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    In her post, Duff credited her success to two things. Counting her how to buy flagyl in usa macros and training with Novo Body Fitness. I gave both a whirl for a week.First, I consulted the team at Novo Body for some insight into the workouts Duff was doing at home. They were kind enough to share a few workout videos with me and explained that Duff completed their strength-training sessions four to five times a week.I then reached out to Dietitian Nicola Moore of Lifeshape about counting my how to buy flagyl in usa macros.

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    I worked hard but was able to complete five workouts without cursing myself for signing up to this experiment.When it comes to food, I mostly felt comfortable with my plan. I usually stuck to the meals that Moore gave me, however, because measuring an item to swap it out for another felt too how to buy flagyl in usa time-consuming.Then there was the fact that I somehow forgot I'd agreed to do this diet over my birthday. Attempting to count the macros in cake and making allowances for that was near impossible for me. It's safe to say I how to buy flagyl in usa failed at least once.

    Sorry, Hilary!. What were how to buy flagyl in usa the results?. This might be the best thing I've done for my health since quarantine kicked off.I was able to approach my diet and fitness with a consistency that I'd lost for months. It became easier to make healthier choices, but I didn't cut anything out of my diet, so I wasn't longing how to buy flagyl in usa for a cheat meal.Getting up in the mornings became easier, and my energy levels lasted throughout the day.

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    Start Preamble flagyl gel generico click site Centers for Medicare &. Medicaid Services (CMS), HHS. Notice of flagyl gel generico meeting.

    This notice announces a Town Hall meeting in accordance with section 1886(d)(5)(K)(viii) of the Social Security Act (the Act) to discuss fiscal year (FY) 2022 applications for add-on payments for new medical services and technologies under the hospital inpatient prospective payment system (IPPS). The United States is responding to an outbreak of respiratory disease caused by the flagyl “antibiotics” and the disease it causes “antibiotics disease 2019” (abbreviated “buy antibiotics”). Due to the flagyl gel generico buy antibiotics flagyl, the Town Hall Meeting will be held virtually rather than as an in-person meeting.

    Interested parties are invited to this meeting to present their comments, recommendations, and data regarding whether the FY 2022 new medical services and technologies applications meet the substantial clinical improvement criterion. Meeting Date(s). The Town Hall Meeting announced in this notice will be flagyl gel generico held virtually on Tuesday, December 15, 2020 and Wednesday, December 16, 2020 (the number of new technology applications submitted will determine if a second day for the meeting is necessary.

    See the SUPPLEMENTARY INFORMATION section for details regarding the second day of the meeting and the posting of the preliminary meeting agenda). The Town Hall flagyl gel generico Meeting will begin each day at 9:00 a.m. Eastern Standard Time (e.s.t.) and check-in via online platform will begin at 8:30 a.m.

    E.s.t. Deadline flagyl gel generico for Requesting Special Accommodations. The deadline to submit requests for special Start Printed Page 65816accommodations is 5:00 p.m., e.s.t.

    On Monday, November 23, 2020. Deadline flagyl gel generico for Registration of Presenters at the Town Hall Meeting. The deadline to register to present at the Town Hall Meeting is 5:00 p.m., e.s.t.

    On Monday, November 23, 2020. Deadline for Submission of Agenda flagyl gel generico Item(s) or Written Comments for the Town Hall Meeting. Written comments and agenda items for discussion at the Town Hall Meeting, including agenda items by presenters, must be received by 5:00 p.m.

    E.s.t. On Monday, November 30, 2020. Deadline for Submission of Written Comments after the Town Hall Meeting for consideration in the Fiscal Year (FY) 2022 Hospital Inpatient Prospective Payment System/Long Term Care PPS (IPPS/LTCH PPS) Proposed Rule.

    Individuals may submit written comments after the Town Hall Meeting, as specified in the ADDRESSES section of this notice, on whether the service or technology represents a substantial clinical improvement. These comments must be received by 5:00 p.m. E.s.t.

    On Monday, December 28, 2020, for consideration in the FY 2022 IPPS/LTCH PPS proposed rule. Meeting Location. The Town Hall Meeting will be held virtually via live stream technology or webinar and listen-only via toll-free teleconference.

    Live stream or webinar and teleconference dial-in information will be provided through an upcoming listserv notice and will appear on the final meeting agenda, which will be posted on the New Technology website when available at. Http://www.cms.gov/​Medicare/​Medicare-Fee-for-Service-Payment/​AcuteInpatientPPS/​newtech.html. Continue to check the website for updates.

    Registration and Special Accommodations. Individuals wishing to present at the meeting must follow the instructions located in section III. Of this notice.

    Individuals who need special accommodations should send an email to newtech@cms.hhs.gov. Submission of Agenda Item(s) or Written Comments for the Town Hall Meeting. Each presenter must submit an agenda item(s) regarding whether a FY 2022 application meets the substantial clinical improvement criterion.

    Agenda items, written comments, questions or other statements must not exceed three single-spaced typed pages and may be sent via email to newtech@cms.hhs.gov. Start Further Info Michelle Joshua, (410) 786-6050, michelle.joshua@cms.hhs.gov. Or Cristina Nigro, (410) 786-7763, cristina.nigro@cms.hhs.gov.

    Alternatively, you may forward your requests via email to newtech@cms.hhs.gov. End Further Info End Preamble Start Supplemental Information I. Background on the Add-On Payments for New Medical Services and Technologies Under the IPPS Sections 1886(d)(5)(K) and (L) of the Social Security Act (the Act) require the Secretary to establish a process of identifying and ensuring adequate payments to acute care hospitals for new medical services and technologies under Medicare.

    Effective for discharges beginning on or after October 1, 2001, section 1886(d)(5)(K)(i) of the Act requires the Secretary to establish (after notice and opportunity for public comment) a mechanism to recognize the costs of new services and technologies under the hospital inpatient prospective payment system (IPPS). In addition, section 1886(d)(5)(K)(vi) of the Act specifies that a medical service or technology will be considered “new” if it meets criteria established by the Secretary (after notice and opportunity for public comment). (See the fiscal year (FY) 2002 IPPS proposed rule (66 FR 22693, May 4, 2001) and final rule (66 FR 46912, September 7, 2001) for a more detailed discussion.) As finalized in the FY 2020 and FY 2021 IPPS/Long-term Care Hospital (LTCH) Prospective Payment System (PPS) final rules, technologies which are eligible for the alternative new technology pathway for transformative new devices or the alternative new technology pathway for certain antimicrobials do not need to meet the requirement under 42 CFR 412.87(b)(1) that the technology represent an advance that substantially improves, relative to technologies previously available, the diagnosis or treatment of Medicare beneficiaries.

    These medical devices or products will also be considered new and not substantially similar to an existing technology for purposes of new technology add-on payment under the IPPS. (See the FY 2020 IPPS/LTCH PPS final rule (84 FR 42292 through 42297) and the FY 2021 IPPS/LTCH PPS final rule (85 FR 58733 through 58742) for additional information.) In the FY 2020 IPPS/LTCH PPS final rule (84 FR 42289 through 42292), we codified in our regulations at § 412.87 the following aspects of how we evaluate substantial clinical improvement for purposes of new technology add-on payments under the IPPS in order to determine if a new technology meets the substantial clinical improvement requirement. The totality of the circumstances is considered when making a determination that a new medical service or technology represents an advance that substantially improves, relative to services or technologies previously available, the diagnosis or treatment of Medicare beneficiaries.

    A determination that a new medical service or technology represents an advance that substantially improves, relative to services or technologies previously available, the diagnosis or treatment of Medicare beneficiaries means— ++ The new medical service or technology offers a treatment option for a patient population unresponsive to, or ineligible for, currently available treatments. ++ The new medical service or technology offers the ability to diagnose a medical condition in a patient population where that medical condition is currently undetectable or offers the ability to diagnose a medical condition earlier in a patient population than allowed by currently available methods, and there must also be evidence that use of the new medical service or technology to make a diagnosis affects the management of the patient. Or ++ The use of the new medical service or technology significantly improves clinical outcomes relative to services or technologies previously available as demonstrated by one or more of the following.

