17 The authors note can you get antabuse without a prescription that for now, the MIRACLE2 score is an effective tool for assessing longer term outcome for patients with cardiac arrest presenting to hospitals which provide primary PCI for acute myocardial infarction. However, they propose that it should not be used as the sole factor to decide who should have aggressive care withheld. It can be included as one of several parameters to identify the unusual patient who may have such a low chance of good recovery at presentation that limiting care may be appropriate. The greatest need now is to develop tools to predict futile care for those with persistent coma several days after arrest.The issue is accompanied can you get antabuse without a prescription by Discussion Forum contributions.

In a contribution entitled ‘Biomarkers in inherited arrhythmias. Opportunities for validation and collaboration’, Robert Hamilton from the Hospital for can you get antabuse without a prescription Sick Children in Toronto, Canada, and colleagues comment on the recent publication ‘A highly specific biomarker for Brugada syndrome. Also too good to be true?. €™ by Arthur Wilde and Elisabeth Lodder from the Academic University Medical Center in Amsterdam, the Netherlands.18,19 Wilde et al.

Respond in a separate comment.20In another Discussion Forum contribution entitled ‘Is the can you get antabuse without a prescription clinical benefit of primary prevention implantable cardioverter-defibrillator overestimated?. The role of sudden cardiac death to total mortality ratio’, Marcello Disertori from the Santa Chiara Hospital in Trento, Italy, and colleagues comment on the recent publication ‘Clinical effectiveness of primary prevention implantable cardioverter-defibrillators. Results of the EU-CERT-ICD controlled multicentre cohort study’ by Markus Zabel from the German Center for Cardiovascular Research in Göttingen, Germany, and colleagues.21,22 Zabel and colleagues respond in can you get antabuse without a prescription a separate comment.23The editors hope that this issue of the European Heart Journal will be of interest of its readers.With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article. References1Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL.

2020 ESC Guidelines for the diagnosis and management can you get antabuse without a prescription of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J 2020;41:doi. 10.1093/eurheartj/ehaa612.2Kirchhof P, Calkins H. Catheter can you get antabuse without a prescription ablation in patients with persistent atrial fibrillation.

Eur Heart J 2017;38:20–26.3Haldar S, Khan HR, Boyalla V, Kralj-Hans I, Jones S, Lord J, Onyimadu O, Satishkumar A, Bahrami T, De Souza A, Clague JR, Francis DP, Hussain W, Jarman JW, Jones DG, Chen Z, Mediratta N, Hyde J, Lewis M, Mohiaddin R, Salukhe TV, Murphy C, Kelly J, Khattar RS, Toff WD, Markides V, McCready J, Gupta D, Wong T. Catheter can you get antabuse without a prescription ablation vs. Thoracoscopic surgical ablation in long-standing persistent atrial fibrillation. CASA-AF randomized controlled trial.

Eur Heart J 2020;41:4471–4481.4Boersma LVA can you get antabuse without a prescription. Surgical or catheter ablation for longstanding persistent atrial fibrillation. A game of rock paper can you get antabuse without a prescription scissors?. Eur Heart J 2020;41:4481–4482.5Kühne M, Krisai P, Conen D, Osswald S.

The can you get antabuse without a prescription heart–brain connection. Further establishing the relationship between atrial fibrillation and dementia?. Eur Heart J 2019;40:2324–2326.6Kim D, Yang PS, Yu HT, Kim TH, Jang E, Sung JH, Pak HN, Lee MY, Lee MH, Lip GYH, Joung B. Risk of dementia in stroke-free patients diagnosed with atrial can you get antabuse without a prescription fibrillation.

Data from a population-based cohort. Eur Heart J 2019;40:2313–2323.7Friberg L, Andersson T, Rosenqvist can you get antabuse without a prescription M. Less dementia and stroke in low-risk patients with atrial fibrillation taking oral anticoagulation. Eur Heart J 2019;40:2327–2335.8Kim D, Yang PS, Sung JH, Jang E, Yu HT, Kim TH, Uhm JS, Kim JY, Pak HN, Lee MH, Lip GYH, Joung B.

Less dementia after catheter ablation for can you get antabuse without a prescription atrial fibrillation. A nationwide cohort study. Eur Heart can you get antabuse without a prescription J 2020;41:4483–4493.9Camm AJ. Does ablation of atrial fibrillation reduce the likelihood of dementia?.

A step closer but not yet there. Eur Heart J 2020;41:4494–4496.10Gargiulo G, Goette A, Tijssen J, Eckardt L, Lewalter T, Vranckx P, Valgimigli M can you get antabuse without a prescription. Safety and efficacy outcomes of double vs. Triple antithrombotic therapy in patients with atrial can you get antabuse without a prescription fibrillation following percutaneous coronary intervention.

A systematic review and meta-analysis of non-vitamin K antagonist oral anticoagulant-based randomized clinical trials. Eur Heart J 2019;40:3757–3767.11Golwala HB, Cannon CP, Steg PG, Doros G, Qamar A, Ellis SG, Oldgren J, Ten Berg JM, Kimura can you get antabuse without a prescription T, Hohnloser SH, Lip GYH, Bhatt DL. Safety and efficacy of dual vs. Triple antithrombotic therapy in patients with atrial fibrillation following percutaneous coronary intervention.

A systematic review and meta-analysis can you get antabuse without a prescription of randomized clinical trials. Eur Heart J 2018;39:1726–1735.12Vranckx P, Valgimigli M, Eckardt L, Lewalter T, Unikas R, Marin F, Schiele F, Laeis P, Reimitz PE, Smolnik R, Zierhut W, Tijssen J, Goette A. Edoxaban in atrial fibrillation patients with percutaneous coronary intervention by acute or can you get antabuse without a prescription chronic coronary syndrome presentation. A pre-specified analysis of the ENTRUST-AF PCI trial.

Eur Heart J 2020;41:4497–4504.13Fanaroff AC, Lopes RD. Antithrombotic therapy for patients with atrial fibrillation undergoing percutaneous coronary can you get antabuse without a prescription intervention. Balance best with double antithrombotic therapy. Eur Heart J can you get antabuse without a prescription 2020;41:4505–4507.14Wellens HJ.

Out-of-hospital cardiac arrest. The need can you get antabuse without a prescription for continuing education. Eur Heart J 2017;38:1674–1675.15Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe.

Epidemiological update can you get antabuse without a prescription 2016. Eur Heart J 2016;37:3232–3245.16Pareek N, Kordis P, Beckley-Hoelscher N, Pimenta D, Kocjancic ST, Jazbec A, Nevett J, Fothergill R, Kalra S, Lockie T, Shah AM, Byrne J, Noc M, MacCarthy P. A practical risk score for can you get antabuse without a prescription early prediction of neurological outcome after out-of-hospital cardiac arrest. MIRACLE2.

Eur Heart J 2020;41:4508–4517.17Granger CB, Hansen CM. Predicting outcome in can you get antabuse without a prescription cardiac arrest. Some progress, but more work needed. Eur Heart can you get antabuse without a prescription J 2020;41:4518–4520.18Hamilton RM, Chatterjee D, Saguner AM.

Biomarkers in inherited arrhythmias. Opportunities for validation can you get antabuse without a prescription and collaboration. Eur Heart J 2020;41:4521–4522.19Wilde AAM, Lodder EM. A highly specific biomarker for Brugada syndrome.

Also too good to be can you get antabuse without a prescription true?. Eur Heart J 2020;41:2891–2893.20Wilde AAM Lodder EM. Biomarkers in can you get antabuse without a prescription inherited arrhythmias. Necessity for validation and collaboration.

Eur Heart J 2020;41:4523–4524.21Disertori M, Masè M, Nollo G. Is the clinical benefit of primary can you get antabuse without a prescription prevention implantable cardioverter-defibrillator overestimated?. The role of sudden cardiac death to total mortality ratio. Eur Heart J 2020;41:4525–4526.22Zabel M, Willems R, Lubinski A, Bauer A, Brugada J, Conen D, Flevari P, Hasenfuß G, Svetlosak M, Huikuri HV, Malik M, Pavlović N, Schmidt G, Sritharan R, Schlögl can you get antabuse without a prescription S, Szavits-Nossan J, Traykov V, Tuinenburg AE, Willich SN, Harden M, Friede T, Svendsen JH, Sticherling C, Merkely B.

Clinical effectiveness of primary prevention implantable cardioverter-defibrillators. Results of the EU-CERT-ICD controlled can you get antabuse without a prescription multicentre cohort study. Eur Heart J 2020;41:3437–3447.23Zabel M, Friede T, Huikuri H, Malik M, Willems R. Role of the proportion of sudden cardiac death to mortality for clinical effectiveness of primary prevention ICDs.

Eur Heart J 2020;41:4527–4528 can you get antabuse without a prescription. Published on behalf of the European Society of Cardiology. All rights can you get antabuse without a prescription reserved. © The Author(s) 2020.

For permissions, please email. Journals.permissions@oup.com.Mark Nicholls focuses on the work of can you get antabuse without a prescription George H. Hitchings and Gertrude B. Elion and their can you get antabuse without a prescription award—with Sir James W.

Black—of the Nobel Prize in Physiology or Medicine 1988 ‘for their discoveries of important principles for drug treatment’George H. Hitchings and Gertrude B can you get antabuse without a prescription. Elion were children of the Great Depression, experiencing hardship and seeing family wealth dissolve during the economic collapse of the USA in the 1930s. Both were also influenced in their choice of career by personal grief.

With Elion, it was the can you get antabuse without a prescription death of her beloved grandfather. For Hitchings, it was the passing of his father when he was 12 years.That choice of a career in science and medicine ultimately brought them together in the same laboratory, where their discoveries changed the approach to drug development. Hitchings and Elion diverged from the historical trial-and-error approach of drug development towards what became termed as rational drug design and can you get antabuse without a prescription designed new molecules with specific molecular structures. They used the technique to create compounds that would interfere with the natural production of deoxyribonucleic acid (DNA) in cells and interrupt cell growth.Together, Black, Elion, and Hitchings received the 1988 Nobel Prize in Physiology or Medicine for ‘their discoveries of important principles for drug treatment’.Black realized the pharmacotherapeutic potential of receptor-blocking drugs and in 1964 developed the first clinically useful beta-receptor-blocking drug, propranolol, which became widely used in the treatment of coronary heart disease and hypertension.Elion and Hitchings demonstrated differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria, and antabuse.

On the basis of such differences, a series of drugs were developed that block nucleic acid synthesis in cancer cells and noxious organisms without damaging the normal human cells.It was this that caught the attention of the Nobel committee, noting that the research work carried out by Black, Elion, and Hitchings had a more fundamental significance.While previous drug development had been built on chemical modification of natural products. They introduced a more rational approach based on the understanding of basic biochemical and physiological processes.Over the years, the research philosophy of Hitchings and Elion has formed the basis for development can you get antabuse without a prescription of new drugs against a variety of diseases. These included. Thioguanine and can you get antabuse without a prescription 6-mercaptopurine against leukaemia.

Pyrimethamine against malaria. Azathioprine which prevents rejection can you get antabuse without a prescription of transplanted organs. And allopurinol used in the treatment of gout.An important discovery was that the chemotherapeutic effects of pyrimethamine and trimethoprim were markedly enhanced by sulfonamides and a successful application of their research ideas is exemplified by acyclovir, the first effective drug in the treatment of herpes antabuse s. Acyclovir was described by Elion and co-workers in 1977 and a decade later an application of these led to the development of azidothymidine and was used in the treatment of AIDS.Having first collaborated in the mid-1940s, when Elion joined Hitchings’ lab at Wellcome Research Laboratories in Tuckahoe, NY, USA, their original research looked for differences in nucleic acid metabolism between normal human cells, cancer cells, protozoa, bacteria, and antabuse, which could be utilized to develop drugs that selectively block the growth of cancer cells and of noxious organisms.Hitchings assigned Elion to investigate the purines, including adenine and guanine, and their role in nucleic acid metabolism in cells.

They soon discovered that bacterial cells required certain purines in order to make DNA.They reasoned that if they could prevent these purines from being incorporated along the metabolic pathway that leads to DNA synthesis, then they could stop the production of DNA, can you get antabuse without a prescription thereby stop cell growth. They set to work on compounds that did just this by locking up the metabolic enzymes necessary for purine incorporation.Born into a family of shipbuilders in Hoquiam, WA, USA, on 18 April 1905, Hitchings recalled ‘a warm and loving home environment’, where a high standard of ethics prevailed, together with a ‘thirst for knowledge’.But in his Nobel biography, he also reflected on the impact of his father’s death, adding. €˜The deep impression made by this event turned my thoughts toward medicine’.He entered the University of Washington as a premedical student in 1923 majoring in chemistry, earned a degree cum laude in 1927 and a master’s degree in 1928 before going to Harvard to achieve his PhD can you get antabuse without a prescription in biochemistry in 1933.He married Beverly Reimer, but his family suffered a ‘nine-year period of impermanence, both financial and intellectual’ during the Depression, with Hitchings holding a series of temporary appointments—including at Harvard, working on analytical methods used in the physiological studies of purines.He points to his career taking a significant step forward in 1942 when he joined the Wellcome Research Laboratories as head and sole member of the Biochemistry Department with the freedom to develop his own programme of research. Elvira Falco was the first permanent member of his staff followed by Gertrude Elion in 1944 and Peter Russell in 1947.

€˜It was always stimulating to work with Elion’, added Hitchings. €˜She is can you get antabuse without a prescription intelligent, hard-working and ambitious. She became my first assistant, and as I was promoted, she succeeded to the position just left’.Initially conducting antiviral work, they began to send compounds to the Sloan Kettering Institute to be screened for activity. Among the first few compounds submitted was 2,6-diaminopurine, which proved active and later produced several notable remissions in acute leukaemia.In 1967, he became Vice President in Charge of Research of Burroughs Wellcome and can you get antabuse without a prescription when the Wellcome Laboratory moved to Research Triangle Park in NC, USA, he and Elion moved with it.

He became Scientist Emeritus in 1976 (until 1994) and also served as Adjunct Professor of Pharmacology and of Experimental Medicine from 1970 to 1985 at Duke University as well as pursuing his interests in philanthropy with roles with The Burroughs Wellcome Fund.Maintaining a lasting interest in innovative methods in drug design, he said. €˜I look back with pride at our contributions to this can you get antabuse without a prescription field. Our research was untargeted, and the line of inquiry we had begun in the 1940s yielded new drug therapies for malaria (pyrimethamine), leukaemia (6-mercaptopurine and thioguanine), gout (allopurinol), organ transplantation (azathioprine) and bacterial s (cotrimoxazole (trimethoprim A). The new knowledge contributed by our studies pointed the way for investigations that led to major antiviral drugs for herpes s (acyclovir) and AIDS (zidovudine).

My greatest satisfaction has come from knowing that our efforts helped to save lives and can you get antabuse without a prescription relieve suffering’.George H. Hitchings died on 27 February 1998, in Chapel Hill, NC, USA, aged 92 years. A few years earlier, in 1991, renowned transplant surgeon Professor Sir Roy Calne, also an acclaimed can you get antabuse without a prescription artist, sketched George Hitchings in charcoal, with the image now part of the Wellcome Collection.Gertrude B. Elion, often known as Trudy, was born in New York City on 23 January 1918, the daughter of a dentist who had arrived in the USA from Lithuania and her mother, who was a Polish immigrant.

Image 3Front cover of Wellcome News, Special Nobel Prize Issue, 1988, showing Hitchings and Elion. Credit. Wellcome Collection. CC BY.Image 3Front cover of Wellcome News, Special Nobel Prize Issue, 1988, showing Hitchings and Elion.

Credit. Wellcome Collection. CC BY.Recalling growing up in the Bronx as ‘a child with an insatiable thirst for knowledge’, she said. €˜When it came time at the end of my high school career to choose a major in which to specialise, I was in a quandary.

One of the deciding factors may have been that my grandfather, whom I loved dearly, died of cancer when I was 15. I was highly motivated to do something that might eventually lead to a cure for this terrible disease’.Entering Hunter College in 1933, she majored in science and then went to New York University in 1939 as the only female in her graduate chemistry class, obtaining her Master of Science degree in chemistry in 1941, having also worked part-time as a doctor’s receptionist to help pay her expenses.During World War II, she was offered a number of positions in research laboratories but the one which intrigued her most was as assistant to Hitchings at Burroughs Wellcome, where she ‘never felt constrained to remain strictly in chemistry, but was able to broaden my horizons into biochemistry, pharmacology, immunology, and eventually virology’.In 1967, she was appointed Head of the Department of Experimental Therapy and a position she held until retirement in 1983 in a department colleagues sometimes termed a ‘mini-institute’ as it contained sections of chemistry, enzymology, pharmacology, immunology, and virology, as well as a tissue culture laboratory. €˜This made it possible to co-ordinate our work and cooperate in a manner that was extremely useful for development of new drugs’, she said.Associated with the National Cancer Institute in many capacities and president of the American Association for Cancer Research (1983–84), she was a member of the American Chemical Society, the Royal Society of Chemistry, the Transplantation Society, the American Society of Biological Chemists, and a Fellow of the New York Academy of Sciences, among many others.After retiring as Department Head, she remained at Burroughs Wellcome (which later became Glaxo Wellcome plc and merged with SmithKlineBeecham in 2000 to create GlaxoSmithKline) as a Scientist Emeritus and Consultant and also became a Research Professor of Medicine and Pharmacology at Duke University.An avid photographer and traveller with interests in opera and ballet, Elion never married after her fiancé Leonard Canter became ill and died in 1941 of bacterial endocarditis.Upon her death aged 81 years on 21 February 1999 at Chapel Hill, NC, USA, wide-ranging tributes were paid to her work. €˜Robert A.

Ingram, Chief Executive of Glaxo Wellcome at the time, said. €˜For oncologists, her work is equivalent to the development of written language, the invention of gunpowder, the lunar landing - all those events that cause mankind to forever alter its view of what’s possible’.Of Hitchings, Ingram said. €˜He revolutionized the world of drug exploration and design’.George H. Hitchings and Gertrude B.