    €”A reduction in at least one clinically significant adverse event, including a reduction in mortality or a clinically significant complication. €”A decreased rate of at least one subsequent diagnostic or therapeutic intervention (for example, due to reduced rate of recurrence of the disease process). €”A decreased number of future hospitalizations or physician visits.

    €”A more rapid beneficial resolution of the disease process treatment including, but not limited to, a reduced length of stay or recovery time. An improvement in one or more activities of daily living. An improved quality of life.

    Or, a demonstrated greater medication adherence or compliance. ++ The totality of the circumstances otherwise demonstrates that the new medical service or technology substantially improves, relative to technologies previously available, the diagnosis or treatment of Medicare beneficiaries. Evidence from the following published or unpublished information Start Printed Page 65817sources from within the United States or elsewhere may be sufficient to establish that a new medical service or technology represents an advance that substantially improves, relative to services or technologies previously available, the diagnosis or treatment of Medicare beneficiaries.

    Clinical trials, peer reviewed journal articles. Study results. Meta-analyses.

    Consensus statements. White papers. Patient surveys.

    Case studies. Reports. Systematic literature reviews.

    Letters from major healthcare associations. Editorials and letters to the editor. And public comments.

    Other appropriate information sources may be considered. The medical condition diagnosed or treated by the new medical service or technology may have a low prevalence among Medicare beneficiaries. The new medical service or technology may represent an advance that substantially improves, relative to services or technologies previously available, the diagnosis or treatment of a subpopulation of patients with the medical condition diagnosed or treated by the new medical service or technology.

    Section 1886(d)(5)(K)(viii) of the Act requires that as part of the process for evaluating new medical services and technology applications, the Secretary shall do the following. Provide for public input regarding whether a new service or technology represents an advance in medical technology that substantially improves the diagnosis or treatment of Medicare beneficiaries before publication of a proposed rule. Make public and periodically update a list of all the services and technologies for which an application is pending.

    Accept comments, recommendations, and data from the public regarding whether the service or technology represents a substantial improvement. Provide for a meeting at which organizations representing hospitals, physicians, manufacturers and any other interested party may present comments, recommendations, and data to the clinical staff of CMS as to whether the service or technology represents a substantial improvement before publication of a proposed rule. The opinions and presentations provided during this meeting will assist us as we evaluate the new medical services and technology applications for FY 2022.

    In addition, they will help us to evaluate our policy on the IPPS new technology add-on payment process before the publication of the FY 2022 IPPS/LTCH PPS proposed rule. II. Town Hall Meeting Format and Conference Call/Live Streaming Information A.

    Format of the Town Hall Meeting As noted in section I. Of this notice, we are required to provide for a meeting at which organizations representing hospitals, physicians, manufacturers and any other interested party may present comments, recommendations, and data to the clinical staff of CMS concerning whether the service or technology represents a substantial clinical improvement. This meeting will allow for a discussion of the substantial clinical improvement criterion for the FY 2022 new medical services and technology add-on payment applications.

    Information regarding the applications can be found on our website at http://www.cms.gov/​Medicare/​Medicare-Fee-for-Service-Payment/​AcuteInpatientPPS/​newtech.html. The majority of the meeting will be reserved for presentations of comments, recommendations, and data from registered presenters. The time for each presenter's comments will be approximately 10 to 15 minutes and will be based on the number of registered presenters.

    Individuals who would like to present must register and submit their agenda item(s) via email to newtech@cms.hhs.gov by the date specified in the DATES section of this notice. Depending on the number of applications received, we will determine if a second meeting day is necessary. A preliminary agenda will be posted on the CMS website at http://www.cms.gov/​Medicare/​Medicare-Fee-for-Service-Payment/​AcuteInpatientPPS/​newtech.html by November 23, 2020 to inform the public of the number of days of the meeting.

    In addition, written comments will also be accepted and presented at the meeting if they are received via email to newtech@cms.hhs.gov by the date specified in the DATES section of this notice. Written comments may also be submitted after the meeting for our consideration. If the comments are to be considered before the publication of the FY 2022 IPPS/LTCH PPS proposed rule, the comments must be received via email to newtech@cms.hhs.gov by the date specified in the DATES section of this notice.

    B. Conference Call, Live Streaming, and Webinar Information As noted previously, the Town Hall meeting will be held virtually due to the buy antibiotics flagyl. There will be an option to participate in the Town Hall Meeting via live streaming technology or webinar and a toll-free teleconference phone line.

    Information on the option to participate via live streaming technology or webinar and a teleconference dial-in will be provided through an upcoming listserv notice and will appear on the final meeting agenda, which will be posted on the New Technology website at. Http://www.cms.gov/​Medicare/​Medicare-Fee-for-Service-Payment/​AcuteInpatientPPS/​newtech.html. Continue to check the website for updates.

    C. Disclaimer We cannot guarantee reliability for live streaming technology or a webinar. III.

    Registration Instructions The Division of New Technology in CMS is coordinating the meeting registration for the Town Hall Meeting on substantial clinical improvement. While there is no registration fee, individuals planning to present at the Town Hall Meeting must register to present. Registration for presenters may be completed by sending an email to newtech@cms.hhs.gov.

    Please include your name, address, telephone number, email address and fax number. Registration for attendees not presenting at the meeting is not required. The Administrator of the Centers for Medicare &.

    Medicaid Services (CMS), Seema Verma, having reviewed and approved this document, authorizes Lynette Wilson, who is the Federal Register Liaison, to electronically sign this document for purposes of publication in the Federal Register. Start Signature Dated. October 8, 2020.

    Lynette Wilson, Federal Register Liaison, Centers for Medicare &. Medicaid Services. End Signature End Supplemental Information [FR Doc.

    2020-22894 Filed 10-14-20. 8:45 am]BILLING CODE 4120-01-PStart Preamble Health Resources and Services Administration (HRSA), Department of Health and Human Services. Notice.

    In compliance with the requirement for opportunity for public comment on proposed data collection projects of the Paperwork Reduction Act of 1995, HRSA announces plans to submit an Information Collection Request (ICR), described below, to the Office of Management and Budget (OMB). Prior to submitting the ICR to OMB, HRSA seeks comments from the public regarding the burden estimate, below, or any other aspect of the ICR. Comments on this ICR should be received no later than December 15, 2020.

    Submit your comments to paperwork@hrsa.gov or mail the HRSA Information Collection Clearance Officer, Room 14N136B, 5600 Fishers Lane, Rockville, MD 20857. Start Further Info To request more information on the proposed project or to obtain a copy of the data collection plans and draft instruments, email paperwork@hrsa.gov or call Lisa Wright-Solomon, the HRSA Information Collection Clearance Officer at (301) 443-1984. End Further Info End Preamble Start Supplemental Information When submitting comments or requesting information, please include the Start Printed Page 65834information request collection title for reference.

    Information Collection Request Title. Survey of Eligible Users of the National Practitioner Data Bank, OMB No. 0915-0366—Reinstatement With Change.

    Abstract. HRSA plans to survey the users National Practitioner Data Bank (NPDB). The purpose of this survey is to assess the overall satisfaction of the eligible users of the NPDB.

    This survey will evaluate the effectiveness of the NPDB as a flagging system, source of information, and its use in decision making. Furthermore, this survey will collect information from organizations and individuals who query the NPDB to understand and improve their user experience. This survey is a reinstatement of the 2012 NPDB survey with some changes.

    Need and Proposed Use of the Information. The survey will collect information regarding the participants' experiences of querying and reporting to the NPDB, perceptions of health care practitioners with reports, impact of NPDB reports on organizations' decision-making, and satisfaction with various NPDB products and services. The survey will also be administered to health care practitioners that use the self-query service provided by the NPDB.