Elion legacy—Professor Curt PetersonProfessor Curt Peterson, Professor Emeritus in the Department of Biomedical and Clinical Sciences at Linköping University, Sweden, outlined the role of Gertrude Elion with George Hitchings in pioneering rational drug development.He knew Trudy Elion, having met her at conferences several times both before and after her Nobel prize, and she also visited his laboratory at the Karolinska Institute for scientific contact, where his team was studying the pharmacokinetics and pharmacodynamics of 6-mercaptopurine and azathioprine used in childhood leukaemia and autoimmune diseases such as inflammatory bowel disease.Professor Peterson said. €˜She was special among Nobel prize winners in two respects. She had no higher education and she worked in a pharmaceutical company. She was originally employed by George Hitchings at Burroughs Wellcome and their approach was different in that they focused on the role of purines and pyrimidines in cell growth.

Previously anticancer drugs were developed by a trial and error approach’.He explained that when George Hitchings and Gertrude Elion started their collaboration during World War II at the Wellcome Research laboratories, drug development had so far been focused on substances of natural origin.‘An antimetabolite theory had been presented to explain the action of sulphonamides on bacteria suggesting that the sulphonamides interfered with the utilization of a nutrient necessary for bacterial growth’, he said.‘At that time the structure and function of nucleic acids was only rudimentarily known, but Hitchings and Elion predicted that nucleic acid bases are important for the growth of rapidly dividing cells like cancer cells and bacteria. They started to synthesize and explore the effects of purine analogues in a bacterial model. Thereby they pioneered rational drug development’.Professor Peterson said that at the start of the 1950s, Dr Elion focused on 6-mercaptopurine and after some animal toxicology studies, clinical trials were started at the Sloan Kettering Memorial Institute in NY, USA.‘It was found that 6-mercaptopurine induced complete remissions in children with acute leukaemia and the drug is still a cornerstone in the treatment of childhood leukaemia’.He said that a close analogue, azathioprine, proved superior to 6-mercaptopurine to prevent rejection of transplanted kidneys in dogs, with azathioprine now being an important drug in the treatment of autoimmune diseases such as inflammatory bowel disease. Further studies led to the development of allopurinol used in gout and acyclovir for the treatment of viral s.Conflict of interest.

None declared. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020.

For permissions, please email. Journals.permissions@oup.com..

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AbstractIntroduction How to get cialis in the us what is antabuse used for in drug treatment. We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the best of our knowledge, this is the what is antabuse used for in drug treatment first report of such an association.Family description.

The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 what is antabuse used for in drug treatment years, because of a history of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer.

She was tested for several what is antabuse used for in drug treatment genes associated with hereditary breast cancer.Results. A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion. This complex situation is challenging what is antabuse used for in drug treatment for genetic counselling and management of at-risk individuals.cancer.

Breastcancer. Gastricclinical geneticsgenetic what is antabuse used for in drug treatment screening/counsellingmolecular geneticsIntroductionGLI-Kruppel family member 3 (GLI3) encodes for a zinc finger transcription factor which plays a key role in the sonic hedgehog (SHH) signalling pathway essential in both limb and craniofacial development.1 2 In hand development, SHH is expressed in the zone of polarising activity (ZPA) on the posterior side of the handplate. The ZPA expresses SHH, creating a gradient of SHH from the posterior to the anterior side of the handplate.

In the presence of SHH, full length GLI3-protein is produced (GLI3A), whereas absence of SHH causes cleavage of GLI3 into its repressor form (GLI3R).3 4 Abnormal expression of this SHH/GLI3R gradient can cause both preaxial and postaxial polydactyly.2Concordantly, pathogenic DNA variants in the GLI3 gene are known to cause multiple syndromes with craniofacial and limb involvement, what is antabuse used for in drug treatment such as. Acrocallosal syndrome5 (OMIM. 200990), Greig cephalopolysyndactyly what is antabuse used for in drug treatment syndrome6 (OMIM.

175700) and Pallister-Hall syndrome7 (OMIM. 146510). Also, in non-syndromic polydactyly, such as preaxial polydactyly-type 4 (PPD4, OMIM.

174700),8 pathogenic variants in GLI3 have been described. Out of these diseases, Pallister-Hall syndrome is the most distinct entity, defined by the presence of central polydactyly and hypothalamic hamartoma.9 The other GLI3 syndromes are defined by the presence of preaxial and/or postaxial polydactyly of the hand and feet with or without syndactyly (Greig syndrome, PPD4). Also, various mild craniofacial features such as hypertelorism and macrocephaly can occur.

Pallister-Hall syndrome is caused by truncating variants in the middle third of the GLI3 gene.10–12 The truncation of GLI3 causes an overexpression of GLI3R, which is believed to be the key difference between Pallister-Hall and the GLI3-mediated polydactyly syndromes.9 11 Although multiple attempts have been made, the clinical and genetic distinction between the GLI3-mediated polydactyly syndromes is less evident. This has for example led to the introduction of subGreig and the formulation of an Oro-facial-digital overlap syndrome.10 Other authors, suggested that we should not regard these diseases as separate entities, but as a spectrum of GLI3-mediated polydactyly syndromes.13Although phenotype/genotype correlation of the different syndromes has been cumbersome, clinical and animal studies do provide evidence that distinct regions within the gene, could be related to the individual anomalies contributing to these syndromes. First, case studies show isolated preaxial polydactyly is caused by both truncating and non-truncating variants throughout the GLI3 gene, whereas in isolated postaxial polydactyly cases truncating variants at the C-terminal side of the gene are observed.12 14 These results suggest two different groups of variants for preaxial and postaxial polydactyly.

Second, recent animal studies suggest that posterior malformations in GLI3-mediated polydactyly syndromes are likely related to a dosage effect of GLI3R rather than due to the influence of an altered GLI3A expression.15Past attempts for phenotype/genotype correlation in GLI3-mediated polydactyly syndromes have directly related the diagnosed syndrome to the observed genotype.10–12 16 Focusing on individual hand phenotypes, such as preaxial and postaxial polydactyly and syndactyly might be more reliable because it prevents misclassification due to inconsistent use of syndrome definition. Subsequently, latent class analysis (LCA) provides the possibility to relate a group of observed variables to a set of latent, or unmeasured, parameters and thereby identifying different subgroups in the obtained dataset.17 As a result, LCA allows us to group different phenotypes within the GLI3-mediated polydactyly syndromes and relate the most important predictors of the grouped phenotypes to the observed GLI3 variants.The aim of our study was to further investigate the correlation of the individual phenotypes to the genotypes observed in GLI3-mediated polydactyly syndromes, using LCA. Cases were obtained by both literature review and the inclusion of local clinical cases.

Subsequently, we identified two subclasses of limb anomalies that relate to the underlying GLI3 variant. We provide evidence for two different phenotypic and genotypic groups with predominantly preaxial and postaxial hand and feet anomalies, and we specify those cases with a higher risk for corpus callosum anomalies.MethodsLiterature reviewThe Human Gene Mutation Database (HGMD Professional 2019) was reviewed to identify known pathogenic variants in GLI3 and corresponding phenotypes.18 All references were obtained and cases were included when they were diagnosed with either Greig or subGreig syndrome or PPD4.10–12 Pallister-Hall syndrome and acrocallosal syndrome were excluded because both are regarded distinct syndromes and rather defined by the presence of the non-hand anomalies, than the presence of preaxial or postaxial polydactyly.13 19 Isolated preaxial or postaxial polydactyly were excluded for two reasons. The phenotype/genotype correlations are better understood and both anomalies can occur sporadically which could introduce falsely assumed pathogenic GLI3 variants in the analysis.

Additionally, cases were excluded when case-specific phenotypic or genotypic information was not reported or if these two could not be related to each other. Families with a combined phenotypic description, not reducible to individual family members, were included as one case in the analysis.Clinical casesThe Sophia Children’s Hospital Database was reviewed for cases with a GLI3 variant. Within this population, the same inclusion criteria for the phenotype were valid.

Relatives of the index patients were also contacted for participation in this study, when they showed comparable hand, foot, or craniofacial malformations or when a GLI3 variant was identified. Phenotypes of the hand, foot and craniofacial anomalies of the patients treated in the Sophia Children's Hospital were collected using patient documentation. Family members were identified and if possible, clinically verified.

Alternatively, family members were contacted to verify their phenotypes. If no verification was possible, cases were excluded.PhenotypesThe phenotypes of both literature cases and local cases were extracted in a similar fashion. The most frequently reported limb and craniofacial phenotypes were dichotomised.

The dichotomised hand and foot phenotypes were preaxial polydactyly, postaxial polydactyly and syndactyly. Broad halluces or thumbs were commonly reported by authors and were dichotomised as a presentation of preaxial polydactyly. The extracted dichotomised craniofacial phenotypes were hypertelorism, macrocephaly and corpus callosum agenesis.

All other phenotypes were registered, but not dichotomised.Pathogenic GLI3 variantsAll GLI3 variants were extracted and checked using Alamut Visual V.2.14. If indicated, variants were renamed according to standard Human Genome Variation Society nomenclature.20 Variants were grouped in either missense, frameshift, nonsense or splice site variants. In the group of frameshift variants, a subgroup with possible splice site effect were identified for subgroup analysis when indicated.

Similarly, nonsense variants prone for nonsense mediated decay (NMD) and nonsense variants with experimentally confirmed NMD were identified.21 Deletions of multiple exons, CNVs and translocations were excluded for analysis. A full list of included mutations is available in the online supplementary materials.Supplemental materialThe location of the variant was compared with five known structural domains of the GLI3 gene. (1) repressor domain, (2) zinc finger domain, (3) cleavage site, (4) activator domain, which we defined as a concatenation of the separately identified transactivation zones, the CBP binding domain and the mediator binding domain (MBD) and (5) the MID1 interaction region domain.1 6 22–24 The boundaries of each of the domains were based on available literature (figure 1, exact locations available in the online supplementary materials).

The boundaries used by different authors did vary, therefore a consensus was made.In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1.

Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations." data-icon-position data-hide-link-title="0">Figure 1 In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1.

Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations.Supplemental materialLatent class analysisTo cluster phenotypes and relate those to the genotypes of the patients, an explorative analysis was done using LCA in R (R V.3.6.1 for Mac. Polytomous variable LCA, poLCA V.1.4.1.). We used our LCA to detect the number of phenotypic subgroups in the dataset and subsequently predict a class membership for each case in the dataset based on the posterior probabilities.In order to make a reliable prediction, only phenotypes that were sufficiently reported and/or ruled out were feasible for LCA, limiting the analysis to preaxial polydactyly, postaxial polydactyly and syndactyly of the hands and feet.

Only full cases were included. To determine the optimal number of classes, we fitted a series of models ranging from a one-class to a six-class model. The optimal number of classes was based on the conditional Akaike information criterion (cAIC), the non adjusted and the sample-size adjusted Bayesian information criterion (BIC and aBIC) and the obtained entropy.25 The explorative LCA produces both posterior probabilities per case for both classes and predicted class membership.

Using the predicted class membership, the phenotypic features per class were determined in a univariate analysis (χ2, SPSS V.25). Using the posterior probabilities on latent class (LC) membership, a scatter plot was created using the location of the variant on the x-axis and the probability of class membership on the y-axis for each of the types of variants (Tibco Spotfire V.7.14). Using these scatter plots, variants that give similar phenotypes were clustered.Genotype/phenotype correlationBecause an LC has no clinical value, the correlation between genotypes and phenotypes was investigated using the predictor phenotypes and the clustered phenotypes.

First, those phenotypes that contribute most to LC membership were identified. Second those phenotypes were directly related to the different types of variants (missense, nonsense, frameshift, splice site) and their clustered locations. Quantification of the relation was performed using a univariate analysis using a χ2 test.

Because of our selection criteria, meaning patients at least have two phenotypes, a multivariate using a logistic regression analysis was used to detect the most significant predictors in the overall phenotype (SPSS V.25). Finally, we explored the relation of the clustered genotypes to the presence of corpus callosum agenesis, a rare malformation in GLI3-mediated polydactyly syndromes which cannot be readily diagnosed without additional imaging.ResultsWe included 251 patients from the literature and 46 local patients,10–12 16 21 26–43 in total 297 patients from 155 different families with 127 different GLI3 variants, 32 of which were large deletions, CNVs or translocations. In six local cases, the exact variant could not be retrieved by status research.The distribution of the most frequently observed phenotypes and variants are presented in table 1.

Other recurring phenotypes included developmental delay (n=22), broad nasal root (n=23), frontal bossing or prominent forehead (n=16) and craniosynostosis (n=13), camptodactyly (n=8) and a broad first interdigital webspace of the foot (n=6).View this table:Table 1 Baseline phenotypes and genotypes of selected populationThe LCA model was fitted using the six defined hand/foot phenotypes. Model fit indices for the LCA are displayed in table 2. Based on the BIC, a two-class model has the best fit for our data.

The four-class model does show a gain in entropy, however with a higher BIC and loss of df. Therefore, based on the majority of performance statistics and the interpretability of the model, a two-class model was chosen. Table 3 displays the distribution of phenotypes and genotypes over the two classes.View this table:Table 2 Model fit indices for the one-class through six-class model evaluated in our LCAView this table:Table 3 Distribution of phenotypes and genotypes in the two latent classes (LC)Table 1 depicts the baseline phenotypes and genotypes in the obtained population.

Note incomplete data especially in the cranium phenotypes. In total 259 valid genotypes were present. In total, 289 cases had complete data for all hand and foot phenotypes (preaxial polydactyly, postaxial polydactyly and syndactyly) and thus were available for LCA.

Combined, for phenotype/genotype correlation 258 cases were available with complete genotypes and complete hand and foot phenotypes.Table 2 depicts the model fit indices for all models that have been fitted to our data.Table 3 depicts the distribution of phenotypes and genotypes over the two assigned LCs. Hand and foot phenotypes were used as input for the LCA, thus are all complete cases. Malformation of the cranium and genotypes do have missing cases.

Note that for the LCA, full case description was required, resulting in eight cases due to incomplete phenotypes. Out of these eight, one also had a genotype that thus needed to be excluded. Missingness of genotypic data was higher in LC2, mostly due to CNVs (table 1).In 54/60 cases, a missense variant produced a posterior phenotype.

Likewise, splice site variants show the same phenotype in 23/24 cases (table 3). For both frameshift and nonsense variants, this relation is not significant (52 anterior vs 54 posterior and 26 anterior vs 42 posterior, respectively). Therefore, only for nonsense and frameshift variants the location of the variant was plotted against the probability for LC2 membership in figure 1.

A full scatterplot of all variants is available in online supplementary figure 1.Figure 1 reveals a pattern for these nonsense and frameshift variants that reveals that variants at the C-terminal of the gene predict anterior phenotypes. When relating the domains of the GLI3 protein to the observed phenotype, we observe that the majority of patients with a nonsense or frameshift variant in the repressor domain, the zinc finger domain or the cleavage site had a high probability of an LC2/anterior phenotype. This group contains all variants that are either experimentally determined to be subject to NMD (triangle marker in figure 1) or predicted to be subject to NMD (diamond marker in figure 1).

Frameshift and nonsense variants in the activator domain result in high probability for an LC1/posterior phenotype. These variants will be further referred to as truncating variants in the activator domain.The univariate relation of the individual phenotypes to these two groups of variants are estimated and presented in table 4. In our multivariate analysis, postaxial polydactyly of the foot and hand are the strongest predictors (Beta.

2.548, p<0001 and Beta. 1.47, p=0.013, respectively) for patients to have a truncating variant in the activator domain. Moreover, the effect sizes of preaxial polydactyly of the hand and feet (Beta.

ˆ’0.797, p=0123 and −1.772, p=0.001) reveals that especially postaxial polydactyly of the foot is the dominant predictor for the genetic substrate of the observed anomalies.View this table:Table 4 Univariate and multivariate analysis of the phenotype/genotype correlationTable 4 shows exploration of the individual phenotypes on the genotype, both univariate and multivariate. The multivariate analysis corrects for the presence of multiple phenotypes in the underlying population.Although the craniofacial anomalies could not be included in the LCA, the relation between the observed anomalies and the identified genetic substrates can be studied. The prevalence of hypertelorism was equally distributed over the two groups of variants (47/135 vs 21/47 respectively, p<0.229).

However for corpus callosum agenesis and macrocephaly, there was a higher prevalence in patients with a truncating variant in the activator domain (3/75 vs 11/41, p<0.001. OR. 8.8, p<0.001) and 42/123 vs 24/48, p<0.05).

Noteworthy is the fact that 11/14 cases with corpus callosum agenesis in the dataset had a truncating variant in the activator domain.DiscussionIn this report, we present new insights into the correlation between the phenotype and the genotype in patients with GLI3-mediated polydactyly syndromes. We illustrate that there are two LCs of patients, best predicted by postaxial polydactyly of the hand and foot for LC1, and the preaxial polydactyly of the hand and foot and syndactyly of the foot for LC2. Patients with postaxial phenotypes have a higher risk of having a truncating variant in the activator domain of the GLI3 gene which is also related to a higher risk of corpus callosum agenesis.

These results suggest a functional difference between truncating variants on the N-terminal and the C-terminal side of the GLI3 cleavage site.Previous attempts of phenotype to genotype correlation have not yet provided the clinical confirmation of these assumed mechanisms in the pathophysiology of GLI3-mediated polydactyly syndromes. Johnston et al have successfully determined the Pallister-Hall region in which truncating variants produce a Pallister-Hall phenotype rather than Greig syndrome.11 However, in their latest population study, subtypes of both syndromes were included to explain the full spectrum of observed malformations. In 2015, Demurger et al reported the higher incidence of corpus callosum agenesis in the Greig syndrome population with truncating mutations in the activator domain.12 Al-Qattan in his review summarises the concept of a spectrum of anomalies dependent on haplo-insufficiency (through different mechanisms) and repressor overexpression.13 However, he bases this theory mainly on reviewed experimental data.