    The self-queriers will be asked about their experiences of querying, the impact of having reports in the NPDB on their careers and health care organizations' perceptions, and their satisfaction with various NPDB products and services. Understanding self-queriers' satisfaction and their use of the information is an important component of the survey. Proposed changes to this ICR include the following.

    1. In the proposed entity survey, there are 37 modules and 258 questions. From the previous 2012 survey, there are 15 deleted questions and 13 new questions in addition to proposed changes to 12 survey questions.

    2. In the proposed self-query survey, there are 22 modules and 88 questions. From the previous 2012 survey, there are 5 deleted questions and 5 new questions in addition to proposed changes to two survey questions.

    Likely Respondents. Eligible users of the NPDB will be asked to complete a web-based survey. Data gathered from the survey will be compared with previous survey results.

    This survey will provide HRSA with the information necessary for research purposes and for improving the usability and effectiveness of the NPDB. Burden Statement. Burden in this context means the time expended by persons to generate, maintain, retain, disclose or provide the information requested.

    This includes the time needed to review instructions, to develop, acquire, install and utilize technology and systems for the purpose of collecting, validating and verifying information, processing and maintaining information, and disclosing and providing information, to train personnel and to be able to respond to a collection of information, to search data sources, to complete and review the collection of information, and to transmit or otherwise disclose the information. The total annual burden hours estimated for this Information Collection Request are summarized in the table below. Total Estimated Annualized Burden HoursForm nameNumber of respondentsNumber of responses per respondentTotal responsesAverage burden per response (in hours)Total burden hoursNPDB Users Entities Respondents15,000115,0000.253,750NPDB Self-Query Respondents2,00012,0000.10200Total17,00017,0003,950 HRSA specifically requests comments on (1) the necessity and utility of the proposed information collection for the proper performance of the agency's functions, (2) the accuracy of the estimated burden, (3) ways to enhance the quality, utility, and clarity of the information to be collected, and (4) the use of automated collection techniques or other forms of information technology to minimize the information collection burden.

    Start Signature Maria G. Button, Director, Executive Secretariat. End Signature End Supplemental Information [FR Doc.

    2020-22964 Filed 10-15-20. 8:45 am]BILLING CODE 4165-15-P.

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    Interested parties are invited to this meeting to present their comments, recommendations, and data regarding whether the FY 2022 new medical services and technologies applications meet the substantial clinical improvement criterion. Meeting Date(s). The Town Hall Meeting announced in this notice will be held virtually on Tuesday, December 15, 2020 and Wednesday, December 16, 2020 (the number of new technology how to buy flagyl in usa applications submitted will determine if a second day for the meeting is necessary.

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    E.s.t. Deadline for Requesting how to buy flagyl in usa Special Accommodations. The deadline to submit requests for special Start Printed Page 65816accommodations is 5:00 p.m., e.s.t.

    On Monday, November 23, 2020. Deadline for how to buy flagyl in usa Registration of Presenters at the Town Hall Meeting. The deadline to register to present at the Town Hall Meeting is 5:00 p.m., e.s.t.

    On Monday, November 23, 2020. Deadline for Submission of Agenda how to buy flagyl in usa Item(s) or Written Comments for the Town Hall Meeting. Written comments and agenda items for discussion at the Town Hall Meeting, including agenda items by presenters, must be received by 5:00 p.m.

    E.s.t. On Monday, November 30, 2020. Deadline for Submission of Written Comments after the Town Hall Meeting for consideration in the Fiscal Year (FY) 2022 Hospital Inpatient Prospective Payment System/Long Term Care PPS (IPPS/LTCH PPS) Proposed Rule.

    Individuals may submit written comments after the Town Hall Meeting, as specified in the ADDRESSES section of this notice, on whether the service or technology represents a substantial clinical improvement. These comments must be received by 5:00 p.m. E.s.t.

    On Monday, December 28, 2020, for consideration in the FY 2022 IPPS/LTCH PPS proposed rule. Meeting Location. The Town Hall Meeting will be held virtually via live stream technology or webinar and listen-only via toll-free teleconference.

    Live stream or webinar and teleconference dial-in information will be provided through an upcoming listserv notice and will appear on the final meeting agenda, which will be posted on the New Technology website when available at. Http://www.cms.gov/​Medicare/​Medicare-Fee-for-Service-Payment/​AcuteInpatientPPS/​newtech.html. Continue to check the website for updates.

    Registration and Special Accommodations. Individuals wishing to present at the meeting must follow the instructions located in section III. Of this notice.

    Individuals who need special accommodations should send an email to newtech@cms.hhs.gov. Submission of Agenda Item(s) or Written Comments for the Town Hall Meeting. Each presenter must submit an agenda item(s) regarding whether a FY 2022 application meets the substantial clinical improvement criterion.

    Agenda items, written comments, questions or other statements must not exceed three single-spaced typed pages and may be sent via email to newtech@cms.hhs.gov. Start Further Info Michelle Joshua, (410) 786-6050, michelle.joshua@cms.hhs.gov. Or Cristina Nigro, (410) 786-7763, cristina.nigro@cms.hhs.gov.

    Alternatively, you may forward your requests via email to newtech@cms.hhs.gov. End Further Info End Preamble Start Supplemental Information I. Background on the Add-On Payments for New Medical Services and Technologies Under the IPPS Sections 1886(d)(5)(K) and (L) of the Social Security Act (the Act) require the Secretary to establish a process of identifying and ensuring adequate payments to acute care hospitals for new medical services and technologies under Medicare.

    Effective for discharges beginning on or after October 1, 2001, section 1886(d)(5)(K)(i) of the Act requires the Secretary to establish (after notice and opportunity for public comment) a mechanism to recognize the costs of new services and technologies under the hospital inpatient prospective payment system (IPPS). In addition, section 1886(d)(5)(K)(vi) of the Act specifies that a medical service or technology will be considered “new” if it meets criteria established by the Secretary (after notice and opportunity for public comment). (See the fiscal year (FY) 2002 IPPS proposed rule (66 FR 22693, May 4, 2001) and final rule (66 FR 46912, September 7, 2001) for a more detailed discussion.) As finalized in the FY 2020 and FY 2021 IPPS/Long-term Care Hospital (LTCH) Prospective Payment System (PPS) final rules, technologies which are eligible for the alternative new technology pathway for transformative new devices or the alternative new technology pathway for certain antimicrobials do not need to meet the requirement under 42 CFR 412.87(b)(1) that the technology represent an advance that substantially improves, relative to technologies previously available, the diagnosis or treatment of Medicare beneficiaries.

    These medical devices or products will also be considered new and not substantially similar to an existing technology for purposes of new technology add-on payment under the IPPS. (See the FY 2020 IPPS/LTCH PPS final rule (84 FR 42292 through 42297) and the FY 2021 IPPS/LTCH PPS final rule (85 FR 58733 through 58742) for additional information.) In the FY 2020 IPPS/LTCH PPS final rule (84 FR 42289 through 42292), we codified in our regulations at § 412.87 the following aspects of how we evaluate substantial clinical improvement for purposes of new technology add-on payments under the IPPS in order to determine if a new technology meets the substantial clinical improvement requirement. The totality of the circumstances is considered when making a determination that a new medical service or technology represents an advance that substantially improves, relative to services or technologies previously available, the diagnosis or treatment of Medicare beneficiaries.

    A determination that a new medical service or technology represents an advance that substantially improves, relative to services or technologies previously available, the diagnosis or treatment of Medicare beneficiaries means— ++ The new medical service or technology offers a treatment option for a patient population unresponsive to, or ineligible for, currently available treatments. ++ The new medical service or technology offers the ability to diagnose a medical condition in a patient population where that medical condition is currently undetectable or offers the ability to diagnose a medical condition earlier in a patient population than allowed by currently available methods, and there must also be evidence that use of the new medical service or technology to make a diagnosis affects the management of the patient. Or ++ The use of the new medical service or technology significantly improves clinical outcomes relative to services or technologies previously available as demonstrated by one or more of the following.