Our report is the first to provide an extensive clinical review of cases that substantiate the phenotypic difference between the two groups that could fit the suggested mechanisms. We agree with Al-Qattan et al that a variation of anomalies can be observed given any pathogenic variant in the GLI3 gene, but overall two dominant phenotypes are present. A population with predominantly preaxial anomalies and one with postaxial anomalies.

The presence of preaxial or postaxial polydactyly and syndactyly is not mutually exclusive for one of these two subclasses. Meaning that preaxial polydactyly can co-occur with postaxial polydactyly. However, truncating mutations in the activator domain produce a postaxial phenotype, as can be derived from the risk in table 4.

The higher risk of corpus callosum agenesis in this population shows that differentiating between a preaxial phenotype and a postaxial phenotype, instead of between the different GLI3-mediated polydactyly syndromes, might be more relevant regarding diagnostics for corpus callosum agenesis.We chose to use LCA as an exploratory tool only in our population for two reasons. First of all, LCA can be useful to identify subgroups, but there is no ‘true’ model or number of subgroups you can detect. The best fitting model can only be estimated based on the available measures and approximates the true subgroups that might be present.

Second, LC membership assignment is a statistical procedure based on the posterior probability, with concordant errors of the estimation, rather than a clinical value that can be measured or evaluated. Therefore, we decided to use our LCA only in an exploratory tool, and perform our statistics using the actual phenotypes that predict LC membership and the associated genotypes. Overall, this method worked well to differentiate the two subgroups present in our dataset.

However, outliers were observed. A qualitative analysis of these outliers is available in the online supplementary data.The genetic substrate for the two phenotypic clusters can be discussed based on multiple experiments. Overall, we hypothesise two genetic clusters.

One that is due to haploinsufficiency and one that is due to abnormal truncation of the activator. The hypothesised cluster of variants that produce haploinsufficiency is mainly based on the experimental data that confirms NMD in two variants and the NMD prediction of other nonsense variants in Alamut. For the frameshift variants, it is also likely that the cleavage of the zinc finger domain results in functional haploinsufficiency either because of a lack of signalling domains or similarly due to NMD.

Missense variants could cause haploinsufficiency through the suggested mechanism by Krauss et al who have illustrated that missense variants in the MID1 domain hamper the functional interaction with the MID1-α4-PP2A complex, leading to a subcellular location of GLI3.24 The observed missense variants in our study exceed the region to which Krauss et al have limited the MID-1 interaction domain. An alternative theory is suggested by Zhou et al who have shown that missense variants in the MBD can cause deficiency in the signalling of GLI3A, functionally implicating a relative overexpression of GLI3R.22 However, GLI3R overexpression would likely produce a posterior phenotype, as determined by Hill et al in their fixed homo and hemizygous GLI3R models.15 Therefore, our hypothesis is that all included missense variants have a similar pathogenesis which is more likely in concordance with the mechanism introduced by Krauss et al. To our knowledge, no splice site variants have been functionally described in literature.

However, it is noted that the 15 and last exon encompasses the entire activator domain, thus any splice site mutation is by definition located on the 5′ side of the activator. Based on the phenotype, we would suggest that these variants fail to produce a functional protein. We hypothesise that the truncating variants of the activator domain lead to overexpression of GLI3R in SHH rich areas.

In normal development, the presence of SHH prevents the processing of full length GLI34 into GLI3R, thus producing the full length activator. In patients with a truncating variant of the activator domain of GLI3, thus these variants likely have the largest effect in SHH rich areas, such as the ZPA located at the posterior side of the hand/footplate. Moreover, the lack of posterior anomalies in the GLI3∆699/- mouse model (hemizygous fixed repressor model) compared with the GLI3∆699/∆699 mouse model (homozygous fixed repressor model), suggesting a dosage effect of GLI3R to be responsible for posterior hand anomalies.15 These findings are supported by Lewandowski et al, who show that the majority of the target genes in GLI signalling are regulated by GLI3R rather than GLI3A.44 Together, these findings suggest a role for the location and type of variant in GLI3-mediated syndromes.Interestingly, the difference between Pallister-Hall syndrome and GLI3-mediated polydactyly syndromes has also been attributed to the GLI3R overexpression.

However, the difference in phenotype observed in the cases with a truncating variant in the activator domain and Pallister-Hall syndrome suggest different functional consequences. When studying figure 1, it is noted that the included truncating variants on the 3′ side of the cleavage site seldomly affect the CBP binding region, which could provide an explanation for the observed differences. This binding region is included in the Pallister-Hall region as defined by Johnston et al and is necessary for the downstream signalling with GLI1.10 11 23 45 Interestingly, recent reports show that pathogenic variants in GLI1 can produce phenotypes concordant with Ellis von Krefeld syndrome, which includes overlapping features with Pallister-Hall syndrome.46 The four truncating variants observed in this study that do affect the CBP but did not result in a Pallister-Hall phenotype are conflicting with this theory.

Krauss et al postulate an alternative hypothesis, they state that the MID1-α4-PP2A complex, which is essential for GLI3A signalling, could also be the reason for overlapping features of Opitz syndrome, caused by variants in MID1, and Pallister-Hall syndrome. Further analysis is required to fully appreciate the functional differences between truncating mutations that cause Pallister-Hall syndrome and those that result in GLI3-mediated polydactyly syndromes.For the clinical evaluation of patients with GLI3-mediated polydactyly syndromes, intracranial anomalies are likely the most important to predict based on the variant. Unfortunately, the presence of corpus callosum agenesis was not routinely investigated or reported thus this feature could not be used as an indicator phenotype for LC membership.

Interestingly when using only hand and foot phenotypes, we did notice a higher prevalence of corpus callosum agenesis in patients with posterior phenotypes. The suggested relation between truncating mutations in the activator domain causing these posterior phenotypes and corpus callosum agenesis was statistically confirmed (OR. 8.8, p<0.001).

Functionally this relation could be caused by the GLI3-MED12 interaction at the MBD. Pathogenic DNA variants in MED12 can cause Opitz-Kaveggia syndrome, a syndrome in which presentation includes corpus callosum agenesis, broad halluces and thumbs.47In conclusion, there are two distinct phenotypes within the GLI3-mediated polydactyly population. Patients with more posteriorly and more anteriorly oriented hand anomalies.

Furthermore, this difference is related to the observed variant in GLI3. We hypothesise that variants that cause haploinsufficiency produce anterior anomalies of the hand, whereas variants with abnormal truncation of the activator domain have more posterior anomalies. Furthermore, patients that have a variant that produces abnormal truncation of the activator domain, have a greater risk for corpus callosum agenesis.

Thus, we advocate to differentiate preaxial or postaxial oriented GLI3 phenotypes to explain the pathophysiology as well as to get a risk assessment for corpus callosum agenesis.Data availability statementData are available upon reasonable request.Ethics statementsPatient consent for publicationNot required.Ethics approvalThe research protocol was approved by the local ethics board of the Erasmus MC University Medical Center (MEC 2015-679)..

AbstractIntroduction How to get cialis in the us can you get antabuse without a prescription. We report a very rare case of familial breast cancer and diffuse gastric cancer, with germline pathogenic variants in both BRCA1 and CDH1 genes. To the can you get antabuse without a prescription best of our knowledge, this is the first report of such an association.Family description.

The proband is a woman diagnosed with breast cancer at the age of 52 years. She requested genetic counselling in 2012, at the age of 91 years, because of a history can you get antabuse without a prescription of breast cancer in her daughter, her sister, her niece and her paternal grandmother and was therefore concerned about her relatives. Her sister and maternal aunt also had gastric cancer.

She was tested for several genes associated with hereditary breast can you get antabuse without a prescription cancer.Results. A large deletion of BRCA1 from exons 1 to 7 and two CDH1 pathogenic cis variants were identified.Conclusion. This complex situation is challenging for genetic counselling and management of at-risk individuals.cancer can you get antabuse without a prescription.

Breastcancer. Gastricclinical geneticsgenetic screening/counsellingmolecular geneticsIntroductionGLI-Kruppel family member 3 (GLI3) encodes for a zinc finger transcription factor which plays a key role in the sonic hedgehog (SHH) signalling pathway essential in both limb and craniofacial development.1 2 In hand development, SHH is expressed in the can you get antabuse without a prescription zone of polarising activity (ZPA) on the posterior side of the handplate. The ZPA expresses SHH, creating a gradient of SHH from the posterior to the anterior side of the handplate.

In the presence of SHH, full length can you get antabuse without a prescription GLI3-protein is produced (GLI3A), whereas absence of SHH causes cleavage of GLI3 into its repressor form (GLI3R).3 4 Abnormal expression of this SHH/GLI3R gradient can cause both preaxial and postaxial polydactyly.2Concordantly, pathogenic DNA variants in the GLI3 gene are known to cause multiple syndromes with craniofacial and limb involvement, such as. Acrocallosal syndrome5 (OMIM. 200990), Greig cephalopolysyndactyly can you get antabuse without a prescription syndrome6 (OMIM.

175700) and Pallister-Hall syndrome7 (OMIM. 146510). Also, in non-syndromic polydactyly, such as preaxial polydactyly-type 4 (PPD4, OMIM.

174700),8 pathogenic variants in GLI3 have been described. Out of these diseases, Pallister-Hall syndrome is the most distinct entity, defined by the presence of central polydactyly and hypothalamic hamartoma.9 The other GLI3 syndromes are defined by the presence of preaxial and/or postaxial polydactyly of the hand and feet with or without syndactyly (Greig syndrome, PPD4). Also, various mild craniofacial features such as hypertelorism and macrocephaly can occur.

Pallister-Hall syndrome is caused by truncating variants in the middle third of the GLI3 gene.10–12 The truncation of GLI3 causes an overexpression of GLI3R, which is believed to be the key difference between Pallister-Hall and the GLI3-mediated polydactyly syndromes.9 11 Although multiple attempts have been made, the clinical and genetic distinction between the GLI3-mediated polydactyly syndromes is less evident. This has for example led to the introduction of subGreig and the formulation of an Oro-facial-digital overlap syndrome.10 Other authors, suggested that we should not regard these diseases as separate entities, but as a spectrum of GLI3-mediated polydactyly syndromes.13Although phenotype/genotype correlation of the different syndromes has been cumbersome, clinical and animal studies do provide evidence that distinct regions within the gene, could be related to the individual anomalies contributing to these syndromes. First, case studies show isolated preaxial polydactyly is caused by both truncating and non-truncating variants throughout the GLI3 gene, whereas in isolated postaxial polydactyly cases truncating variants at the C-terminal side of the gene are observed.12 14 These results suggest two different groups of variants for preaxial and postaxial polydactyly.

Second, recent animal studies suggest that posterior malformations in GLI3-mediated polydactyly syndromes are likely related to a dosage effect of GLI3R rather than due to the influence of an altered GLI3A expression.15Past attempts for phenotype/genotype correlation in GLI3-mediated polydactyly syndromes have directly related the diagnosed syndrome to the observed genotype.10–12 16 Focusing on individual hand phenotypes, such as preaxial and postaxial polydactyly and syndactyly might be more reliable because it prevents misclassification due to inconsistent use of syndrome definition. Subsequently, latent class analysis (LCA) provides the possibility to relate a group of observed variables to a set of latent, or unmeasured, parameters and thereby identifying different subgroups in the obtained dataset.17 As a result, LCA allows us to group different phenotypes within the GLI3-mediated polydactyly syndromes and relate the most important predictors of the grouped phenotypes to the observed GLI3 variants.The aim of our study was to further investigate the correlation of the individual phenotypes to the genotypes observed in GLI3-mediated polydactyly syndromes, using LCA. Cases were obtained by both literature review and the inclusion of local clinical cases.

Subsequently, we identified two subclasses of limb anomalies that relate to the underlying GLI3 variant. We provide evidence for two different phenotypic and genotypic groups with predominantly preaxial and postaxial hand and feet anomalies, and we specify those cases with a higher risk for corpus callosum anomalies.MethodsLiterature reviewThe Human Gene Mutation Database (HGMD Professional 2019) was reviewed to identify known pathogenic variants in GLI3 and corresponding phenotypes.18 All references were obtained and cases were included when they were diagnosed with either Greig or subGreig syndrome or PPD4.10–12 Pallister-Hall syndrome and acrocallosal syndrome were excluded because both are regarded distinct syndromes and rather defined by the presence of the non-hand anomalies, than the presence of preaxial or postaxial polydactyly.13 19 Isolated preaxial or postaxial polydactyly were excluded for two reasons. The phenotype/genotype correlations are better understood and both anomalies can occur sporadically which could introduce falsely assumed pathogenic GLI3 variants in the analysis.

Additionally, cases were excluded when case-specific phenotypic or genotypic information was not reported or if these two could not be related to each other. Families with a combined phenotypic description, not reducible to individual family members, were included as one case in the analysis.Clinical casesThe Sophia Children’s Hospital Database was reviewed for cases with a GLI3 variant. Within this population, the same inclusion criteria for the phenotype were valid.

Relatives of the index patients were also contacted for participation in this study, when they showed comparable hand, foot, or craniofacial malformations or when a GLI3 variant was identified. Phenotypes of the hand, foot and craniofacial anomalies of the patients treated in the Sophia Children's Hospital were collected using patient documentation. Family members were identified and if possible, clinically verified.

Alternatively, family members were contacted to verify their phenotypes. If no verification was possible, cases were excluded.PhenotypesThe phenotypes of both literature cases and local cases were extracted in a similar fashion. The most frequently reported limb and craniofacial phenotypes were dichotomised.

The dichotomised hand and foot phenotypes were preaxial polydactyly, postaxial polydactyly and syndactyly. Broad halluces or thumbs were commonly reported by authors and were dichotomised as a presentation of preaxial polydactyly. The extracted dichotomised craniofacial phenotypes were hypertelorism, macrocephaly and corpus callosum agenesis.

All other phenotypes were registered, but not dichotomised.Pathogenic GLI3 variantsAll GLI3 variants were extracted and checked using Alamut Visual V.2.14. If indicated, variants were renamed according to standard Human Genome Variation Society nomenclature.20 Variants were grouped in either missense, frameshift, nonsense or splice site variants. In the group of frameshift variants, a subgroup with possible splice site effect were identified for subgroup analysis when indicated.

Similarly, nonsense variants prone for nonsense mediated decay (NMD) and nonsense variants with experimentally confirmed NMD were identified.21 Deletions of multiple exons, CNVs and translocations were excluded for analysis. A full list of included mutations is available in the online supplementary materials.Supplemental materialThe location of the variant was compared with five known structural domains of the GLI3 gene. (1) repressor domain, (2) zinc finger domain, (3) cleavage site, (4) activator domain, which we defined as a concatenation of the separately identified transactivation zones, the CBP binding domain and the mediator binding domain (MBD) and (5) the MID1 interaction region domain.1 6 22–24 The boundaries of each of the domains were based on available literature (figure 1, exact locations available in the online supplementary materials).

The boundaries used by different authors did vary, therefore a consensus was made.In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1.

Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations." data-icon-position data-hide-link-title="0">Figure 1 In this figure the posterior probability of an anterior phenotype is plotted against the location of the variant, stratified for the type of mutation that was observed. For better overview, only variants with a location effect were displayed. The full figure, including all variant types, can be found in the online supplementary figure 1.

Each mutation is depicted as a dot, the size of the dot represents the number of observations for that variant. If multiple observations were made, the mean posterior odds and IQR are plotted. For the nonsense variants, variants that were predicted to produce nonsense mediated decay, are depicted using a triangle.

Again, the size indicates the number of observations.Supplemental materialLatent class analysisTo cluster phenotypes and relate those to the genotypes of the patients, an explorative analysis was done using LCA in R (R V.3.6.1 for Mac. Polytomous variable LCA, poLCA V.1.4.1.). We used our LCA to detect the number of phenotypic subgroups in the dataset and subsequently predict a class membership for each case in the dataset based on the posterior probabilities.In order to make a reliable prediction, only phenotypes that were sufficiently reported and/or ruled out were feasible for LCA, limiting the analysis to preaxial polydactyly, postaxial polydactyly and syndactyly of the hands and feet.

Only full cases were included. To determine the optimal number of classes, we fitted a series of models ranging from a one-class to a six-class model. The optimal number of classes was based on the conditional Akaike information criterion (cAIC), the non adjusted and the sample-size adjusted Bayesian information criterion (BIC and aBIC) and the obtained entropy.25 The explorative LCA produces both posterior probabilities per case for both classes and predicted class membership.

Using the predicted class membership, the phenotypic features per class were determined in a univariate analysis (χ2, SPSS V.25). Using the posterior probabilities on latent class (LC) membership, a scatter plot was created using the location of the variant on the x-axis and the probability of class membership on the y-axis for each of the types of variants (Tibco Spotfire V.7.14). Using these scatter plots, variants that give similar phenotypes were clustered.Genotype/phenotype correlationBecause an LC has no clinical value, the correlation between genotypes and phenotypes was investigated using the predictor phenotypes and the clustered phenotypes.

First, those phenotypes that contribute most to LC membership were identified. Second those phenotypes were directly related to the different types of variants (missense, nonsense, frameshift, splice site) and their clustered locations. Quantification of the relation was performed using a univariate analysis using a χ2 test.

Because of our selection criteria, meaning patients at least have two phenotypes, a multivariate using a logistic regression analysis was used to detect the most significant predictors in the overall phenotype (SPSS V.25). Finally, we explored the relation of the clustered genotypes to the presence of corpus callosum agenesis, a rare malformation in GLI3-mediated polydactyly syndromes which cannot be readily diagnosed without additional imaging.ResultsWe included 251 patients from the literature and 46 local patients,10–12 16 21 26–43 in total 297 patients from 155 different families with 127 different GLI3 variants, 32 of which were large deletions, CNVs or translocations. In six local cases, the exact variant could not be retrieved by status research.The distribution of the most frequently observed phenotypes and variants are presented in table 1.

Other recurring phenotypes included developmental delay (n=22), broad nasal root (n=23), frontal bossing or prominent forehead (n=16) and craniosynostosis (n=13), camptodactyly (n=8) and a broad first interdigital webspace of the foot (n=6).View this table:Table 1 Baseline phenotypes and genotypes of selected populationThe LCA model was fitted using the six defined hand/foot phenotypes. Model fit indices for the LCA are displayed in table 2. Based on the BIC, a two-class model has the best fit for our data.

The four-class model does show a gain in entropy, however with a higher BIC and loss of df. Therefore, based on the majority of performance statistics and the interpretability of the model, a two-class model was chosen. Table 3 displays the distribution of phenotypes and genotypes over the two classes.View this table:Table 2 Model fit indices for the one-class through six-class model evaluated in our LCAView this table:Table 3 Distribution of phenotypes and genotypes in the two latent classes (LC)Table 1 depicts the baseline phenotypes and genotypes in the obtained population.

Note incomplete data especially in the cranium phenotypes. In total 259 valid genotypes were present. In total, 289 cases had complete data for all hand and foot phenotypes (preaxial polydactyly, postaxial polydactyly and syndactyly) and thus were available for LCA.

Combined, for phenotype/genotype correlation 258 cases were available with complete genotypes and complete hand and foot phenotypes.Table 2 depicts the model fit indices for all models that have been fitted to our data.Table 3 depicts the distribution of phenotypes and genotypes over the two assigned LCs. Hand and foot phenotypes were used as input for the LCA, thus are all complete cases. Malformation of the cranium and genotypes do have missing cases.

Note that for the LCA, full case description was required, resulting in eight cases due to incomplete phenotypes. Out of these eight, one also had a genotype that thus needed to be excluded. Missingness of genotypic data was higher in LC2, mostly due to CNVs (table 1).In 54/60 cases, a missense variant produced a posterior phenotype.

Likewise, splice site variants show the same phenotype in 23/24 cases (table 3). For both frameshift and nonsense variants, this relation is not significant (52 anterior vs 54 posterior and 26 anterior vs 42 posterior, respectively). Therefore, only for nonsense and frameshift variants the location of the variant was plotted against the probability for LC2 membership in figure 1.

A full scatterplot of all variants is available in online supplementary figure 1.Figure 1 reveals a pattern for these nonsense and frameshift variants that reveals that variants at the C-terminal of the gene predict anterior phenotypes. When relating the domains of the GLI3 protein to the observed phenotype, we observe that the majority of patients with a nonsense or frameshift variant in the repressor domain, the zinc finger domain or the cleavage site had a high probability of an LC2/anterior phenotype. This group contains all variants that are either experimentally determined to be subject to NMD (triangle marker in figure 1) or predicted to be subject to NMD (diamond marker in figure 1).

Frameshift and nonsense variants in the activator domain result in high probability for an LC1/posterior phenotype. These variants will be further referred to as truncating variants in the activator domain.The univariate relation of the individual phenotypes to these two groups of variants are estimated and presented in table 4. In our multivariate analysis, postaxial polydactyly of the foot and hand are the strongest predictors (Beta.

2.548, p<0001 and Beta. 1.47, p=0.013, respectively) for patients to have a truncating variant in the activator domain. Moreover, the effect sizes of preaxial polydactyly of the hand and feet (Beta.

ˆ’0.797, p=0123 and −1.772, p=0.001) reveals that especially postaxial polydactyly of the foot is the dominant predictor for the genetic substrate of the observed anomalies.View this table:Table 4 Univariate and multivariate analysis of the phenotype/genotype correlationTable 4 shows exploration of the individual phenotypes on the genotype, both univariate and multivariate. The multivariate analysis corrects for the presence of multiple phenotypes in the underlying population.Although the craniofacial anomalies could not be included in the LCA, the relation between the observed anomalies and the identified genetic substrates can be studied. The prevalence of hypertelorism was equally distributed over the two groups of variants (47/135 vs 21/47 respectively, p<0.229).

However for corpus callosum agenesis and macrocephaly, there was a higher prevalence in patients with a truncating variant in the activator domain (3/75 vs 11/41, p<0.001. OR. 8.8, p<0.001) and 42/123 vs 24/48, p<0.05).

Noteworthy is the fact that 11/14 cases with corpus callosum agenesis in the dataset had a truncating variant in the activator domain.DiscussionIn this report, we present new insights into the correlation between the phenotype and the genotype in patients with GLI3-mediated polydactyly syndromes. We illustrate that there are two LCs of patients, best predicted by postaxial polydactyly of the hand and foot for LC1, and the preaxial polydactyly of the hand and foot and syndactyly of the foot for LC2. Patients with postaxial phenotypes have a higher risk of having a truncating variant in the activator domain of the GLI3 gene which is also related to a higher risk of corpus callosum agenesis.

These results suggest a functional difference between truncating variants on the N-terminal and the C-terminal side of the GLI3 cleavage site.Previous attempts of phenotype to genotype correlation have not yet provided the clinical confirmation of these assumed mechanisms in the pathophysiology of GLI3-mediated polydactyly syndromes. Johnston et al have successfully determined the Pallister-Hall region in which truncating variants produce a Pallister-Hall phenotype rather than Greig syndrome.11 However, in their latest population study, subtypes of both syndromes were included to explain the full spectrum of observed malformations. In 2015, Demurger et al reported the higher incidence of corpus callosum agenesis in the Greig syndrome population with truncating mutations in the activator domain.12 Al-Qattan in his review summarises the concept of a spectrum of anomalies dependent on haplo-insufficiency (through different mechanisms) and repressor overexpression.13 However, he bases this theory mainly on reviewed experimental data.

Our report is the first to provide an extensive clinical review of cases that substantiate the phenotypic difference between the two groups that could fit the suggested mechanisms. We agree with Al-Qattan et al that a variation of anomalies can be observed given any pathogenic variant in the GLI3 gene, but overall two dominant phenotypes are present. A population with predominantly preaxial anomalies and one with postaxial anomalies.

The presence of preaxial or postaxial polydactyly and syndactyly is not mutually exclusive for one of these two subclasses. Meaning that preaxial polydactyly can co-occur with postaxial polydactyly. However, truncating mutations in the activator domain produce a postaxial phenotype, as can be derived from the risk in table 4.

The higher risk of corpus callosum agenesis in this population shows that differentiating between a preaxial phenotype and a postaxial phenotype, instead of between the different GLI3-mediated polydactyly syndromes, might be more relevant regarding diagnostics for corpus callosum agenesis.We chose to use LCA as an exploratory tool only in our population for two reasons. First of all, LCA can be useful to identify subgroups, but there is no ‘true’ model or number of subgroups you can detect. The best fitting model can only be estimated based on the available measures and approximates the true subgroups that might be present.

Second, LC membership assignment is a statistical procedure based on the posterior probability, with concordant errors of the estimation, rather than a clinical value that can be measured or evaluated. Therefore, we decided to use our LCA only in an exploratory tool, and perform our statistics using the actual phenotypes that predict LC membership and the associated genotypes. Overall, this method worked well to differentiate the two subgroups present in our dataset.

However, outliers were observed. A qualitative analysis of these outliers is available in the online supplementary data.The genetic substrate for the two phenotypic clusters can be discussed based on multiple experiments. Overall, we hypothesise two genetic clusters.

One that is due to haploinsufficiency and one that is due to abnormal truncation of the activator. The hypothesised cluster of variants that produce haploinsufficiency is mainly based on the experimental data that confirms NMD in two variants and the NMD prediction of other nonsense variants in Alamut. For the frameshift variants, it is also likely that the cleavage of the zinc finger domain results in functional haploinsufficiency either because of a lack of signalling domains or similarly due to NMD.

Missense variants could cause haploinsufficiency through the suggested mechanism by Krauss et al who have illustrated that missense variants in the MID1 domain hamper the functional interaction with the MID1-α4-PP2A complex, leading to a subcellular location of GLI3.24 The observed missense variants in our study exceed the region to which Krauss et al have limited the MID-1 interaction domain. An alternative theory is suggested by Zhou et al who have shown that missense variants in the MBD can cause deficiency in the signalling of GLI3A, functionally implicating a relative overexpression of GLI3R.22 However, GLI3R overexpression would likely produce a posterior phenotype, as determined by Hill et al in their fixed homo and hemizygous GLI3R models.15 Therefore, our hypothesis is that all included missense variants have a similar pathogenesis which is more likely in concordance with the mechanism introduced by Krauss et al. To our knowledge, no splice site variants have been functionally described in literature.

However, it is noted that the 15 and last exon encompasses the entire activator domain, thus any splice site mutation is by definition located on the 5′ side of the activator. Based on the phenotype, we would suggest that these variants fail to produce a functional protein. We hypothesise that the truncating variants of the activator domain lead to overexpression of GLI3R in SHH rich areas.

In normal development, the presence of SHH prevents the processing of full length GLI34 into GLI3R, thus producing the full length activator. In patients with a truncating variant of the activator domain of GLI3, thus these variants likely have the largest effect in SHH rich areas, such as the ZPA located at the posterior side of the hand/footplate. Moreover, the lack of posterior anomalies in the GLI3∆699/- mouse model (hemizygous fixed repressor model) compared with the GLI3∆699/∆699 mouse model (homozygous fixed repressor model), suggesting a dosage effect of GLI3R to be responsible for posterior hand anomalies.15 These findings are supported by Lewandowski et al, who show that the majority of the target genes in GLI signalling are regulated by GLI3R rather than GLI3A.44 Together, these findings suggest a role for the location and type of variant in GLI3-mediated syndromes.Interestingly, the difference between Pallister-Hall syndrome and GLI3-mediated polydactyly syndromes has also been attributed to the GLI3R overexpression.

However, the difference in phenotype observed in the cases with a truncating variant in the activator domain and Pallister-Hall syndrome suggest different functional consequences. When studying figure 1, it is noted that the included truncating variants on the 3′ side of the cleavage site seldomly affect the CBP binding region, which could provide an explanation for the observed differences. This binding region is included in the Pallister-Hall region as defined by Johnston et al and is necessary for the downstream signalling with GLI1.10 11 23 45 Interestingly, recent reports show that pathogenic variants in GLI1 can produce phenotypes concordant with Ellis von Krefeld syndrome, which includes overlapping features with Pallister-Hall syndrome.46 The four truncating variants observed in this study that do affect the CBP but did not result in a Pallister-Hall phenotype are conflicting with this theory.

Krauss et al postulate an alternative hypothesis, they state that the MID1-α4-PP2A complex, which is essential for GLI3A signalling, could also be the reason for overlapping features of Opitz syndrome, caused by variants in MID1, and Pallister-Hall syndrome. Further analysis is required to fully appreciate the functional differences between truncating mutations that cause Pallister-Hall syndrome and those that result in GLI3-mediated polydactyly syndromes.For the clinical evaluation of patients with GLI3-mediated polydactyly syndromes, intracranial anomalies are likely the most important to predict based on the variant. Unfortunately, the presence of corpus callosum agenesis was not routinely investigated or reported thus this feature could not be used as an indicator phenotype for LC membership.

Interestingly when using only hand and foot phenotypes, we did notice a higher prevalence of corpus callosum agenesis in patients with posterior phenotypes. The suggested relation between truncating mutations in the activator domain causing these posterior phenotypes and corpus callosum agenesis was statistically confirmed (OR. 8.8, p<0.001).

Functionally this relation could be caused by the GLI3-MED12 interaction at the MBD. Pathogenic DNA variants in MED12 can cause Opitz-Kaveggia syndrome, a syndrome in which presentation includes corpus callosum agenesis, broad halluces and thumbs.47In conclusion, there are two distinct phenotypes within the GLI3-mediated polydactyly population. Patients with more posteriorly and more anteriorly oriented hand anomalies.

Furthermore, this difference is related to the observed variant in GLI3. We hypothesise that variants that cause haploinsufficiency produce anterior anomalies of the hand, whereas variants with abnormal truncation of the activator domain have more posterior anomalies. Furthermore, patients that have a variant that produces abnormal truncation of the activator domain, have a greater risk for corpus callosum agenesis.

Thus, we advocate to differentiate preaxial or postaxial oriented GLI3 phenotypes to explain the pathophysiology as well as to get a risk assessment for corpus callosum agenesis.Data availability statementData are available upon reasonable request.Ethics statementsPatient consent for publicationNot required.Ethics approvalThe research protocol was approved by the local ethics board of the Erasmus MC University Medical Center (MEC 2015-679)..

Cetyl alcohol and antabuse

Now that I’m the age she was then, I just as often go looking for my glasses for several Buy zithromax online next day delivery minutes before I realize they’re propped on my head.“Senior moments” frighten me, as I’m still earning my living cetyl alcohol and antabuse in a brain-tasking field. It’s even worse if dementia runs in your family. As we age, connections between cells in the brain are damaged, or some cells are lost—a process that has scarily been called “brain atrophy” or simply “cognitive decline.” And it’s quite clear that hearing loss, at the very least, puts you at increased risk of cognitive impairment as you get older.

How does dementia affect hearing? cetyl alcohol and antabuse. Many studies have found an association between untreated hearing loss, Alzheimer's disease and other types of dementia. Meaning, people with hearing loss are more likely to develop cognitive problems than people who do not have hearing loss.

This is an area of intense research cetyl alcohol and antabuse with many unanswered questions. For example, we still don’t know yet if hearing loss causes dementia, or vice versa. Researchers are also not sure if hearing aids can prevent or reverse cognitive decline, though early data looks promising, especially when it comes to delaying the onset of dementia.

Clinical trials currently underway cetyl alcohol and antabuse on this topic will provide more clarity in the next few years. Hearing loss can mimic cognitive decline Don’t assume you’re suffering from dementia if you’re having trouble understanding speech, or finding it exhausting to have simple conversations. Hearing loss has some of the same symptoms as cognitive impairment, so it’s vital to have regular hearing checks.

More. 'I thought I had cognitive decline, but it was hearing loss' If you do have confirmed hearing loss, though, it’s important to know you are at higher risk of developing dementia. Take as many preventative steps as possible, such as healthy lifestyle choices, wearing hearing aids taking medications as recommended, and staying active and socially engaged (hearing aids help!.

). How hearing loss may change the brain Hearing loss does seem to shrink some parts of the brain responsible for auditory response. In a study led by Jonathan Peelle, now at Washington University in St.

Louis, older adults underwent brain scans while they listened to sentences of varying complexity. They also took tests that measured “gray matter,” the regions of the brain involved in muscle control, and sensory perception such as seeing and hearing, memory, emotions, speech, decision making, and self-control. It turned out that the neurons (brain cells) in people with hearing loss were less active when they focused on complex sentences.

They also had less gray matter in the auditory areas. These effects may accumulate with time or be triggered by age. In other research, Peelle found that older adults with hearing loss do worse on speech comprehension tasks than younger adults with hearing loss.

What research on dementia and hearing loss reveals Several studies indicate that people with hearing loss may develop cognitive decline earlier than peers with normal hearing. A team at Johns Hopkins looked at cognitive impairment scores over six years in a study of nearly 2,000 seniors. They concluded that those with hearing loss had a faster decline.

The volunteers were all cognitively normal when the research began. But by the study’s end, people with hearing loss were 24 percent more likely to meet the standard of cognitive “impairment” compared to people with normal hearing. Another approach is to ask people whether they’ve noticed a change.

Measures of “subjective” decline can pick up losses before they’ll show up on a test. A recent and large study—using data drawn from more than 10,000 men age 62 and up—ran over eight years. It found that the greater their hearing loss, the more likely men were to express concerns about their memory or thinking over time.

With even a mild hearing loss, their chance of reporting cognitive decline was 30 percent higher than among those who did not report any hearing loss. With moderate or severe hearing loss, the risk was 42 and 52 percent higher. (At age 80 or above, moderate hearing loss is more common than mild hearing loss.) Dr.

Sharon Curhan, a doctor and epidemiologist at Brigham and Women’s Hospital in Boston, who led this study, said she plans further research with women and younger populations. Lastly, a Salt Lake City team found that among nearly 4,500 seniors without dementia, 16.3 percent of those with hearing loss developed dementia compared to 12.1 percent of those with normal hearing. It also tended to occur faster in people with hearing loss.

On average, it took a bit over a decade to develop dementia among the group with hearing loss, and 12 years if your hearing was fine. More. Slight hearing loss linked to cognitive decline in new study What about tinnitus and Alzheimer's?.

Alzheimer's disease is slightly more common among people who have tinnitus than people who don't, at least one study has indicated. In that study, conducted in Taiwan, 3.1% of tinnitus patients developed Alzheimer's over a 10-year period, compared to 2% of those who did not have tinnitus. However, scientists do not know why this relationship exists, and more research is needed.

Do hearing aids reverse cognitive decline?. Dr. Curhan’s research didn’t get a clear answer to this question.

Among volunteers with severe hearing loss, those who wore hearing aids had a slightly lower risk of subsequent subjective cognitive than those who didn’t. But the effect was too small to be statistically significant. Because they keep you connected withothers, hearing aids can help preventsocial isolation.

She would like to see hearing aids and cognitive decline get a hard look. There isn’t much evidence over long periods of time and what we have isn’t conclusive, she notes. €œSeveral studies have found no relation between hearing aid use and cognitive function decline, while others have been suggestive of a possible association,” she told Healthy Hearing.

€œThis relation merits further study.” One recent and very large observational study did shed more light on this issue, finding that hearing aids appeared to delay the onset of cognitive impairment and dementia, along with depression and falls that cause injuries. However, it was not a randomized controlled trial, so the results could have been for other reasons (for example, hearing aid wearers have higher incomes and thus more access to good medical care). As well, one large 2018 study analyzed results from more than 2,000 Americans age 50 and up who took word recall tests every two years for up to 18 years.

Among those who acquired hearing aids along the way, the evidence suggested that the aids slowed the rate they lost memory of words. Personally, I’m grateful I have my hearing aids as they help keep me connected with loved ones and friends. My father, a retired statistician who hasn’t lost a single marble, isn’t fond of wearing his.

To nudge him, I go so far as to mention the research. €œDad, I just saw some interesting numbers. Did you know that hearing aids may prevent falls and cognitive loss?.

€ His answer, “Do they do it from the drawer?. € More. Health benefits of hearing aids What are the best hearing aids for dementia?.