    €”A reduction in at least one clinically significant adverse event, including a reduction in mortality or a clinically significant complication. €”A decreased rate of at least one subsequent diagnostic or therapeutic intervention (for example, due to reduced rate of recurrence of the disease process). €”A decreased number of future hospitalizations or physician visits.

    €”A more rapid beneficial resolution of the disease process treatment including, but not limited to, a reduced length of stay or recovery time. An improvement in one or more activities of daily living. An improved quality of life.

    Or, a demonstrated greater medication adherence or compliance. ++ The totality of the circumstances otherwise demonstrates that the new medical service or technology substantially improves, relative to technologies previously available, the diagnosis or treatment of Medicare beneficiaries. Evidence from the following published or unpublished information Start Printed Page 65817sources from within the United States or elsewhere may be sufficient to establish that a new medical service or technology represents an advance that substantially improves, relative to services or technologies previously available, the diagnosis or treatment of Medicare beneficiaries.

    Clinical trials, peer reviewed journal articles. Study results. Meta-analyses.

    Consensus statements. White papers. Patient surveys.

    Case studies. Reports. Systematic literature reviews.

    Letters from major healthcare associations. Editorials and letters to the editor. And public comments.

    Other appropriate information sources may be considered. The medical condition diagnosed or treated by the new medical service or technology may have a low prevalence among Medicare beneficiaries. The new medical service or technology may represent an advance that substantially improves, relative to services or technologies previously available, the diagnosis or treatment of a subpopulation of patients with the medical condition diagnosed or treated by the new medical service or technology.

    Section 1886(d)(5)(K)(viii) of the Act requires that as part of the process for evaluating new medical services and technology applications, the Secretary shall do the following. Provide for public input regarding whether a new service or technology represents an advance in medical technology that substantially improves the diagnosis or treatment of Medicare beneficiaries before publication of a proposed rule. Make public and periodically update a list of all the services and technologies for which an application is pending.

    Accept comments, recommendations, and data from the public regarding whether the service or technology represents a substantial improvement. Provide for a meeting at which organizations representing hospitals, physicians, manufacturers and any other interested party may present comments, recommendations, and data to the clinical staff of CMS as to whether the service or technology represents a substantial improvement before publication of a proposed rule. The opinions and presentations provided during this meeting will assist us as we evaluate the new medical services and technology applications for FY 2022.

    In addition, they will help us to evaluate our policy on the IPPS new technology add-on payment process before the publication of the FY 2022 IPPS/LTCH PPS proposed rule. II. Town Hall Meeting Format and Conference Call/Live Streaming Information A.

    Format of the Town Hall Meeting As noted in section I. Of this notice, we are required to provide for a meeting at which organizations representing hospitals, physicians, manufacturers and any other interested party may present comments, recommendations, and data to the clinical staff of CMS concerning whether the service or technology represents a substantial clinical improvement. This meeting will allow for a discussion of the substantial clinical improvement criterion for the FY 2022 new medical services and technology add-on payment applications.

    Information regarding the applications can be found on our website at http://www.cms.gov/​Medicare/​Medicare-Fee-for-Service-Payment/​AcuteInpatientPPS/​newtech.html. The majority of the meeting will be reserved for presentations of comments, recommendations, and data from registered presenters. The time for each presenter's comments will be approximately 10 to 15 minutes and will be based on the number of registered presenters.

    Individuals who would like to present must register and submit their agenda item(s) via email to newtech@cms.hhs.gov by the date specified in the DATES section of this notice. Depending on the number of applications received, we will determine if a second meeting day is necessary. A preliminary agenda will be posted on the CMS website at http://www.cms.gov/​Medicare/​Medicare-Fee-for-Service-Payment/​AcuteInpatientPPS/​newtech.html by November 23, 2020 to inform the public of the number of days of the meeting.

    In addition, written comments will also be accepted and presented at the meeting if they are received via email to newtech@cms.hhs.gov by the date specified in the DATES section of this notice. Written comments may also be submitted after the meeting for our consideration. If the comments are to be considered before the publication of the FY 2022 IPPS/LTCH PPS proposed rule, the comments must be received via email to newtech@cms.hhs.gov by the date specified in the DATES section of this notice.

    B. Conference Call, Live Streaming, and Webinar Information As noted previously, the Town Hall meeting will be held virtually due to the buy antibiotics flagyl. There will be an option to participate in the Town Hall Meeting via live streaming technology or webinar and a toll-free teleconference phone line.

    Information on the option to participate via live streaming technology or webinar and a teleconference dial-in will be provided through an upcoming listserv notice and will appear on the final meeting agenda, which will be posted on the New Technology website at. Http://www.cms.gov/​Medicare/​Medicare-Fee-for-Service-Payment/​AcuteInpatientPPS/​newtech.html. Continue to check the website for updates.

    C. Disclaimer We cannot guarantee reliability for live streaming technology or a webinar. III.

    Registration Instructions The Division of New Technology in CMS is coordinating the meeting registration for the Town Hall Meeting on substantial clinical improvement. While there is no registration fee, individuals planning to present at the Town Hall Meeting must register to present. Registration for presenters may be completed by sending an email to newtech@cms.hhs.gov.

    Please include your name, address, telephone number, email address and fax number. Registration for attendees not presenting at the meeting is not required. The Administrator of the Centers for Medicare &.

    Medicaid Services (CMS), Seema Verma, having reviewed and approved this document, authorizes Lynette Wilson, who is the Federal Register Liaison, to electronically sign this document for purposes of publication in the Federal Register. Start Signature Dated. October 8, 2020.

    Lynette Wilson, Federal Register Liaison, Centers for Medicare &. Medicaid Services. End Signature End Supplemental Information [FR Doc.

    2020-22894 Filed 10-14-20. 8:45 am]BILLING CODE 4120-01-PStart Preamble Health Resources and Services Administration (HRSA), Department of Health and Human Services. Notice.

    In compliance with the requirement for opportunity for public comment on proposed data collection projects of the Paperwork Reduction Act of 1995, HRSA announces plans to submit an Information Collection Request (ICR), described below, to the Office of Management and Budget (OMB). Prior to submitting the ICR to OMB, HRSA seeks comments from the public regarding the burden estimate, below, or any other aspect of the ICR. Comments on this ICR should be received no later than December 15, 2020.

    Submit your comments to paperwork@hrsa.gov or mail the HRSA Information Collection Clearance Officer, Room 14N136B, 5600 Fishers Lane, Rockville, MD 20857. Start Further Info To request more information on the proposed project or to obtain a copy of the data collection plans and draft instruments, email paperwork@hrsa.gov or call Lisa Wright-Solomon, the HRSA Information Collection Clearance Officer at (301) 443-1984. End Further Info End Preamble Start Supplemental Information When submitting comments or requesting information, please include the Start Printed Page 65834information request collection title for reference.

    Information Collection Request Title. Survey of Eligible Users of the National Practitioner Data Bank, OMB No. 0915-0366—Reinstatement With Change.

    Abstract. HRSA plans to survey the users National Practitioner Data Bank (NPDB). The purpose of this survey is to assess the overall satisfaction of the eligible users of the NPDB.

    This survey will evaluate the effectiveness of the NPDB as a flagging system, source of information, and its use in decision making. Furthermore, this survey will collect information from organizations and individuals who query the NPDB to understand and improve their user experience. This survey is a reinstatement of the 2012 NPDB survey with some changes.

    Need and Proposed Use of the Information. The survey will collect information regarding the participants' experiences of querying and reporting to the NPDB, perceptions of health care practitioners with reports, impact of NPDB reports on organizations' decision-making, and satisfaction with various NPDB products and services. The survey will also be administered to health care practitioners that use the self-query service provided by the NPDB.

    The self-queriers will be asked about their experiences of querying, the impact of having reports in the NPDB on their careers and health care organizations' perceptions, and their satisfaction with various NPDB products and services. Understanding self-queriers' satisfaction and their use of the information is an important component of the survey. Proposed changes to this ICR include the following.

    1. In the proposed entity survey, there are 37 modules and 258 questions. From the previous 2012 survey, there are 15 deleted questions and 13 new questions in addition to proposed changes to 12 survey questions.

    2. In the proposed self-query survey, there are 22 modules and 88 questions. From the previous 2012 survey, there are 5 deleted questions and 5 new questions in addition to proposed changes to two survey questions.

    Likely Respondents. Eligible users of the NPDB will be asked to complete a web-based survey. Data gathered from the survey will be compared with previous survey results.

    This survey will provide HRSA with the information necessary for research purposes and for improving the usability and effectiveness of the NPDB. Burden Statement. Burden in this context means the time expended by persons to generate, maintain, retain, disclose or provide the information requested.

    This includes the time needed to review instructions, to develop, acquire, install and utilize technology and systems for the purpose of collecting, validating and verifying information, processing and maintaining information, and disclosing and providing information, to train personnel and to be able to respond to a collection of information, to search data sources, to complete and review the collection of information, and to transmit or otherwise disclose the information. The total annual burden hours estimated for this Information Collection Request are summarized in the table below. Total Estimated Annualized Burden HoursForm nameNumber of respondentsNumber of responses per respondentTotal responsesAverage burden per response (in hours)Total burden hoursNPDB Users Entities Respondents15,000115,0000.253,750NPDB Self-Query Respondents2,00012,0000.10200Total17,00017,0003,950 HRSA specifically requests comments on (1) the necessity and utility of the proposed information collection for the proper performance of the agency's functions, (2) the accuracy of the estimated burden, (3) ways to enhance the quality, utility, and clarity of the information to be collected, and (4) the use of automated collection techniques or other forms of information technology to minimize the information collection burden.

    Start Signature Maria G. Button, Director, Executive Secretariat. End Signature End Supplemental Information [FR Doc.

    2020-22964 Filed 10-15-20. 8:45 am]BILLING CODE 4165-15-P.

    What should I watch for while taking Flagyl?

    Tell your doctor or health care professional if your symptoms do not improve or if they get worse.

    You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how Flagyl affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells.

    Avoid alcoholic drinks while you are taking Flagyl and for three days afterward. Alcohol may make you feel dizzy, sick, or flushed.

    If you are being treated for a sexually transmitted disease, avoid sexual contact until you have finished your treatment. Your sexual partner may also need treatment.

    What flagyl is used to treat

    NONE

    Western NSW residents will have even greater access to mental health support with the opening of a new Lifeline centre in Dubbo.Minister for Mental Health Bronnie Taylor will open the new, purpose-built centre today, thanks to $600,000 in special funding from the NSW Government.“We want people living in the Central West to be able to access timely support from counsellors who understand their local community and the pressures they might be under,” Mrs Taylor said.“As well as establishing a dedicated Lifeline presence in Dubbo, the funding will also allow Lifeline Central West to triple the number of crisis telephone calls answered in Dubbo and its surrounds.”Member for Dubbo Dugald Saunders said the centre comes at a critical time for his community.“The brutal forces of drought, buy antibiotics and financial uncertainty are taking a toll on the strongest and most what flagyl is used to treat resilient among us,” Mr Saunders said.“One of my priorities after being elected was to see Lifeline’s local footprint expanded and supported, and funding for an appropriate building has been a key component of that.“It’s important for people to know they can lean on trained counsellors who live in the area and know the situations confronting people in central west NSW.”The new centre will also be the base for the Rapid Community Support Program (Rapid) – an outreach program which goes directly to towns hit by significant events such as drought and bushfire to provide counselling and support within their own community.The service received a $500,000 boost from the NSW Government to enable it to continue operations as part of an additional $6 million investment provided to Lifeline in response to the buy antibiotics flagyl.CEO of Lifeline Central West Stephanie Robinson said the Dubbo-based team willserve a vast area, including Wellington, Narromine, Mendooran, Coonabarabran, Coonamble, Walgett, Bourke and Lightning Ridge.“Our new centre will be a safe space for people to have group or one-on-one counselling sessions and will also serve as a base for our trained volunteers to provide community outreach,” Ms Robinson said.Lifeline Central West is a not-for-profit organisation with offices in Bathurst, Orange and Dubbo with nine full-time staff and approximately 130 trained volunteers. The NSW Government has invested over $25 million in Lifeline over 4 years.As part of SafeWork Month 2020, a number of prominent business and industry leaders have been appointed to help drive positive change by breaking down the barriers and stigma associated with mental health in NSW workplaces.Minister for Better Regulation and Innovation Kevin Anderson and Minister for Mental Health Bronnie Taylor today announced the NSW Government has appointed 12 ambassadors to champion the importance of good mental health in the workplace.Mr Anderson said the ambassadors will play a critical role in assisting the NSW Government meet its target of 90,000 business taking effective action to create work environments which benefit mental health by 2022.“Statistically we know that one-in-six people struggle with their mental health, and I would suggest those figures are conservative given the current challenging social and economic environment,” Mr Anderson said.“The ambassadors will work alongside us to send a message to employees in every corner of NSW that if you are struggling and need help, we will be there for you.”Among the new mental health ambassadors are Landcom CEO and Lifeline Chairman John Brogden AM, Westpac Group Chief Mental Health Officer David Burroughs and what flagyl is used to treat Business Chicks CEO Olivia Ruello.Mr Anderson said there will also be significant financial benefits for businesses.“The financial cost of mental health to NSW employers is $2.8 billion a year, but for every dollar invested into improving culture and outcomes for those living with mental ill-health, there is a return on investment of up to four dollars,” Mr Anderson said.“Our ambassadors recognise that a mentally healthy workplace is good business, and have committed to continuing the great work they do to support their workers and to encourage others in their industry to do the same.”Mrs Taylor said the event is another example of the NSW Government’s commitment to leading the nation in mental health reform.“Most of us spend about one-third or more of our waking lives at work. It’s a huge part of what we do and can have a huge impact on our mental health in a positive or negative way,” Mrs Taylor said.“Everyone in the workplace can contribute to a culture where people feel safe and supported to talk about mental health what flagyl is used to treat and it’s really encouraging to see so many leaders from NSW’s business sector stepping up.” For more information please visit SafeWork NSW..