For patients living with both dementia, hearing loss should never be ignored, as it may be exacerbating dementia symptoms, increase their disorientation and make their environment less safe (they can't hear a running faucet, for example). While there are no hearing products made specifically for dementia patients, there are plenty of devices out there that can still be helpful. They range from the relatively simple, such as a wearable microphone (known as a "pocket talker") to premium hearing aids.

Hearing loss makes living with diseases like Alzheimer's even more challenging. For people currently affected by dementia, hearing aids or other hearing devices are recommended to improve their quality of life and make communication easier. If you are the caretaker of someone with Alzheimer's or a similar disease that affects cognition, you are wise to investigate what hearing devices might work best.

A hearing care provider will be your ally in this journey, as they'll know the latest products that may work for your loved one. You'll also be able to discuss your loved one's specific needs, habits and abilities with the hearing care specialist. For example, hearing aids may not always be the best solution.

Most premium hearing aids are designed to be discreet, so they may be too small and too easy to lose for a patient with dementia, especially if they have dexterity problems. Hearing aids also require that a person (or their caretaker) remember to keep the batteries fresh and the device clean and in good working condition. Instead, assistive listening devices may work better.

If you need help with hearing loss If you're noticing trouble hearing in yourself or a loved one, don't delay—prompt treatment can help you or your loved one stay engaged in the world and avoid social isolation, a common problem for people with untreated hearing loss. Hearing loss is exhausting, but it doesn't have to be. To find a hearing care professional, see our directory of consumer-reviewed hearing clinics to find a hearing specialist or audiologist near you.Pregnancy is a wonderful time for many women, but most of us would agree the side effects can be exhausting.

For some unlucky women, this includes tinnitus and more rarely, hearing loss.Tinnitus, which is a fancy way of saying ringing in the ears, affects roughly 1 in 3 women during pregnancy. It affects approximately 1 in 10 women who aren't pregnant. Most of the time tinnitus is harmless, but it can be an important warning sign that something more serious is going on.

Causes of tinnitus and hearing loss during pregnancy Why are these changes in hearing so common?. Normal hormonal and circulatory changes during pregnancy are largely to blame. Less commonly, tinnitus and hearing impairments during pregnancy may be due to several medical causes, including high blood pressure, migraines/headaches, anemia, ear and sinus s, stress and poor sleep, and earwax blockage.

Below, we discuss these causes in more detail. Note. If you're pregnant and experiencing tinnitus or other hearing problems, talk to your medical provider as some causes require prompt medical care.

High blood pressure High blood pressure can lead to hearing loss and tinnitus because our delicate inner ears are highly sensitive to any changes in blood flow. High blood pressure is an especially dangerous condition during pregnancy, so it’s something you should take seriously and monitor. In pregnant women, high blood pressure can indicate preeclampsia or the more rare HELLP syndrome, both of which can escalate into medical emergencies for both mom and baby.

Preeclampsia and related conditions affect between 3 and 10% of pregnancies. While tinnitus and muffled hearing doesn't affect all pregnant women with high blood pressure, it's still considered a red flag. What does it sound like?.

For some pregnant women, the tinnitus may match the rhythm of their pulse or heartbeat, known as pulsatile tinnitus. Some women report that their hearing feels muffled and they hear a loud whooshing sound. With so many blood vessels near the ears, it’s no wonder tinnitus is a sign of elevated blood pressure.

Even if you don't have a history of high blood pressure, pregnancy can trigger it in healthy women. It's vital to have it monitored and treated properly by a knowledgeable pregnancy care provider. Iron-deficiency anemia Pregnant women are at elevated risk of developing iron-deficiency anemia.

(Iron helps red blood cells carry oxygen to the body, including the auditory system.) If you don't get enough iron in your diet while pregnant, you may experience a range of symptoms, including hearing problems. Studies show that anemia and hearing impairment, including tinnitus, are linked—though the relationship isn't well understood and the research was conducted on older adults. If your pregnant, make sure your prenatal vitamin has sufficient iron because your body will need approximately twice as much iron as it did in your pre-pregnancy days.

Try focusing on eating iron-rich foods as well to see if that helps decrease the ringing you’re hearing. Some great foods to include are spinach, legumes, turkey, red meat, broccoli and the occasional treat of dark chocolate. Headaches or migraines If you’re prone to getting headaches, you could be at increased risk for developing tinnitus or hearing problems (including sound sensitivity, known as hyperacusis) when you’re pregnant.

It doesn’t help that pregnancy can trigger more frequent headaches. If you suffer from migraines, and pregnancy is making that condition worse, you may find that you have hearing loss, tinnitus or muffled hearing that comes on or gets worse during your migraines. If you frequently get headaches or migraines during pregnancy, you should mention it to your doctor.

They can go over your treatment options with you, while carefully weighing the risk to your unborn baby. Colds that lead to sinus or ear s Pregnancy isn’t just hard on you, it’s also tough on your immune system. Your immune system is temporarily suppressed while you’re pregnant.

That can mean more colds and antabusees for you. It also might mean more allergy symptoms. The risk of getting colds is that they can cause sinus or middle ear s.

Those s can cause temporary hearing issues and may require treatment. To avoid catching colds and other antabusees while pregnant, you should focus on making healthy food choices, taking your prenatal vitamin every day, getting enough sleep, and staying away from people who are obviously sick. It’s always better to prevent something than it is to try to treat it.

Earwax Even if we think of it as gross, earwax can keep your ears safe from things like microorganisms and dust. But it can also backfire on you. Too much earwax can lead to hearing loss and tinnitus.

If an earwax blockage happens, you might notice hearing loss that won’t improve until the excess wax is removed. You can try using earwax removal drops at home, or you can let your doctor remove the excess by using a little instrument called a curette. Fortunately, this is usually a simple problem to fix.

Stress and poor sleep Pregnancy can be extremely stressful, especially when you throw the anxiety over a worldwide antabuse into the mix. Hearing loss and chronic stress are linked, especially when stress is causing physical problems like high blood pressure. If you have a history of tinnitus, it also may be aggravated because you feel stressed all the time and aren't getting enough sleep.

It can be difficult to relax when you’re planning for a baby, but you may benefit from going for a walk outside, doing some meditation exercises, practicing deep breathing or getting a massage. More. Issues with your bite TMJ disorder (jaw clicking and pain) is more common among pregnant women, due to hormonal changes, swelling, stress and other factors.

It’s hard to believe that tinnitus can be caused by dental issues, but it’s true. Problems relating to the jaw joint can cause tinnitus or a feeling of clogged ears because an imbalance in the joint results in pressure in the ear. If you suspect this may be an issue for you, it might be a good idea to see a dentist if all other medical reasons have been ruled out.

A simple oral device can lead to better alignment, which may improve your tinnitus and potentially improve the feeling of clogged ears. Discuss your symptoms with your provider Temporary hearing loss and tinnitus can be a big challenge when you’re pregnant. You worry that something is going horribly wrong and wonder how you’re going to function when you’re not hearing your best.

It’s even worse if can you get antabuse without a prescription dementia runs in your family. As we age, connections between cells in the brain are damaged, or some cells are lost—a process that has scarily been called “brain atrophy” or simply “cognitive decline.” And it’s quite clear that hearing loss, at the very least, puts you at increased risk of cognitive impairment as you get older. How does dementia affect hearing?. Many studies have can you get antabuse without a prescription found an association between untreated hearing loss, Alzheimer's disease and other types of dementia.

Meaning, people with hearing loss are more likely to develop cognitive problems than people who do not have hearing loss. This is an area of intense research with many unanswered questions. For example, can you get antabuse without a prescription we still don’t know yet if hearing loss causes dementia, or vice versa. Researchers are also not sure if hearing aids can prevent or reverse cognitive decline, though early data looks promising, especially when it comes to delaying the onset of dementia.

Clinical trials currently underway on this topic will provide more clarity in the next few years. Hearing loss can mimic cognitive decline Don’t assume you’re suffering from dementia if you’re having trouble understanding speech, or finding it exhausting can you get antabuse without a prescription to have simple conversations. Hearing loss has some of the same symptoms as cognitive impairment, so it’s vital to have regular hearing checks. More.

'I thought I had cognitive can you get antabuse without a prescription decline, but it was hearing loss' If you do have confirmed hearing loss, though, it’s important to know you are at higher risk of developing dementia. Take as many preventative steps as possible, such as healthy lifestyle choices, wearing hearing aids taking medications as recommended, and staying active and socially engaged (hearing aids help!. ). How hearing loss may change the brain Hearing loss does seem to shrink some parts of the brain responsible for auditory response can you get antabuse without a prescription.

In a study led by Jonathan Peelle, now at Washington University in St. Louis, older adults underwent brain scans while they listened to sentences of varying complexity. They also took tests that measured “gray matter,” the regions of the brain involved in muscle control, and sensory perception such as can you get antabuse without a prescription seeing and hearing, memory, emotions, speech, decision making, and self-control. It turned out that the neurons (brain cells) in people with hearing loss were less active when they focused on complex sentences.

They also had less gray matter in the auditory areas. These effects may accumulate with time or be can you get antabuse without a prescription triggered by age. In other research, Peelle found that older adults with hearing loss do worse on speech comprehension tasks than younger adults with hearing loss. What research on dementia and hearing loss reveals Several studies indicate that people with hearing loss may develop cognitive decline earlier than peers with normal hearing.

A team at can you get antabuse without a prescription Johns Hopkins looked at cognitive impairment scores over six years in a study of nearly 2,000 seniors. They concluded that those with hearing loss had a faster decline. The volunteers were all cognitively normal when the research began. But by the study’s end, people with hearing loss were 24 percent more likely to meet the standard of cognitive “impairment” compared to people with normal can you get antabuse without a prescription hearing.

Another approach is to ask people whether they’ve noticed a change. Measures of “subjective” decline can pick up losses before they’ll show up on a test. A recent and large study—using data drawn from more than 10,000 men age can you get antabuse without a prescription 62 and up—ran over eight years. It found that the greater their hearing loss, the more likely men were to express concerns about their memory or thinking over time.

With even a mild hearing loss, their chance of reporting cognitive decline was 30 percent higher than among those who did not report any hearing loss. With moderate or severe hearing can you get antabuse without a prescription loss, the risk was 42 and 52 percent higher. (At age 80 or above, moderate hearing loss is more common than mild hearing loss.) Dr. Sharon Curhan, a doctor and epidemiologist at Brigham and Women’s Hospital in Boston, who led this study, said she plans further research with women and younger populations.

Lastly, a Salt Lake City team found that among nearly 4,500 seniors without dementia, 16.3 percent of those with can you get antabuse without a prescription hearing loss developed dementia compared to 12.1 percent of those with normal hearing. It also tended to occur faster in people with hearing loss. On average, it took a bit over a decade to develop dementia among the group with hearing loss, and 12 years if your hearing was fine. More.

Slight hearing loss linked to cognitive decline in new study What about tinnitus and Alzheimer's?. Alzheimer's disease is slightly more common among people who have tinnitus than people who don't, at least one study has indicated. In that study, conducted in Taiwan, 3.1% of tinnitus patients developed Alzheimer's over a 10-year period, compared to 2% of those who did not have tinnitus. However, scientists do not know why this relationship exists, and more research is needed.

Do hearing aids reverse cognitive decline?. Dr. Curhan’s research didn’t get a clear answer to this question. Among volunteers with severe hearing loss, those who wore hearing aids had a slightly lower risk of subsequent subjective cognitive than those who didn’t.

But the effect was too small to be statistically significant. Because they keep you connected withothers, hearing aids can help preventsocial isolation. She would like to see hearing aids and cognitive decline get a hard look. There isn’t much evidence over long periods of time and what we have isn’t conclusive, she notes.

€œSeveral studies have found no relation between hearing aid use and cognitive function decline, while others have been suggestive of a possible association,” she told Healthy Hearing. €œThis relation merits further study.” One recent and very large observational study did shed more light on this issue, finding that hearing aids appeared to delay the onset of cognitive impairment and dementia, along with depression and falls that cause injuries. However, it was not a randomized controlled trial, so the results could have been for other reasons (for example, hearing aid wearers have higher incomes and thus more access to good medical care). As well, one large 2018 study analyzed results from more than 2,000 Americans age 50 and up who took word recall tests every two years for up to 18 years.

Among those who acquired hearing aids along the way, the evidence suggested that the aids slowed the rate they lost memory of words. Personally, I’m grateful I have my hearing aids as they help keep me connected with loved ones and friends. My father, a retired statistician who hasn’t lost a single marble, isn’t fond of wearing his. To nudge him, I go so far as to mention the research.

€œDad, I just saw some interesting numbers. Did you know that hearing aids may prevent falls and cognitive loss?. € His answer, “Do they do it from the drawer?. € More.

Health benefits of hearing aids What are the best hearing aids for dementia?. For patients living with both dementia, hearing loss should never be ignored, as it may be exacerbating dementia symptoms, increase their disorientation and make their environment less safe (they can't hear a running faucet, for example). While there are no hearing products made specifically for dementia patients, there are plenty of devices out there that can still be helpful. They range from the relatively simple, such as a wearable microphone (known as a "pocket talker") to premium hearing aids.

Hearing loss makes living with diseases like Alzheimer's even more challenging. For people currently affected by dementia, hearing aids or other hearing devices are recommended to improve their quality of life and make communication easier. If you are the caretaker of someone with Alzheimer's or a similar disease that affects cognition, you are wise to investigate what hearing devices might work best. A hearing care provider will be your ally in this journey, as they'll know the latest products that may work for your loved one.

You'll also be able to discuss your loved one's specific needs, habits and abilities with the hearing care specialist. For example, hearing aids may not always be the best solution. Most premium hearing aids are designed to be discreet, so they may be too small and too easy to lose for a patient with dementia, especially if they have dexterity problems. Hearing aids also require that a person (or their caretaker) remember to keep the batteries fresh and the device clean and in good working condition.

Instead, assistive listening devices may work better. If you need help with hearing loss If you're noticing trouble hearing in yourself or a loved one, don't delay—prompt treatment can help you or your loved one stay engaged in the world and avoid social isolation, a common problem for people with untreated hearing loss. Hearing loss is exhausting, but it doesn't have to be. To find a hearing care professional, see our directory of consumer-reviewed hearing clinics to find a hearing specialist or audiologist near you.Pregnancy is a wonderful time for many women, but most of us would agree the side effects can be exhausting.

For some unlucky women, this includes tinnitus and more rarely, hearing loss.Tinnitus, which is a fancy way of saying ringing in the ears, affects roughly 1 in 3 women during pregnancy. It affects approximately 1 in 10 women who aren't pregnant. Most of the time tinnitus is harmless, but it can be an important warning sign that something more serious is going on. Causes of tinnitus and hearing loss during pregnancy Why are these changes in hearing so common?.

Normal hormonal and circulatory changes during pregnancy are largely to blame. Less commonly, tinnitus and hearing impairments during pregnancy may be due to several medical causes, including high blood pressure, migraines/headaches, anemia, ear and sinus s, stress and poor sleep, and earwax blockage. Below, we discuss these causes in more detail. Note.

If you're pregnant and experiencing tinnitus or other hearing problems, talk to your medical provider as some causes require prompt medical care. High blood pressure High blood pressure can lead to hearing loss and tinnitus because our delicate inner ears are highly sensitive to any changes in blood flow. High blood pressure is an especially dangerous condition during pregnancy, so it’s something you should take seriously and monitor. In pregnant women, high blood pressure can indicate preeclampsia or the more rare HELLP syndrome, both of which can escalate into medical emergencies for both mom and baby.

Preeclampsia and related conditions affect between 3 and 10% of pregnancies. While tinnitus and muffled hearing doesn't affect all pregnant women with high blood pressure, it's still considered a red flag. What does it sound like?. For some pregnant women, the tinnitus may match the rhythm of their pulse or heartbeat, known as pulsatile tinnitus.

Some women report that their hearing feels muffled and they hear a loud whooshing sound. With so many blood vessels near the ears, it’s no wonder tinnitus is a sign of elevated blood pressure. Even if you don't have a history of high blood pressure, pregnancy can trigger it in healthy women. It's vital to have it monitored and treated properly by a knowledgeable pregnancy care provider.

Iron-deficiency anemia Pregnant women are at elevated risk of developing iron-deficiency anemia. (Iron helps red blood cells carry oxygen to the body, including the auditory system.) If you don't get enough iron in your diet while pregnant, you may experience a range of symptoms, including hearing problems. Studies show that anemia and hearing impairment, including tinnitus, are linked—though the relationship isn't well understood and the research was conducted on older adults. If your pregnant, make sure your prenatal vitamin has sufficient iron because your body will need approximately twice as much iron as it did in your pre-pregnancy days.

Try focusing on eating iron-rich foods as well to see if that helps decrease the ringing you’re hearing. Some great foods to include are spinach, legumes, turkey, red meat, broccoli and the occasional treat of dark chocolate. Headaches or migraines If you’re prone to getting headaches, you could be at increased risk for developing tinnitus or hearing problems (including sound sensitivity, known as hyperacusis) when you’re pregnant. It doesn’t help that pregnancy can trigger more frequent headaches.

If you suffer from migraines, and pregnancy is making that condition worse, you may find that you have hearing loss, tinnitus or muffled hearing that comes on or gets worse during your migraines. If you frequently get headaches or migraines during pregnancy, you should mention it to your doctor. They can go over your treatment options with you, while carefully weighing the risk to your unborn baby. Colds that lead to sinus or ear s Pregnancy isn’t just hard on you, it’s also tough on your immune system.

Your immune system is temporarily suppressed while you’re pregnant. That can mean more colds and antabusees for you. It also might mean more allergy symptoms. The risk of getting colds is that they can cause sinus or middle ear s.

Those s can cause temporary hearing issues and may require treatment. To avoid catching colds and other antabusees while pregnant, you should focus on making healthy food choices, taking your prenatal vitamin every day, getting enough sleep, and staying away from people who are obviously sick. It’s always better to prevent something than it is to try to treat it. Earwax Even if we think of it as gross, earwax can keep your ears safe from things like microorganisms and dust.