    Western NSW residents will have even greater access to mental health support with the opening of a new Lifeline centre in Dubbo.Minister for Mental Health Bronnie Taylor will open the new, purpose-built centre today, thanks to $600,000 in special funding from the NSW Government.“We want people living in the Central West to be able to access timely support from counsellors who understand their local community and the pressures they might be under,” Mrs Taylor said.“As well as establishing a dedicated Lifeline presence in Dubbo, the funding will also allow Lifeline Central West to triple the number of crisis telephone calls answered in Dubbo and its surrounds.”Member for Dubbo Dugald Saunders said the centre comes at a critical time for his community.“The brutal forces of drought, buy antibiotics and financial uncertainty are taking a toll on how to buy flagyl in usa the strongest and most resilient among us,” Mr Saunders said.“One of my priorities after being elected was to see Lifeline’s local footprint expanded and supported, and funding for an appropriate building has been a key component of that.“It’s important for people to know they can lean on trained counsellors who live in the area and know the situations confronting people in central west NSW.”The new centre will also be the base for the Rapid Community Support Program (Rapid) – an outreach program which goes directly to towns hit by significant events such as drought and bushfire to provide counselling and support within their own community.The service received a $500,000 boost from the NSW Government to enable it to continue operations as part of http://basey.com/homepage/home-v2-3-col-images-contact/ an additional $6 million investment provided to Lifeline in response to the buy antibiotics flagyl.CEO of Lifeline Central West Stephanie Robinson said the Dubbo-based team willserve a vast area, including Wellington, Narromine, Mendooran, Coonabarabran, Coonamble, Walgett, Bourke and Lightning Ridge.“Our new centre will be a safe space for people to have group or one-on-one counselling sessions and will also serve as a base for our trained volunteers to provide community outreach,” Ms Robinson said.Lifeline Central West is a not-for-profit organisation with offices in Bathurst, Orange and Dubbo with nine full-time staff and approximately 130 trained volunteers. The NSW Government has invested over $25 million in Lifeline over 4 years.As part of SafeWork Month 2020, a number of prominent business and industry leaders have been appointed to help drive positive change by breaking down the barriers and stigma associated with mental health in NSW workplaces.Minister for Better Regulation and Innovation Kevin Anderson and Minister for Mental Health Bronnie Taylor today announced the NSW Government has appointed 12 ambassadors to champion the importance of good mental health in the workplace.Mr Anderson said the ambassadors will play a critical role in assisting the NSW Government meet http://www.storybones.net/general_info/new-storybones-site/ its target of 90,000 business taking effective action to create work environments which benefit mental health by 2022.“Statistically we know that one-in-six people struggle with their mental health, and I would suggest those figures are conservative given the current challenging social and economic environment,” Mr Anderson said.“The ambassadors will work alongside us to send a message to employees in every corner of NSW that if you are struggling and need help, we will be there for you.”Among the new mental health ambassadors are Landcom CEO and Lifeline Chairman John Brogden AM, Westpac Group Chief Mental Health Officer David Burroughs and Business Chicks CEO Olivia Ruello.Mr Anderson said there will also be significant financial benefits for businesses.“The financial cost how to buy flagyl in usa of mental health to NSW employers is $2.8 billion a year, but for every dollar invested into improving culture and outcomes for those living with mental ill-health, there is a return on investment of up to four dollars,” Mr Anderson said.“Our ambassadors recognise that a mentally healthy workplace is good business, and have committed to continuing the great work they do to support their workers and to encourage others in their industry to do the same.”Mrs Taylor said the event is another example of the NSW Government’s commitment to leading the nation in mental health reform.“Most of us spend about one-third or more of our waking lives at work. It’s a huge part of what we do and can have a huge impact on our mental health in a positive or negative way,” Mrs Taylor said.“Everyone in the workplace can contribute to a culture where people feel safe and supported to talk about mental health and it’s really encouraging to see so many leaders from NSW’s business sector stepping how to buy flagyl in usa up.” For more information please visit SafeWork NSW..

    Flagyl treats what

    NONE

    On 1 September 2020, we took on the Read Full Article roles flagyl treats what of co-editors-in-chief for BMJ Quality and Safety, and want to take this opportunity to introduce ourselves and our vision for the journal. We represent two different continents, two different professions and two different sets of research expertise. What we have in common is a passion for conducting and flagyl treats what publishing high-quality research and quality improvement work to benefit the quality and safety of patient care, as well as encouraging others to do likewise.We assume leadership of the journal during a major worldwide crisis brought on by the buy antibiotics flagyl, which has affected almost every aspect of society. Response to the flagyl is requiring engagement from every part of our health care systems—government policy, public health, ambulatory care, inpatient and long-term care, every type of healthcare worker, and of course patients and their care partners. Most journals, including ours, have flagyl treats what seen a substantial increase in manuscript submissions.

    We have published several articles related to buy antibiotics that address quality and safety issues central to the journal’s interests—including staffing levels, teamwork, how the flagyl has exposed weaknesses in healthcare systems, and how it may even stimulate efforts to address deficiencies in quality and safety.1–5We take note of the flagyl not only because of its significance but also because, like the flagyl, quality and safety problems are international issues that affect and require engagement from all parts of our healthcare systems and from all stakeholders. These stakeholders include patients and their care partners, every type of healthcare worker, organisational leaders, policy makers and, of course, researchers and quality improvement teams. Improving quality and safety also requires engagement from experts from other disciplines and industries whose research and practice can inform our flagyl treats what efforts to improve care.As new co-editors-in-chief, we find this comprehensive view of the stakeholders for quality and safety to be both necessary to improve care and intellectually stimulating. Of course, with so many stakeholders, there needs to be some additional focus, and we find that on BMJ Quality and Safety’s masthead6. €˜The journal integrates the academic and clinical aspects of quality and safety in healthcare by encouraging academics to create evidence and knowledge valued by clinicians, and clinicians to value using evidence and knowledge to improve quality’.We will continue to publish research and opinion that creates ‘evidence and knowledge valued by flagyl treats what clinicians’.

    To accomplish this, we will maintain high methodological standards, along with collegial communications between the journal and authors. We will also build on the current interdisciplinary focus of the journal, both flagyl treats what from within and outside the healthcare disciplines, and are considering special articles on new methods or ideas from other areas and how they can be adapted and used within the healthcare setting. We recognise that a strength of the journal is its international focus, although the majority of published papers are currently from North America and the UK. We would like to encourage a wider range of international submissions that meet our high standards for methodological quality and relevance for an international readership. We would like to further increase our social media presence, building on the flagyl treats what blogs and Tweets already being led by our two social media editors.

    We also want to maintain the journal’s current reputation for constructive peer review and timely publication, in which editors aim to provide personalised, specific and constructive feedback not just for papers for which revision is invited but also for those that are rejected.These are promising times for the journal. The previous co-editors-in-chief, Kaveh Shojania and Mary Dixon-Woods, are handing over a journal with a stellar reputation for rigorous research, thoughtful and challenging commentary, and timely flagyl treats what and constructive peer review. We therefore end with our thanks to Mary and Kaveh for their strong leadership and vision, together with an incredibly strong team of senior editors, associate editors and reviewers. We are sure that readers of BMJ flagyl treats what Quality and Safety will echo our thanks.Patients entrust their lives to healthcare providers. Healthcare providers, in turn, aim to promote wellness, heal what can be healed and relieve suffering, all with comfort and compassion.

    Yet, when patients are harmed by their healthcare, too often they experience defensiveness and disregard that actually exacerbates their suffering, adding insult to injury.1 2 Communication and resolution programmes (CRP) can mitigate this further harm and avoid pouring salt on the wounds of patients whom the healthcare system has hurt instead of helped. These programmes strive to ensure that patients and families injured by medical care receive prompt attention, honest and empathic explanations, sincere expressions of reconciliation including financial and non-financial restitution, and reassurance from efforts to prevent future harm to others.3 Decades of study and interest in CRPs seem to be resulting in increased implementation with the hope that supporting patients, families and caregivers after harm could flagyl treats what become the norm rather than the exception.4Yet a central problem looms, and unless effective solutions are enacted, the potential of CRPs may go largely unrealised. The field is rife with inconsistent implementation, which often reflects a selective focus on claims resolution rather than a fully implemented (‘authentic’) CRP.5 Inconsistent CRP implementation means that fewer patients and families benefit from this model and opportunities for improving quality and safety are missed. Authentic CRPs, in contrast, are comprehensive, systematic and principled programmes motivated by flagyl treats what fundamental culture change which prioritises patient safety and learning. In an authentic CRP, honesty and transparency after patient harm are viewed as integral to the clinical mission, not as selective claims management devices.6 CRPs appear to improve patient and provider experiences, patient safety, and in many settings lower defence and liability costs in the short term and improve peer review and stimulate quality and safety over time.7–10 While the claims savings often associated with a CRP are welcome, authentic CRPs focus on a more ambitious goal.