But it can also backfire on you. Too much earwax can lead to hearing loss and tinnitus. If an earwax blockage happens, you might notice hearing loss that won’t improve until the excess wax is removed. You can try using earwax removal drops at home, or you can let your doctor remove the excess by using a little instrument called a curette.

Fortunately, this is usually a simple problem to fix. Stress and poor sleep Pregnancy can be extremely stressful, especially when you throw the anxiety over a worldwide antabuse into the mix. Hearing loss and chronic stress are linked, especially when stress is causing physical problems like high blood pressure. If you have a history of tinnitus, it also may be aggravated because you feel stressed all the time and aren't getting enough sleep.

It can be difficult to relax when you’re planning for a baby, but you may benefit from going for a walk outside, doing some meditation exercises, practicing deep breathing or getting a massage. More. Issues with your bite TMJ disorder (jaw clicking and pain) is more common among pregnant women, due to hormonal changes, swelling, stress and other factors. It’s hard to believe that tinnitus can be caused by dental issues, but it’s true.

Problems relating to the jaw joint can cause tinnitus or a feeling of clogged ears because an imbalance in the joint results in pressure in the ear. If you suspect this may be an issue for you, it might be a good idea to see a dentist if all other medical reasons have been ruled out. A simple oral device can lead to better alignment, which may improve your tinnitus and potentially improve the feeling of clogged ears. Discuss your symptoms with your provider Temporary hearing loss and tinnitus can be a big challenge when you’re pregnant.

You worry that something is going horribly wrong and wonder how you’re going to function when you’re not hearing your best. It's vital that you receive regular prenatal care and discuss your symptoms with your healthcare provider.

Drinking 24 hours after antabuse

Elon Musk on Friday unveiled a coin-sized prototype of a brain implant developed drinking 24 hours after antabuse by his startup Neuralink to enable people who are paralyzed to operate smartphones and robotic limbs with their thoughts — and said the company had worked to “dramatically simplify” the device since presenting an earlier version last summer.In an event live-streamed on YouTube to more than 150,000 viewers at one point, the company staged a demonstration in which it trotted out a pig named Gertrude that was said to have had the company’s device implanted in its head two months ago. The live stream showed what Musk claimed to be Gertrude’s real-time brain activity as it sniffed around a pen. At no point, though, did he provide evidence that the signals — rendered in beeps and bright blue wave patterns on screen — were, in fact, emanating from the pig’s brain.A pig presented at a Neuralink demonstration was said to have one drinking 24 hours after antabuse of the company’s brain implants in its head. YouTube screenshot“This is obviously sounding increasingly like a Black Mirror episode,” Musk said at one point during the event as he responded affirmatively to a question about whether the company’s implant could eventually be used to save and replay memories. €œThe future’s going to be weird.”advertisement Musk drinking 24 hours after antabuse said that in July Neuralink received a breakthrough device designation from the Food and Drug Administration — a regulatory pathway that could allow the company to soon start a clinical trial in people with paraplegia and tetraplegia.

The big reveal came after four former Neuralink employees told STAT that the company’s leaders have long fostered an internal culture characterized by rushed timelines and the “move fast and break things” ethos of a tech company — a pace sometimes at odds with the slow and incremental pace that’s typical of medical device development. Advertisement Friday’s event began, 40 minutes late, with drinking 24 hours after antabuse a glossy video about the company’s work — and then panned to Musk, standing in front of a blue curtain beside a gleaming new version of the company’s surgical “sewing machine” robot that could easily have been mistaken for a giant Apple device. Musk described the event as a “product demo” and said its primary purpose was to recruit potential new employees. It was unclear whether the demonstration was taking place at the company’s Fremont, Calif., headquarters or drinking 24 hours after antabuse elsewhere. Musk proceeded to reveal the new version of Neuralink’s brain implant, which he said was designed to fit snugly into the top of the skull.

Neuralink’s technological design has changed significantly drinking 24 hours after antabuse since its last big update in July 2019. At that time, the company’s brain implant system involved a credit-card sized device designed to be positioned behind the back of a person’s ear, with several wires stretching to the top of the skull. After demonstrating the pig’s brain activity at Friday’s event, Musk showed video footage of a pig walking on a treadmill and said Neuralink’s device could be used to “predict the position of limbs with high accuracy.” That capability would be critical to allowing someone drinking 24 hours after antabuse using the device to do something like controlling a prosthetic limb, for example.Neuralink for months has signaled that it initially plans to develop its device for people who are paralyzed. It said at its July 2019 event that it wanted to start human testing by the end of 2020. Receiving the breakthrough device designation drinking 24 hours after antabuse from the FDA — designed to speed up the lengthy regulatory process — is a step forward, but it by no means guarantees that a device will receive a green light, either in a short or longer-term time frame.

After Musk’s presentation, a handful of the company’s employees — all wearing masks, but seated only inches apart — joined him to take questions submitted on Twitter or from the small audience in the room.In typical fashion for a man who in 2018 sent a Tesla Roadster into space, Musk didn’t hesitate to use the event to cross-promote his electric car company. Asked whether drinking 24 hours after antabuse the Neuralink chip would allow people to summon their Tesla telepathically, Musk responded. €œDefinitely — of course.”Matthew MacDougall, the company’s head neurosurgeon, appearing in scrubs, said the company had so far only implanted its technology into the brain’s cortical surface, the coaster-width layer enveloping the brain, but added that it hoped to go deeper in the future. Still, Musk drinking 24 hours after antabuse said. €œYou could solve blindness, you could solve paralysis, you could solve hearing — you can solve a lot just by interfacing with the cortex.”Musk and MacDougall said they hoped to eventually implant Neuralink’s devices — which they referred to on stage simply as “links” — in the deeper structures of the brain, such as in the hypothalamus, which is believed to play a critical role in mental illnesses including depression, anxiety, and PTSD.There were no updates at the event of Neuralink’s research in monkeys, which the company has been conducting in partnership with the University of California, Davis since 2017.

At last July’s event, Musk said — without providing evidence — that a monkey had controlled a computer with its brain.At that same July 2019 event, Neuralink released a preprint paper — published a few months later — that claimed to show that a series of Neuralink electrodes implanted in drinking 24 hours after antabuse the brains of rats could record neural signals. Critically, the work did not show where in the brain the implanted electrodes were recording from, for how long they were recording, or whether the recordings could be linked to any of the rats’ bodily movements.In touting Friday’s event — and Neuralink’s technological capabilities — on Twitter in recent weeks, Musk spoke of “AI symbiosis while u wait” and referenced the “matrix in the matrix” — a science-fiction reference about revealing the true nature of reality. The progress the company reported on Friday fell far short of that drinking 24 hours after antabuse. Neuralink’s prototype is ambitious, but it has yet to show evidence that it can match up to the brain-machine interfaces developed by academic labs and other companies. Other groups have shown that they can listen in on neural activity and allow primates and people to control a computer cursor with their brain — so-called “read-out” technology — and have drinking 24 hours after antabuse also shown that they can use electrical stimulation to input information, such as a command or the heat of a hot cup of coffee, using “write-in” technology.

Neuralink said on Friday that its technology would have both read-out and write-in capabilities.Musk acknowledged that Neuralink still has a long way to go. In closing the event after more drinking 24 hours after antabuse than 70 minutes, Musk said. €œThere’s a tremendous amount of work to be done to go from here to a device that is widely available and affordable and reliable.”Following the news this week of what appears to have been the first confirmed case of a alcoholism treatment re, other researchers have been coming forward with their own reports. One in Belgium, another in the Netherlands. And now, one drinking 24 hours after antabuse in Nevada.What caught experts’ attention about the case of the 25-year-old Reno man was not that he appears to have contracted alcoholism (the name of the antabuse that causes alcoholism treatment) a second time.

Rather, it’s that his second bout was more serious than his first.Immunologists had expected that if the immune response generated after an initial could not prevent a second case, then it should at least stave off more severe illness. That’s what occurred with the first known re case, drinking 24 hours after antabuse in a 33-year-old Hong Kong man.advertisement Still, despite what happened to the man in Nevada, researchers are stressing this is not a sky-is-falling situation or one that should result in firm conclusions. They always presumed people would become vulnerable to alcoholism treatment again some time after recovering from an initial case, based on how our immune systems respond to other respiratory antabusees, including other alcoholismes. It’s possible that these early cases of re are outliers and have features that drinking 24 hours after antabuse won’t apply to the tens of millions of other people who have already shaken off alcoholism treatment.“There are millions and millions of cases,” said Michael Mina, an epidemiologist at Harvard’s T.H. Chan School of Public Health.

The real question that drinking 24 hours after antabuse should get the most focus, Mina said, is, “What happens to most people?. €advertisement But with more re reports likely to make it into the scientific literature soon, and from there into the mainstream press, here are some things to look for in assessing them.What’s the deal with the Nevada case?. The Reno resident in question first tested positive for alcoholism in April after coming down with a sore throat, cough, and headache, as well drinking 24 hours after antabuse as nausea and diarrhea. He got better over time and later tested negative twice. But then, drinking 24 hours after antabuse some 48 days later, the man started experiencing headaches, cough, and other symptoms again.

Eventually, he became so sick that he had to be hospitalized and was found to have pneumonia.Researchers sequenced antabuse samples from both of his s and found they were different, providing evidence that this was a new distinct from the first. What happens when drinking 24 hours after antabuse we get alcoholism treatment in the first case?. Researchers are finding that, generally, people who get alcoholism treatment develop a healthy immune response replete with both antibodies (molecules that can block pathogens from infecting cells) and T cells (which help wipe out the antabuse). This is what happens after other viral s.In addition to fending off the antabuse the first time, that immune drinking 24 hours after antabuse response also creates memories of the antabuse, should it try to invade a second time. It’s thought, then, that people who recover from alcoholism treatment will typically be protected from another case for some amount of time.

With other alcoholismes, protection is thought to last for perhaps a little less than a year to about three years.But researchers can’t tell how long immunity will last with a new pathogen drinking 24 hours after antabuse (like alcoholism) until people start getting reinfected. They also don’t know exactly what mechanisms provide protection against alcoholism treatment, nor do they know what levels of antibodies or T cells are required to signal that someone is protected through a blood test. (These are called the “correlates drinking 24 hours after antabuse of protection.”) Why do experts expect second cases to be milder?. With other antabusees, protective immunity doesn’t just vanish one day. Instead, it drinking 24 hours after antabuse wanes over time.

Researchers have then hypothesized that with alcoholism, perhaps our immune systems might not always be able to prevent it from getting a toehold in our cells — to halt entirely — but that it could still put up enough of a fight to guard us from getting really sick. Again, this is what happens with other respiratory drinking 24 hours after antabuse pathogens.And it’s why some researchers actually looked at the Hong Kong case with relief. The man had mild to moderate alcoholism treatment symptoms during the first case, but was asymptomatic the second time. It was a demonstration, experts said, of what you would want drinking 24 hours after antabuse your immune system to do. (The case was only detected because the man’s sample was taken at the airport when he arrived back in Hong Kong after traveling in Europe.)“The fact that somebody may get reinfected is not surprising,” Malik Peiris, a virologist at the University of Hong Kong, told STAT earlier this week about the first re.

€œBut the re didn’t cause disease, so that’s the first point.”The Nevada case, then, provides a counterexample to that. What drinking 24 hours after antabuse kind of immune response did the person who was reinfected generate initially?. Earlier, we described the robust immune response that most people who have alcoholism treatment seem to mount. But that was drinking 24 hours after antabuse a generalization. s and the immune responses they induce in different people are “heterogeneous,” said Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago.Older people often generate weaker immune responses than younger people.

Some studies have also indicated that milder cases drinking 24 hours after antabuse of alcoholism treatment induce tamer immune responses that might not provide as lasting or as thorough of a defense as stronger immune responses. The man in Hong Kong, for example, did not generate antibodies to the antabuse after his first , at least to the level that could be detected by blood tests. Perhaps that explains why he contracted the antabuse again just about 4 1/2 months after recovering from his initial .In the Nevada case, researchers did not test what kind of immune response the man generated after the drinking 24 hours after antabuse first case.“ is not some binary event,” Cobey said. And with re, “there’s going to be some viral replication, but the question is how much is the immune system getting engaged?. €What might drinking 24 hours after antabuse be broadly meaningful is when people who mounted robust immune responses start getting reinfected, and how severe their second cases are.

Are people who have alcoholism treatment a second time infectious?. As discussed, immune drinking 24 hours after antabuse memory can prevent re. If it can’t, it might stave off serious illness. But there’s a third aspect of this, too.“The most important question for re, with the most serious implications for controlling the antabuse, is whether reinfected people can transmit the antabuse to others,” Columbia University virologist Angela Rasmussen wrote in Slate this week.Unfortunately, neither the Hong Kong nor the Reno studies looked at drinking 24 hours after antabuse this question. But if most people who get reinfected don’t spread the antabuse, that’s obviously good news.

What drinking 24 hours after antabuse happens when people broadly become susceptible again?. Whether it’s six months after the first or nine months or a year or longer, at some point, protection for most people who recover from alcoholism treatment is expected to wane. And without the arrival of a treatment and broad uptake of it, that could change the dynamics of drinking 24 hours after antabuse local outbreaks.In some communities, it’s thought that more than 20% of residents have experienced an initial alcoholism treatment case, and are thus theoretically protected from another case for some time. That is still below the point of herd immunity — when enough people are immune that transmission doesn’t occur — but still, the fewer vulnerable people there are, the less likely spread is to occur.On the flip side though, if more people become susceptible to the antabuse again, that could increase the risk of transmission. Modelers are starting to factor that possibility into their forecasts.A crucial question for which there is not an answer yet is whether what happened to the man in Reno, where drinking 24 hours after antabuse the second case was more severe than the first, remains a rare occurrence, as researchers expect and hope.

As the Nevada researchers wrote, “the generalizability of this finding is unknown.”An advocacy group has asked the Department of Defense to investigate what it called “an apparent failure” by Moderna (MRNA) to disclose millions of dollars in awards received from the Defense Advanced Research Projects Agency in patent applications the company filed for treatments.In a letter to the agency, Knowledge Ecology International explained that a review of dozens of patent applications found the company received approximately $20 million from the federal government in grants several years ago and the funds “likely” led to the creation of its treatment technology. This was used to develop treatments to combat different antabusees, such as Zika and, later, the antabuse that causes alcoholism treatment.In arguing for an investigation, the advocacy group maintained Moderna is obligated under federal drinking 24 hours after antabuse law to disclose the grants that led to nearly a dozen specific patent applications and explained the financial support means the U.S. Government would have certain rights over the patents. In other drinking 24 hours after antabuse words, U.S. Taxpayers would have an ownership stake in treatments developed by the company.advertisement “This clarifies the public’s right in the inventions,” said Jamie Love, who heads Knowledge Ecology International, a nonprofit that tracks patents and access to medicines issues.

€œThe disclosure (also) changes the narrative about who has financed the inventive activity, often the most risky part of development.” drinking 24 hours after antabuse One particular patent assigned to Moderna concerns methods and compositions that can be used specifically against alcoholismes, including alcoholism treatment. The patent names a Moderna scientist and a former Moderna scientist as inventors, both of which acknowledged performing work under the DARPA awards in two academic papers, according to the report by the advocacy group.advertisement The group examined the 126 patents assigned to Moderna or ModernaTx as well as 154 patent applications. €œDespite the evidence that multiple inventions were conceived in the course of research supported by the DARPA awards, not a single one of the patents or applications assigned to Moderna disclose U.S. Federal government funding,” the drinking 24 hours after antabuse report stated.[UPDATE. A DARPA spokesman sent us this over the weekend.

€œIt appears that all past and present DARPA awards drinking 24 hours after antabuse to Moderna include the requirement to report the role of government funding for related inventions. Further, DARPA is actively researching agency awards to Moderna to identify which patents and pending patents, if any at all, may be associated with DARPA support. This effort is ongoing.”]We asked Moderna for comment and will update you accordingly.The missive to the Department of Defense follows a recent analysis by Public Citizen, another advocacy group, indicating the National drinking 24 hours after antabuse Institutes of Health may own mRNA-1273, the Moderna treatment candidate for alcoholism treatment. The advocacy group noted the federal government filed multiple patents covering the treatment and two patent applications, in particular, list federal scientists as co-inventors.The analyses are part of a larger campaign among advocacy groups and others in the U.S. And elsewhere drinking 24 hours after antabuse to ensure that alcoholism treatment medical products are available to poor populations around the world.

The concern reflects the unprecedented global demand for therapies and treatments, and a race among wealthy nations to snap up supplies from treatment makers. In the U.S., the effort has focused on the extent to which the federal government has provided taxpayer dollars to different companies drinking 24 hours after antabuse to help fund their discoveries. In some cases, advocates argue that federal funding matters because it clarifies the rights that the U.S. Government has to ensure a therapy or treatment is available to Americans on reasonable terms.One example has been remdesivir, the Gilead Sciences (GILD) treatment drinking 24 hours after antabuse being given to hospitalized alcoholism treatment patients. The role played by the U.S.

Government in developing remdesivir to combat drinking 24 hours after antabuse alcoholismes involved contributions from government personnel at such agencies as the U.S. Army Medical Research Institute of Infectious Diseases.As for the Moderna treatment, earlier this month, the company was awarded a $1.525 billion contract by the Department of Defense and the Department of Health and Human Services to manufacture and deliver 100 million doses of its alcoholism treatment. The agreement drinking 24 hours after antabuse also includes an option to purchase another 400 million doses, although the terms were not disclosed. In announcing the agreement, the government said it would ensure Americans receive the alcoholism treatment at no cost, although they may be charged by health care providers for administering a shot.In this instance, however, Love said the “letter is not about price or profits. It’s about (Moderna) not owning up to DARPA funding inventions drinking 24 hours after antabuse.