    Fostering an accountable culture. Nurturing accountability flagyl treats what produces better and safer care which serves the overall clinical mission, happily accomplishing more durable claims reduction along the way.Two thoughtful papers in this issue of BMJ Quality &. Safety highlight barriers to effective CRP implementation and offer important insights to aid in the spread of this critical model.11 12 Below we outline four suggested strategies for realising the vision of authentic CRPs.Strategy 1. Make CRPs a critical organisational priority grounded in the clinical missionThe most important cause of flagyl treats what inconsistent CRP implementation is the failure of institutional leaders, including boards and senior executives (‘C-suites’), to recognise them as a mission-critical component of modern healthcare. As a result, even at organisations professing to embrace accountability and transparency after patient harm, CRPs rarely receive overt leadership support or the resources and performance expectations associated with other mission-critical initiatives.13The reasons why CRPs have not been elevated to mission-critical status at healthcare organisations are complex.

    Competing and distracting clinical flagyl treats what and financial priorities abound. But a central challenge that has hampered CRPs is the tendency of many C-suites to rely on their liability insurance, risk and legal partners to direct the response to injured patients. Neither the insurance industry nor the legal profession naturally shares the same values and mission as healthcare organisations.14 Healthcare leaders need to insist that responses to injured patients align with their organisations’ clinical missions. In the absence of such C-suite insistence, ‘deny and defend’ will remain the dominant response to injured patients.This C-suite deference to the claims expertise of the flagyl treats what insurance industry and legal profession has additional causes, including. (A) resignation that unintended adverse outcomes will happen even with reasonable care.

    (B) acceptance of litigation as unavoidable and a cost flagyl treats what of doing business. (C) reluctance of chief executive officers/board members (who are not trial lawyers) to challenge worst-case scenarios painted by defence lawyers and insurance claims professionals. And (D) human nature that avoids confrontation and exaggerates the potential challenges of dealing flagyl treats what with injured patients. These factors inform the attitude of some health systems that no adverse events deserve compensation and that the caregivers/organisations are the real victims.While it is encouraging to see a few large liability insurers developing CRPs and even incentivising their adoption,15 more insurers are engaging with CRPs as passive observers, with others remaining actively opposed. Insurers and attorneys will align as CRP partners only when healthcare organisations identify CRPs as a mission-critical http://djblast.com/latin-mix-masters/ priority.Strategy 2.

    Compel institutional flagyl treats what leaders to recognise the critical importance of CRPsWhat would persuade boards and C-suites to prioritise a CRP?. The study by Prentice et al suggests the answer lies in making institutional leaders recognise the necessity of CRPs through engagement with injured patients and their families.11Prentice and colleagues report the first truly population-based assessment of the impact of medical errors on patients. Their results highlight the continuing emotional toll flagyl treats what that patients and their families suffer from preventable injuries. On an encouraging note, they also document the potential that open and honest communication has for reducing emotional harm. While over half of the patients who reported experiencing medical errors 3–6 years ago described at least one emotional impact from the event, those who reported the greatest degree of open communication with healthcare providers after flagyl treats what an error were less likely to experience persisting sadness, depression or feelings of abandonment and betrayal.

    Open and honest communication after an error also predicted less doctor/facility avoidance.When boards and C-suites acknowledge the additional emotional harm inflicted on injured patients and their families (not to mention staff) when a CRP is not used or is poorly implemented, the mission-critical nature of CRPs will become paramount.16 17 The emotions of patients and families who have been harmed can be complex, intense and intimidating.18 It has been all too easy for board members and senior executives to look away and avoid direct involvement when their organisations harm the very patients they exist to serve. Patients and their families, of course, cannot enjoy the luxury of looking away.19While boards are sometimes made aware of selected high-value harm events, these cases represent only the tip of the iceberg. Cases of patient harm that are less flagyl treats what than catastrophic are rarely shared with boards, but represent a large reservoir of patient and family suffering as well as opportunities for learning. Many patients who experience injuries hesitate to complain, fearing their ongoing care may be adversely affected.20 21 Patients who have experienced serious harm may have difficulty garnering representation from a qualified plaintiff attorney especially if their claim is deemed to be worth under $500 000. Boards aware only of a few high-value cases will fail to appreciate the magnitude of harm caused by substandard care and falsely believe that their flagyl treats what organisation is responding optimally to the few they know about.Engaging a patient as soon as possible after an unplanned clinical event is a CRP hallmark.

    Listening, with the explicit goal of understanding the experiences of patients and families who have been harmed, is invaluable to any organisation striving for patient centricity and generates insights not available to ‘deny and defend’ adherents. Partnering with patients who have had unplanned clinical outcomes changes the way healthcare organisations value informed consent, transitions of care and communication in general. As patient engagement is normalised across organisations, boards and C-suites flagyl treats what will readily recognise the importance to their clinical mission and the value of the return on investment in the CRP model beyond financial gains. The accountable culture which emerges has the potential to generate other benefits unthinkable in a defensive environment. Improved staff morale with better staff retention, an open environment which values speaking up for safety, accelerated and flagyl treats what more effective clinical outcomes and evidence-based peer review, to name a few.Strategy 3.

    Invest in CRP implementation tools and resourcesEquating CRPs to early claims resolution predictably yields inconsistent and selective application of the model and, worse, a failure to realise its full potential for cultural improvement.22 Even as boards and C-suites accept the mission-critical status of CRPs (the ‘why’), they may not appreciate the importance of the ‘how’. The second CRP-related paper in this issue of BMJ Quality and Safety emphasises how successful CRPs rely on the development of systems and standard work to promote consistent application.12 Mello and colleagues describe the work of the Massachusetts Alliance for Communication and Resolution after Medical Injury (MACRMI) and articulate the most important elements flagyl treats what of their success to date. Their findings reinforce other papers that emphasize the critical nature of having the right people, processes and systems in place.23One essential element of the MACRMI model is the commitment to a process of reviewing unplanned clinical outcomes eligible for a CRP approach. Normalising a triaged review and then faithfully using the CRP for all eligible cases, regardless of whether that case might become a claim, allows the CRP to meet patient, family and caregiver needs, as well as to drive process improvements faster on a much broader group of harm events. This systematic approach to case selection also demonstrates to clinical audiences that the CRP is not premised primarily on saving money, but is a norm expected within flagyl treats what the clinical mission.The MACRMI experience also highlights the importance of devoting sufficient resources to planning and executing a CRP.

    Many organisations focus most of their CRP efforts around training different teams to enact key steps in the CRP process. While trainings may be a necessary element, reproducible workflows and simple tools are flagyl treats what far more important. With clear leadership support, these tools and processes must be developed with and by the people in the organisation who will actually use them, rather than imposing approaches that may have worked in another system that is organised differently. Organisations should understand that potential litigation is an ever-present flagyl treats what reality. Sometimes, despite the CRP’s principled assessment and engagement, reasonable minds may still differ, and in a small minority of cases litigation is required.

    Because the motivation for CRPs is to instil the accountable culture required for continual clinical improvement, success cannot be contingent on erasing the threat of litigation altogether.Finally, a significant element of MACRMI’s success involved a shared learning community in which organisational leaders and key managers came together to discuss CRP cases supported by unfiltered patient experiences, clinical and patient safety findings and measures of implementation. The community acquired a moral authority which encouraged accountability, consistent application of CRP principles, and ultimately demonstrated broad results of the favourable impact on patients, providers, system learning flagyl treats what and liability costs.Strategy 4. Deploy CRP metrics to govern CRP and track progressMetrics matter. Organisations measure what they deem important.5 At present it is rare that organisations know how many unintended flagyl treats what clinical events occurred in the previous year, how many of the affected patients and families were treated with honesty and transparency, how many of those deemed worthy of compensation actually received it, how many of the affected providers received care, or how many of those cases resulted in clinical improvements. The absence of these data makes it nearly impossible to assign appropriate leadership accountabilities for CRPs and to understand how well a CRP is functioning in service to the organisational mission.