If the U.S. Wants to pay for all of the development of Moderna’s drinking 24 hours after antabuse treatment, as Moderna now acknowledges, and throw in a few more billion now, and an option to spend billions more, it’s not unreasonable to have some transparency over who paid for their inventions.”This is not the first time Moderna has been accused of insufficient disclosure. Earlier this month, Knowledge Ecology International and Public Citizen maintained the company failed to disclose development costs in a $955 million contract awarded by BARDA for its alcoholism treatment. In all, the federal government has awarded the company approximately $2.5 billion to develop the treatment.The coming few weeks represent a drinking 24 hours after antabuse crucial moment for an ambitious plan to try to secure alcoholism treatments for roughly 170 countries around the world without the deep pockets to compete for what will be scarce initial supplies.Under the plan, countries that want to pool resources to buy treatments must notify the World Health Organization and other organizers — Gavi, the treatment Alliance, as well as the Coalition for Epidemic Preparedness Innovations — of their intentions by Monday. That means it’s fish-or-cut-bait time for the so-called COVAX facility.Already, wealthy countries — the United States, the United Kingdom, Japan, Canada, and Australia, among others, as well as the European Union — have opted to buy their own treatment, signing bilateral contracts with manufacturers that have secured billions of doses of treatment already.

That raises the possibility that less wealthy countries will be boxed out of supplies.advertisement drinking 24 hours after antabuse And yet Richard Hatchett, the CEO of CEPI, insists there is a path to billions of doses of treatment for the rest of the world in 2021. STAT spoke with Hatchett this week. A transcript of the conversation, lightly edited for clarity drinking 24 hours after antabuse and length, follows. You said this is a critical time for CEPI. Can you explain what needs to happen between now and mid-September for this joint purchasing approach to be a success?.

Advertisement The critical drinking 24 hours after antabuse moment is now for countries to commit to the COVAX facility, because that will enable us to secure ample quantities of treatment and then to be able to convey when that treatment is likely to become available based on current information.What we’re now here asking countries to do is to indicate their intent to participate by Aug. 31, and to make a binding commitment by Sept. 18. And to provide funds in support of that binding commitment by early October. Our negotiations with companies are already taking place and it will be important for us from a planning purpose that countries indicate their intent to participate.Those binding commitments we think will be sufficient to allow us to then secure the advance purchase agreements, particularly with those companies that don’t have a prior contractual obligation to COVAX.

And then obviously, we need the funds to live up to those advance purchase agreements.Is it possible this thing could still fall apart?. There appears to be some concern COVAX has been boxed out by rich countries. There was always a possibility that there wouldn’t be sufficient uptake. But I think we’re very encouraged at this point by the level of commitment, both from countries that would be beneficiaries of the advance market commitment — that’s the lower-income, lower-middle-income countries — as well as the self-financing countries. To have over 170 countries expressing interest in participating — they see the value.We’re much more encouraged now that it’s not going to fall apart.

We still need to bring it off to maximize its value. And we’re right at the crunch moment where countries are going to have to make these commitments. So, the next month is really absolutely critical to the facility. I am confident at this point that the world recognizes the value and wants it to work.I’ve been keeping tabs on advance purchase agreements that have been announced. And at this point, a small number of rich countries have nailed down a lot of treatment — more than 3 billion doses.

How hard does that make your job?. The fact that they’re doing it creates anxiety among other countries. And that in itself can accelerate the pace. So, I’m not going to say that we’re not watching that with concern.I will say that for COVAX and the facility, this is absolutely critical moment. I think we still have a window of opportunity between now and mid-September — when we’re asking that the self-financing countries to make their commitments — to make the facility real and to make it work.

Between doses that are committed to COVAX through the access agreements and other agreements — these are discussions with partners that CEPI has funded as well as partners that CEPI has not funded — we still see a pathway for COVAX to well over 3 billion doses in 2021.I think it’s really important to bear in mind is that there are at least a few countries — and I think the U.S. And the U.K. Most publicly — that may be in a situation of significant oversupply. I believe the U.S. And U.K.

Numbers, if you add them together, would result in enough treatment for 600 million people to receive two doses of treatment each. And, you know, there is no possible way that the U.S. Or the U.K. Can use that much treatment.So, there may be a lot of extra supply that looks like it’s been tied up sloshing around later. I don’t think that the bilateral deals that have been struck are going to prevent COVAX from achieving its goals.But if so much treatment has been pre-ordered by rich countries, can countries in the COVAX pool get enough for their needs?.

One of the things that we’ve argued through COVAX is that to control the antabuse or to end the acute phase of the antabuse to allow normalcy to start to reassert itself, you don’t have to vaccinate 100% of your population.You need to vaccinate those at greatest risk for bad outcomes and you need to vaccinate certain critical workers, particularly your health care workforce. And if you can achieve that goal, which for most countries means vaccinating between 20% and maybe 30% of the population, then you can transform the antabuse into something that is much more manageable. Then you can buy yourself time to vaccinate everybody who wants to be vaccinated.We’ve argued the COVAX facility really offers the world the best shot at doing that globally in the fastest possible way, as well as providing for equitable access. This is a case where doing the equitable thing is also doing the efficient thing.CEPI has provided funding to nine treatments. Is it true that all those manufacturers aren’t required to provide the COVAX facility with treatment?.

That is correct. One of the things that we did, and I think it was an important role that CEPI played early on, was that we moved money very, very quickly, in small increments. You know, some of the early contracts were only $5 million or $10 million, to get programs up and running while we potentially put in place much larger-scale, longer-term contracts.If you were doing it over again, would you have given money without strings attached?. Yes, I think I would have. I think that was critically important to initiating programs.Our contract with Moderna was established in about 48 hours.

And that provided critical funding to them to manufacture doses that got them into clinical trials within nine weeks of the genetic sequences [of the alcoholism antabuse] being released.And if you look at the nine programs that we’ve invested in, seven are in clinical trials. Two — the AstraZeneca program now and the Moderna program — are among the handful in Phase 3 clinical trials. And, I think the number of projects that that we funded initially, which started in kind of a biotech or academic phase that have now been picked up by large multinational corporations, there’s at least four. The Themis program being picked up by Merck, Oxford University by AstraZeneca, the University of Queensland by CSL, and Clover being in partnership with GSK, I think that speaks to the quality of the programs that we selected.So, I think that combination of rapid review, speed of funding, getting those programs started, getting them oriented in the right direction, I think all of that is critical to where we are now.Companies that got money from CEPI to build out production capacity — that money came with strings attached, right?. Yes, exactly.

So, where CEPI has made investments that create manufacturing, or secure manufacturing capacity, the commitment has been that the capacity that is attributable to the CEPI investment is committed — at least right of first refusal — to the global procurement facility.WASHINGTON — The Trump administration removed a top Food and Drug Administration communications official from her post on Friday in the wake of several controversial agency misstatements, a senior administration official confirmed to STAT.The spokeswoman, Emily Miller, had played a lead role in defending the FDA commissioner, Stephen Hahn, after he misrepresented data regarding the use of blood plasma from recovered alcoholism treatment patients. The New York Times first reported Miller’s ouster. Miller’s tenure at as the top FDA spokeswoman lasted only 11 days. Her appointment was viewed with alarm by agency officials who felt her presence at the agency was emblematic of broader political pressure from the Trump administration, STAT first reported earlier this week.advertisement Before joining the FDA, Miller had no experience in health or medicine. Her former role as assistant commissioner for media affairs is typically not an appointment filled by political appointees.

The FDA’s communications arm typically maintains a neutral, nonpolitical tone.Miller’s appointment particularly alarmed FDA staff and outside scientists given her history in right-wing political advocacy and conservatism journalism. Her résumé included a stint as a Washington Times columnist, where she penned columns with titles that include “New Obamacare ads make young women look like sluts,” and a 2013 book on gun rights titled “Emily Gets Her Gun. But Obama Wants to Take Yours.”advertisement She also worked as a reporter for One America News Network, a right-wing cable channel that frequently espouses conspiracy theories and has declared an open alliance with President Trump.Miller quickly made her presence known at the FDA. In the wake of Hahn’s misstatements on blood plasma, she aggressively defended the commissioner, falsely claiming in a tweet that the therapy “has shown to be beneficial for 35% of patients.” An FDA press release on blood plasma, issued less than a week after her appointment, similarly alarmed agency insiders by trumpeting the emergency authorization as “Another Achievement in Administration’s Fight Against [the] antabuse.”.

Elon Musk on Friday unveiled a coin-sized prototype of a brain implant developed by his startup can you get antabuse without a prescription Neuralink to enable people who are paralyzed to operate smartphones and robotic limbs with their thoughts where can i buy antabuse — and said the company had worked to “dramatically simplify” the device since presenting an earlier version last summer.In an event live-streamed on YouTube to more than 150,000 viewers at one point, the company staged a demonstration in which it trotted out a pig named Gertrude that was said to have had the company’s device implanted in its head two months ago. The live stream showed what Musk claimed to be Gertrude’s real-time brain activity as it sniffed around a pen. At no point, though, did he provide evidence that the signals — rendered in beeps and bright blue wave patterns on screen — were, in fact, emanating from the pig’s brain.A pig presented at a Neuralink demonstration was said to have can you get antabuse without a prescription one of the company’s brain implants in its head. YouTube screenshot“This is obviously sounding increasingly like a Black Mirror episode,” Musk said at one point during the event as he responded affirmatively to a question about whether the company’s implant could eventually be used to save and replay memories. €œThe future’s going to be weird.”advertisement Musk can you get antabuse without a prescription said that in July Neuralink received a breakthrough device designation from the Food and Drug Administration — a regulatory pathway that could allow the company to soon start a clinical trial in people with paraplegia and tetraplegia.

The big reveal came after four former Neuralink employees told STAT that the company’s leaders have long fostered an internal culture characterized by rushed timelines and the “move fast and break things” ethos of a tech company — a pace sometimes at odds with the slow and incremental pace that’s typical of medical device development. Advertisement Friday’s event began, 40 minutes late, with a glossy video about the company’s work — and can you get antabuse without a prescription then panned to Musk, standing in front of a blue curtain beside a gleaming new version of the company’s surgical “sewing machine” robot that could easily have been mistaken for a giant Apple device. Musk described the event as a “product demo” and said its primary purpose was to recruit potential new employees. It was unclear whether the can you get antabuse without a prescription demonstration was taking place at the company’s Fremont, Calif., headquarters or elsewhere. Musk proceeded to reveal the new version of Neuralink’s brain implant, which he said was designed to fit snugly into the top of the skull.

Neuralink’s technological design can you get antabuse without a prescription has changed significantly since its last big update in July 2019. At that time, the company’s brain implant system involved a credit-card sized device designed to be positioned behind the back of a person’s ear, with several wires stretching to the top of the skull. After demonstrating the pig’s brain activity at Friday’s event, Musk showed video footage of a pig walking on a treadmill and said Neuralink’s device could be used to “predict can you get antabuse without a prescription the position of limbs with high accuracy.” That capability would be critical to allowing someone using the device to do something like controlling a prosthetic limb, for example.Neuralink for months has signaled that it initially plans to develop its device for people who are paralyzed. It said at its July 2019 event that it wanted to start human testing by the end of 2020. Receiving the breakthrough device designation from the can you get antabuse without a prescription FDA — designed to speed up the lengthy regulatory process — is a step forward, but it by no means guarantees that a device will receive a green light, either in a short or longer-term time frame.

After Musk’s presentation, a handful of the company’s employees — all wearing masks, but seated only inches apart — joined him to take questions submitted on Twitter or from the small audience in the room.In typical fashion for a man who in 2018 sent a Tesla Roadster into space, Musk didn’t hesitate to use the event to cross-promote his electric car company. Asked whether the Neuralink chip would allow people to can you get antabuse without a prescription summon their Tesla telepathically, Musk responded. €œDefinitely — of course.”Matthew MacDougall, the company’s head neurosurgeon, appearing in scrubs, said the company had so far only implanted its technology into the brain’s cortical surface, the coaster-width layer enveloping the brain, but added that it hoped to go deeper in the future. Still, Musk can you get antabuse without a prescription said. €œYou could solve blindness, you could solve paralysis, you could solve hearing — you can solve a lot just by interfacing with the cortex.”Musk and MacDougall said they hoped to eventually implant Neuralink’s devices — which they referred to on stage simply as “links” — in the deeper structures of the brain, such as in the hypothalamus, which is believed to play a critical role in mental illnesses including depression, anxiety, and PTSD.There were no updates at the event of Neuralink’s research in monkeys, which the company has been conducting in partnership with the University of California, Davis since 2017.

At last July’s event, Musk said — without providing evidence — that a monkey had controlled a computer with can you get antabuse without a prescription its brain.At that same July 2019 event, Neuralink released a preprint paper — published a few months later — that claimed to show that a series of Neuralink electrodes implanted in the brains of rats could record neural signals. Critically, the work did not show where in the brain the implanted electrodes were recording from, for how long they were recording, or whether the recordings could be linked to any of the rats’ bodily movements.In touting Friday’s event — and Neuralink’s technological capabilities — on Twitter in recent weeks, Musk spoke of “AI symbiosis while u wait” and referenced the “matrix in the matrix” — a science-fiction reference about revealing the true nature of reality. The progress the company reported on Friday fell far short of can you get antabuse without a prescription that. Neuralink’s prototype is ambitious, but it has yet to show evidence that it can match up to the brain-machine interfaces developed by academic labs and other companies. Other groups have shown that they can listen in on neural activity and allow primates and people to control a computer can you get antabuse without a prescription cursor with their brain — so-called “read-out” technology — and have also shown that they can use electrical stimulation to input information, such as a command or the heat of a hot cup of coffee, using “write-in” technology.

Neuralink said on Friday that its technology would have both read-out and write-in capabilities.Musk acknowledged that Neuralink still has a long way to go. In closing the event after more than 70 minutes, Musk can you get antabuse without a prescription said. €œThere’s a tremendous amount of work to be done to go from here to a device that is widely available and affordable and reliable.”Following the news this week of what appears to have been the first confirmed case of a alcoholism treatment re, other researchers have been coming forward with their own reports. One in Belgium, another in the Netherlands. And now, one in Nevada.What caught experts’ attention about the case of the 25-year-old Reno man was not that he can you get antabuse without a prescription appears to have contracted alcoholism (the name of the antabuse that causes alcoholism treatment) a second time.

Rather, it’s that his second bout was more serious than his first.Immunologists had expected that if the immune response generated after an initial could not prevent a second case, then it should at least stave off more severe illness. That’s what occurred with the first known re case, in a 33-year-old Hong Kong man.advertisement Still, despite what happened to the can you get antabuse without a prescription man in Nevada, researchers are stressing this is not a sky-is-falling situation or one that should result in firm conclusions. They always presumed people would become vulnerable to alcoholism treatment again some time after recovering from an initial case, based on how our immune systems respond to other respiratory antabusees, including other alcoholismes. It’s possible that these early cases of re are outliers and have features that won’t apply to the tens of millions of other people who have already can you get antabuse without a prescription shaken off alcoholism treatment.“There are millions and millions of cases,” said Michael Mina, an epidemiologist at Harvard’s T.H. Chan School of Public Health.

The real can you get antabuse without a prescription question that should get the most focus, Mina said, is, “What happens to most people?. €advertisement But with more re reports likely to make it into the scientific literature soon, and from there into the mainstream press, here are some things to look for in assessing them.What’s the deal with the Nevada case?. The Reno resident in question first tested positive for can you get antabuse without a prescription alcoholism in April after coming down with a sore throat, cough, and headache, as well as nausea and diarrhea. He got better over time and later tested negative twice. But then, some 48 days later, the man started experiencing headaches, can you get antabuse without a prescription cough, and other symptoms again.

Eventually, he became so sick that he had to be hospitalized and was found to have pneumonia.Researchers sequenced antabuse samples from both of his s and found they were different, providing evidence that this was a new distinct from the first. What happens when we get can you get antabuse without a prescription alcoholism treatment in the first case?. Researchers are finding that, generally, people who get alcoholism treatment develop a healthy immune response replete with both antibodies (molecules that can block pathogens from infecting cells) and T cells (which help wipe out the antabuse). This is what happens after other viral s.In addition to fending off the antabuse the first time, that immune response also creates memories of the antabuse, should it try to invade a second time can you get antabuse without a prescription. It’s thought, then, that people who recover from alcoholism treatment will typically be protected from another case for some amount of time.

With other alcoholismes, protection is can you get antabuse without a prescription thought to last for perhaps a little less than a year to about three years.But researchers can’t tell how long immunity will last with a new pathogen (like alcoholism) until people start getting reinfected. They also don’t know exactly what mechanisms provide protection against alcoholism treatment, nor do they know what levels of antibodies or T cells are required to signal that someone is protected through a blood test. (These are called the “correlates of can you get antabuse without a prescription protection.”) Why do experts expect second cases to be milder?. With other antabusees, protective immunity doesn’t just vanish one day. Instead, it can you get antabuse without a prescription wanes over time.

Researchers have then hypothesized that with alcoholism, perhaps our immune systems might not always be able to prevent it from getting a toehold in our cells — to halt entirely — but that it could still put up enough of a fight to guard us from getting really sick. Again, this is what happens with other can you get antabuse without a prescription respiratory pathogens.And it’s why some researchers actually looked at the Hong Kong case with relief. The man had mild to moderate alcoholism treatment symptoms during the first case, but was asymptomatic the second time. It was a demonstration, experts can you get antabuse without a prescription said, of what you would want your immune system to do. (The case was only detected because the man’s sample was taken at the airport when he arrived back in Hong Kong after traveling in Europe.)“The fact that somebody may get reinfected is not surprising,” Malik Peiris, a virologist at the University of Hong Kong, told STAT earlier this week about the first re.

€œBut the re didn’t cause disease, so that’s the first point.”The Nevada case, then, provides a counterexample to that. What kind of immune response did the person who was can you get antabuse without a prescription reinfected generate initially?. Earlier, we described the robust immune response that most people who have alcoholism treatment seem to mount. But that was a can you get antabuse without a prescription generalization. s and the immune responses they induce in different people are “heterogeneous,” said Sarah Cobey, an epidemiologist and evolutionary biologist at the University of Chicago.Older people often generate weaker immune responses than younger people.

Some studies have also indicated that milder cases of alcoholism treatment induce tamer immune responses that might not provide as lasting or as thorough of a defense as stronger immune can you get antabuse without a prescription responses. The man in Hong Kong, for example, did not generate antibodies to the antabuse after his first , at least to the level that could be detected by blood tests. Perhaps that explains why he contracted the antabuse again just about 4 1/2 months after recovering from his initial .In the Nevada case, researchers did not test what kind of immune can you get antabuse without a prescription response the man generated after the first case.“ is not some binary event,” Cobey said. And with re, “there’s going to be some viral replication, but the question is how much is the immune system getting engaged?. €What might be broadly meaningful is when people who mounted robust immune responses start getting reinfected, and how severe their can you get antabuse without a prescription second cases are.

Are people who have alcoholism treatment a second time infectious?. As discussed, immune memory can can you get antabuse without a prescription prevent re. If it can’t, it might stave off serious illness. But there’s a third aspect of this, too.“The most important question for re, with the most serious implications for controlling the antabuse, is whether reinfected people can transmit the antabuse to others,” Columbia University virologist Angela Rasmussen wrote in can you get antabuse without a prescription Slate this week.Unfortunately, neither the Hong Kong nor the Reno studies looked at this question. But if most people who get reinfected don’t spread the antabuse, that’s obviously good news.

What happens when can you get antabuse without a prescription people broadly become susceptible again?. Whether it’s six months after the first or nine months or a year or longer, at some point, protection for most people who recover from alcoholism treatment is expected to wane. And without the arrival of a treatment and broad uptake of it, that could change the dynamics of local outbreaks.In some communities, it’s thought that more than 20% of residents can you get antabuse without a prescription have experienced an initial alcoholism treatment case, and are thus theoretically protected from another case for some time. That is still below the point of herd immunity — when enough people are immune that transmission doesn’t occur — but still, the fewer vulnerable people there are, the less likely spread is to occur.On the flip side though, if more people become susceptible to the antabuse again, that could increase the risk of transmission. Modelers are starting to factor that possibility into their forecasts.A crucial question for which there is not an answer yet is whether what happened to can you get antabuse without a prescription the man in Reno, where the second case was more severe than the first, remains a rare occurrence, as researchers expect and hope.

As the Nevada researchers wrote, “the generalizability of this finding is unknown.”An advocacy group has asked the Department of Defense to investigate what it called “an apparent failure” by Moderna (MRNA) to disclose millions of dollars in awards received from the Defense Advanced Research Projects Agency in patent applications the company filed for treatments.In a letter to the agency, Knowledge Ecology International explained that a review of dozens of patent applications found the company received approximately $20 million from the federal government in grants several years ago and the funds “likely” led to the creation of its treatment technology. This was used to develop treatments to combat different antabusees, such as Zika and, later, the antabuse that causes alcoholism treatment.In arguing for an investigation, the advocacy group maintained Moderna is obligated under federal law can you get antabuse without a prescription to disclose the grants that led to nearly a dozen specific patent applications and explained the financial support means the U.S. Government would have certain rights over the patents. In other words, can you get antabuse without a prescription U.S. Taxpayers would have an ownership stake in treatments developed by the company.advertisement “This clarifies the public’s right in the inventions,” said Jamie Love, who heads Knowledge Ecology International, a nonprofit that tracks patents and access to medicines issues.

€œThe disclosure (also) changes the narrative about who has financed the inventive activity, often the most risky part of development.” One particular patent assigned to Moderna concerns methods and compositions that can be used can you get antabuse without a prescription specifically against alcoholismes, including alcoholism treatment. The patent names a Moderna scientist and a former Moderna scientist as inventors, both of which acknowledged performing work under the DARPA awards in two academic papers, according to the report by the advocacy group.advertisement The group examined the 126 patents assigned to Moderna or ModernaTx as well as 154 patent applications. €œDespite the evidence that multiple inventions were conceived in the course of research supported by the DARPA awards, not a single one of the patents can i buy antabuse over the counter or applications assigned to Moderna disclose U.S. Federal government funding,” the report stated.[UPDATE can you get antabuse without a prescription. A DARPA spokesman sent us this over the weekend.

€œIt appears that all past and present DARPA awards to Moderna include the requirement can you get antabuse without a prescription to report the role of government funding for related inventions. Further, DARPA is actively researching agency awards to Moderna to identify which patents and pending patents, if any at all, may be associated with DARPA support. This effort is ongoing.”]We asked Moderna for comment and will can you get antabuse without a prescription update you accordingly.The missive to the Department of Defense follows a recent analysis by Public Citizen, another advocacy group, indicating the National Institutes of Health may own mRNA-1273, the Moderna treatment candidate for alcoholism treatment. The advocacy group noted the federal government filed multiple patents covering the treatment and two patent applications, in particular, list federal scientists as co-inventors.The analyses are part of a larger campaign among advocacy groups and others in the U.S. And elsewhere to ensure that alcoholism treatment medical products are available to poor populations can you get antabuse without a prescription around the world.

The concern reflects the unprecedented global demand for therapies and treatments, and a race among wealthy nations to snap up supplies from treatment makers. In the can you get antabuse without a prescription U.S., the effort has focused on the extent to which the federal government has provided taxpayer dollars to different companies to help fund their discoveries. In some cases, advocates argue that federal funding matters because it clarifies the rights that the U.S. Government has to ensure a therapy or treatment is available to Americans on reasonable terms.One example has been remdesivir, the Gilead Sciences can you get antabuse without a prescription (GILD) treatment being given to hospitalized alcoholism treatment patients. The role played by the U.S.

Government in developing remdesivir to combat alcoholismes can you get antabuse without a prescription involved contributions from government personnel at such agencies as the U.S. Army Medical Research Institute of Infectious Diseases.As for the Moderna treatment, earlier this month, the company was awarded a $1.525 billion contract by the Department of Defense and the Department of Health and Human Services to manufacture and deliver 100 million doses of its alcoholism treatment. The agreement also includes can you get antabuse without a prescription an option to purchase another 400 million doses, although the terms were not disclosed. In announcing the agreement, the government said it would ensure Americans receive the alcoholism treatment at no cost, although they may be charged by health care providers for administering a shot.In this instance, however, Love said the “letter is not about price or profits. It’s about can you get antabuse without a prescription (Moderna) not owning up to DARPA funding inventions.

If the U.S. Wants to can you get antabuse without a prescription pay for all of the development of Moderna’s treatment, as Moderna now acknowledges, and throw in a few more billion now, and an option to spend billions more, it’s not unreasonable to have some transparency over who paid for their inventions.”This is not the first time Moderna has been accused of insufficient disclosure. Earlier this month, Knowledge Ecology International and Public Citizen maintained the company failed to disclose development costs in a $955 million contract awarded by BARDA for its alcoholism treatment. In all, the federal government has awarded the company approximately $2.5 billion to develop the treatment.The coming few weeks can you get antabuse without a prescription represent a crucial moment for an ambitious plan to try to secure alcoholism treatments for roughly 170 countries around the world without the deep pockets to compete for what will be scarce initial supplies.Under the plan, countries that want to pool resources to buy treatments must notify the World Health Organization and other organizers — Gavi, the treatment Alliance, as well as the Coalition for Epidemic Preparedness Innovations — of their intentions by Monday. That means it’s fish-or-cut-bait time for the so-called COVAX facility.Already, wealthy countries — the United States, the United Kingdom, Japan, Canada, and Australia, among others, as well as the European Union — have opted to buy their own treatment, signing bilateral contracts with manufacturers that have secured billions of doses of treatment already.

That raises the possibility that less wealthy countries will be boxed out of supplies.advertisement And yet Richard Hatchett, the CEO of can you get antabuse without a prescription CEPI, insists there is a path to billions of doses of treatment for the rest of the world in 2021. STAT spoke with Hatchett this week. A transcript can you get antabuse without a prescription of the conversation, lightly edited for clarity and length, follows. You said this is a critical time for CEPI. Can you explain what needs to happen between now and mid-September for this joint purchasing approach to be a success?.

Advertisement The critical moment is now for countries to commit to the COVAX facility, because that will enable us can you get antabuse without a prescription to secure ample quantities of treatment and then to be able to convey when that treatment is likely to become available based on current information.What we’re now here asking countries to do is to indicate their intent to participate by Aug. 31, and to make a binding commitment by Sept. 18. And to provide funds in support of that binding commitment by early October. Our negotiations with companies are already taking place and it will be important for us from a planning purpose that countries indicate their intent to participate.Those binding commitments we think will be sufficient to allow us to then secure the advance purchase agreements, particularly with those companies that don’t have a prior contractual obligation to COVAX.

And then obviously, we need the funds to live up to those advance purchase agreements.Is it possible this thing could still fall apart?. There appears to be some concern COVAX has been boxed out by rich countries. There was always a possibility that there wouldn’t be sufficient uptake. But I think we’re very encouraged at this point by the level of commitment, both from countries that would be beneficiaries of the advance market commitment — that’s the lower-income, lower-middle-income countries — as well as the self-financing countries. To have over 170 countries expressing interest in participating — they see the value.We’re much more encouraged now that it’s not going to fall apart.

We still need to bring it off to maximize its value. And we’re right at the crunch moment where countries are going to have to make these commitments. So, the next month is really absolutely critical to the facility. I am confident at this point that the world recognizes the value and wants it to work.I’ve been keeping tabs on advance purchase agreements that have been announced. And at this point, a small number of rich countries have nailed down a lot of treatment — more than 3 billion doses.

How hard does that make your job?. The fact that they’re doing it creates anxiety among other countries. And that in itself can accelerate the pace. So, I’m not going to say that we’re not watching that with concern.I will say that for COVAX and the facility, this is absolutely critical moment. I think we still have a window of opportunity between now and mid-September — when we’re asking that the self-financing countries to make their commitments — to make the facility real and to make it work.

Between doses that are committed to COVAX through the access agreements and other agreements — these are discussions with partners that CEPI has funded as well as partners that CEPI has not funded — we still see a pathway for COVAX to well over 3 billion doses in 2021.I think it’s really important to bear in mind is that there are at least a few countries — and I think the U.S. And the U.K. Most publicly — that may be in a situation of significant oversupply. I believe the U.S. And U.K.

Numbers, if you add them together, would result in enough treatment for 600 million people to receive two doses of treatment each. And, you know, there is no possible way that the U.S. Or the U.K. Can use that much treatment.So, there may be a lot of extra supply that looks like it’s been tied up sloshing around later. I don’t think that the bilateral deals that have been struck are going to prevent COVAX from achieving its goals.But if so much treatment has been pre-ordered by rich countries, can countries in the COVAX pool get enough for their needs?.

One of the things that we’ve argued through COVAX is that to control the antabuse or to end the acute phase of the antabuse to allow normalcy to start to reassert itself, you don’t have to vaccinate 100% of your population.You need to vaccinate those at greatest risk for bad outcomes and you need to vaccinate certain critical workers, particularly your health care workforce. And if you can achieve that goal, which for most countries means vaccinating between 20% and maybe 30% of the population, then you can transform the antabuse into something that is much more manageable. Then you can buy yourself time to vaccinate everybody who wants to be vaccinated.We’ve argued the COVAX facility really offers the world the best shot at doing that globally in the fastest possible way, as well as providing for equitable access. This is a case where doing the equitable thing is also doing the efficient thing.CEPI has provided funding to nine treatments. Is it true that all those manufacturers aren’t required to provide the COVAX facility with treatment?.

That is correct. One of the things that we did, and I think it was an important role that CEPI played early on, was that we moved money very, very quickly, in small increments. You know, some of the early contracts were only $5 million or $10 million, to get programs up and running while we potentially put in place much larger-scale, longer-term contracts.If you were doing it over again, would you have given money without strings attached?. Yes, I think I would have. I think that was critically important to initiating programs.Our contract with Moderna was established in about 48 hours.

And that provided critical funding to them to manufacture doses that got them into clinical trials within nine weeks of the genetic sequences [of the alcoholism antabuse] being released.And if you look at the nine programs that we’ve invested in, seven are in clinical trials. Two — the AstraZeneca program now and the Moderna program — are among the handful in Phase 3 clinical trials. And, I think the number of projects that that we funded initially, which started in kind of a biotech or academic phase that have now been picked up by large multinational corporations, there’s at least four. The Themis program being picked up by Merck, Oxford University by AstraZeneca, the University of Queensland by CSL, and Clover being in partnership with GSK, I think that speaks to the quality of the programs that we selected.So, I think that combination of rapid review, speed of funding, getting those programs started, getting them oriented in the right direction, I think all of that is critical to where we are now.Companies that got money from CEPI to build out production capacity — that money came with strings attached, right?. Yes, exactly.

So, where CEPI has made investments that create manufacturing, or secure manufacturing capacity, the commitment has been that the capacity that is attributable to the CEPI investment is committed — at least right of first refusal — to the global procurement facility.WASHINGTON — The Trump administration removed a top Food and Drug Administration communications official from her post on Friday in the wake of several controversial agency misstatements, a senior administration official confirmed to STAT.The spokeswoman, Emily Miller, had played a lead role in defending the FDA commissioner, Stephen Hahn, after he misrepresented data regarding the use of blood plasma from recovered alcoholism treatment patients. The New York Times first reported Miller’s ouster. Miller’s tenure at as the top FDA spokeswoman lasted only 11 days. Her appointment was viewed with alarm by agency officials who felt her presence at the agency was emblematic of broader political pressure from the Trump administration, STAT first reported earlier this week.advertisement Before joining the FDA, Miller had no experience in health or medicine. Her former role as assistant commissioner for media affairs is typically not an appointment filled by political appointees.

The FDA’s communications arm typically maintains a neutral, nonpolitical tone.Miller’s appointment particularly alarmed FDA staff and outside scientists given her history in right-wing political advocacy and conservatism journalism. Her résumé included a stint as a Washington Times columnist, where she penned columns with titles that include “New Obamacare ads make young women look like sluts,” and a 2013 book on gun rights titled “Emily Gets Her Gun. But Obama Wants to Take Yours.”advertisement She also worked as a reporter for One America News Network, a right-wing cable channel that frequently espouses conspiracy theories and has declared an open alliance with President Trump.Miller quickly made her presence known at the FDA. In the wake of Hahn’s misstatements on blood plasma, she aggressively defended the commissioner, falsely claiming in a tweet that the therapy “has shown to be beneficial for 35% of patients.” An FDA press release on blood plasma, issued less than a week after her appointment, similarly alarmed agency insiders by trumpeting the emergency authorization as “Another Achievement in Administration’s Fight Against [the] antabuse.”.

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47.0

162x0

183.4

183.4

183.5

156.7

162x98

116.3

116.3

116.3

162x118

86.1

73.5

162x128

68.9

162x138

50.3

50.3

172x0

207.0

207.0

172x108

125.2

*107,0

172x128

92.2

172x138

73.6

172x148

53.7

53.7

182x0

232.0

232.0

EXT 197.8

182x118

134.1

182x128

117.5

*99,9

182x138

98.4

182x148

78.4

182x158

57.0

57.0

192x0

258.0

258.0

EXT 220.1

192x128

143.1

192x148

104.5

*89,3

192x168

60.4

202x0

285.0

285.0

202x98

218.0

218.0

218.0

202x138

152.0

152.0

202x148

*112,8

202x158

110.7

202x178

63.7

205x82

*246,8

212x138

180.4

212x148

161.0

212x158

*119,2

212x168

116.8

212x178

92.6

212x188

66.0

222x0

344.0

344.0

222x98

277.2

277.2

222x148

191.3

222x168

147.1

*125,7

222x178

123.0

222x188

97.4

232x158

201.6

201.6

232x178

154.7

*132,1

232x188

129.1

232x198

102.1

242x168

212.0

212.0

242x188

162.2

*138,6

242x198

135.3

242x208

106.9

252x0

444.0

444.0

252x178

222.3

*189,9

252x198

169.8

252x208

141.4

252x218

111.6

262x198

*175,7

262x218

147.6

262x228

116.4

272x168

319.7

319.7

272x228

153.7

272x238

121.1

276x0

*532,5

282x218

*191,0

282x238

159.9

282x248

125.9

292x188

348.8

292x248

166.0

302x148

484.4

302x198

363.3

363.3

*310,4

302x258

172.1

322x238

*280,8

332x248

*290,9

332x273

249.4

352x148

713.0

362x293

315.8

*269,8

392x343

251.6

402x148

976.5

402x348

*241,8

Firkant stænger
Standard dimensioner og legeringer
Standardlængder: 500, 1000, 2000 mm

A x B mm

JM 1-15 Rødgods

JM 3-15
Tin-bronze

JM 7-15/20 Aluminiumbronze

30x30

*6,8

32x32

9,1

9,1

40x40

*12,0

42x42

15,7

15,7

45x45

*15,2

52x12

5,6

5,6

52x14

6,5

6,5

52x18

8,3

8,3

52x22

10,2

10,2

52x52

24,1

24,1

55x55

*22,7

60x60

*27,4

67x12

7,2

7,2

67x14

8,3

8,3

67x18

10,7

10,7

67x22

13,1

13,1

67x32

19,1

19,1

16,3

70x70

*43,6

80x42

25,8

80x51

31.3

82x12

8,8

8,8

82x14

10,2

10,2

82x18

13,1

13,1

82x22

16,1

16,1

102x12

10,9

10,9

102x14

12,7

12,7

102x18

16,3

16,3

102x22

20,2

20,2

102x52

47

103x30

*23,5

105x55

44.2

122x18

19,5

19,5

122x22

23,9

23,9

130x63

62.6

130x65

74,7

142x18

22,7

22,7

142x22

27,8

27,8

150x70

*79,8

150x90

102,6

162x18

26

26

162x22

31,7

31,7

162x72

103

182x18

29,2

29,2

182x22

35,6

35,6

185x90

*126,5

202x18

32,4

32,4

202x22

39,6

39,6

202x30

*46,1

Sekskant stænger
Standard dimensioner og legeringer
Standardlængder: 500, 1000, 2000, 3000 mm. Sekskantstænger m/ hul fremstilles på bestilling

NV mm

JM 1-15 Rødgods

17

2,2

18

2,5

22

3,7

24

4,4

26

5,2

28

6

32

7,9

36

10

44

14,9

50

19,3