    Measuring mainly claims and costs signals a preoccupation with money, not continual clinical improvement, flagyl treats what and certainly not patient centricity or care for the caregiver workforce. A comprehensive suite of national CRP measures is currently being developed and refined jointly by the Collaborative for Accountability and Improvement and Ariadne Labs, and should be ready for widespread dissemination by the end of this year.ClosingHealthcare organisations exist to serve with compassion and clinical excellence the patients and their families who entrust them with their lives. Our society expects no less. The privilege of delivering healthcare, a practice that flagyl treats what is intrinsically dangerous, carries a heavy responsibility to minimise the risk of harm. When patients are harmed, CRPs honour patients’ trust and caregivers’ selfless dedication with honesty, transparency, best efforts at reconciliation for all and relentless determination to improve.

    One thing flagyl treats what is clear. Shedding ‘deny and defend’ in favour of a transition to an authentic CRP undoubtedly requires leadership from boards and C-suites focused on their organisations’ clinical mission. If healthcare organisations are sincere in striving to attain their clinical goals, they will insist on nothing less than elevating their CRPs to mission-critical status and using the requisite tools and resources to ensure consistent application of this model.AcknowledgmentsMany thanks to Gary S Kaplan, MD, for contributing to the concepts presented in this paper, and to Paulina H Osinska, MPH, for her assistance with manuscript preparation..

    On 1 September 2020, we took on the roles of co-editors-in-chief for BMJ Quality and Safety, and want to take this opportunity to introduce ourselves and our vision for how to buy flagyl in usa the journal. We represent two different continents, two different professions and two different sets of research expertise. What we have in common is a passion for conducting and publishing high-quality research and quality improvement work to benefit the quality and safety of patient care, as well as encouraging others to do likewise.We assume how to buy flagyl in usa leadership of the journal during a major worldwide crisis brought on by the buy antibiotics flagyl, which has affected almost every aspect of society. Response to the flagyl is requiring engagement from every part of our health care systems—government policy, public health, ambulatory care, inpatient and long-term care, every type of healthcare worker, and of course patients and their care partners.

    Most journals, including ours, have seen a how to buy flagyl in usa substantial increase in manuscript submissions. We have published several articles related to buy antibiotics that address quality and safety issues central to the journal’s interests—including staffing levels, teamwork, how the flagyl has exposed weaknesses in healthcare systems, and how it may even stimulate efforts to address deficiencies in quality and safety.1–5We take note of the flagyl not only because of its significance but also because, like the flagyl, quality and safety problems are international issues that affect and require engagement from all parts of our healthcare systems and from all stakeholders. These stakeholders include patients and their care partners, every type of healthcare worker, organisational leaders, policy makers and, of course, researchers and quality improvement teams. Improving quality and safety also requires how to buy flagyl in usa engagement from experts from other disciplines and industries whose research and practice can inform our efforts to improve care.As new co-editors-in-chief, we find this comprehensive view of the stakeholders for quality and safety to be both necessary to improve care and intellectually stimulating.

    Of course, with so many stakeholders, there needs to be some additional focus, and we find that on BMJ Quality and Safety’s masthead6. €˜The journal integrates the academic and clinical aspects of quality and safety in healthcare by encouraging academics to create evidence and knowledge valued by clinicians, and clinicians to value using evidence and knowledge to improve quality’.We will continue to publish research and opinion that how to buy flagyl in usa creates ‘evidence and knowledge valued by clinicians’. To accomplish this, we will maintain high methodological standards, along with collegial communications between the journal and authors. We will also build on how to buy flagyl in usa the current interdisciplinary focus of the journal, both from within and outside the healthcare disciplines, and are considering special articles on new methods or ideas from other areas and how they can be adapted and used within the healthcare setting.

    We recognise that a strength of the journal is its international focus, although the majority of published papers are currently from North America and the UK. We would like to encourage a wider range of international submissions that meet our high standards for methodological quality and relevance for an international readership. We would like to further how to buy flagyl in usa increase our social media presence, building on the blogs and Tweets already being led by our two social media editors. We also want to maintain the journal’s current reputation for constructive peer review and timely publication, in which editors aim to provide personalised, specific and constructive feedback not just for papers for which revision is invited but also for those that are rejected.These are promising times for the journal.

    The previous co-editors-in-chief, Kaveh Shojania and Mary Dixon-Woods, are handing over a journal with a stellar reputation for rigorous research, thoughtful and how to buy flagyl in usa challenging commentary, and timely and constructive peer review. We therefore end with our thanks to Mary and Kaveh for their strong leadership and vision, together with an incredibly strong team of senior editors, associate editors and reviewers. We are sure that readers of BMJ Quality and Safety will echo our thanks.Patients entrust their lives to how to buy flagyl in usa healthcare providers. Healthcare providers, in turn, aim to promote wellness, heal what can be healed and relieve suffering, all with comfort and compassion.

    Yet, when patients are harmed by their healthcare, too often they experience defensiveness and disregard that actually exacerbates their suffering, adding insult to injury.1 2 Communication and resolution programmes (CRP) can mitigate this further harm and avoid pouring salt on the wounds of patients whom the healthcare system has hurt instead of helped. These programmes strive to ensure that patients and families injured by medical care receive prompt attention, honest and empathic explanations, sincere expressions of reconciliation including financial and non-financial restitution, and reassurance from efforts to prevent future harm to others.3 Decades of study and interest in CRPs how to buy flagyl in usa seem to be resulting in increased implementation with the hope that supporting patients, families and caregivers after harm could become the norm rather than the exception.4Yet a central problem looms, and unless effective solutions are enacted, the potential of CRPs may go largely unrealised. The field is rife with inconsistent implementation, which often reflects a selective focus on claims resolution rather than a fully implemented (‘authentic’) CRP.5 Inconsistent CRP implementation means that fewer patients and families benefit from this model and opportunities for improving quality and safety are missed. Authentic CRPs, in contrast, are comprehensive, systematic and principled programmes motivated by how to buy flagyl in usa fundamental culture change which prioritises patient safety and learning.

    In an authentic CRP, honesty and transparency after patient harm are viewed as integral to the clinical mission, not as selective claims management devices.6 CRPs appear to improve patient and provider experiences, patient safety, and in many settings lower defence and liability costs in the short term and improve peer review and stimulate quality and safety over time.7–10 While the claims savings often associated with a CRP are welcome, authentic CRPs focus on a more ambitious goal. Fostering an accountable culture. Nurturing accountability produces better and safer care which serves the overall clinical mission, happily how to buy flagyl in usa accomplishing more durable claims reduction along the way.Two thoughtful papers in this issue of BMJ Quality &. Safety highlight barriers to effective CRP implementation and offer important insights to aid in the spread of this critical model.11 12 Below we outline four suggested strategies for realising the vision of authentic CRPs.Strategy 1.

    Make CRPs a critical organisational priority grounded in the clinical missionThe most important cause of inconsistent CRP implementation is the failure of institutional leaders, including boards and senior executives (‘C-suites’), to recognise them as a mission-critical component of modern healthcare how to buy flagyl in usa. As a result, even at organisations professing to embrace accountability and transparency after patient harm, CRPs rarely receive overt leadership support or the resources and performance expectations associated with other mission-critical initiatives.13The reasons why CRPs have not been elevated to mission-critical status at healthcare organisations are complex. Competing and distracting clinical and financial priorities abound how to buy flagyl in usa. But a central challenge that has hampered CRPs is the tendency of many C-suites to rely on their liability insurance, risk and legal partners to direct the response to injured patients.

    Neither the insurance industry nor the legal profession naturally shares the same values and mission as healthcare organisations.14 Healthcare leaders need to insist that responses to injured patients align with their organisations’ clinical missions. In the absence of such C-suite insistence, ‘deny and defend’ will remain the dominant response to injured patients.This C-suite deference how to buy flagyl in usa to the claims expertise of the insurance industry and legal profession has additional causes, including. (A) resignation that unintended adverse outcomes will happen even with reasonable care. (B) acceptance of litigation how to buy flagyl in usa as unavoidable and a cost of doing business.

    (C) reluctance of chief executive officers/board members (who are not trial lawyers) to challenge worst-case scenarios painted by defence lawyers and insurance claims professionals. And (D) human nature that avoids confrontation and exaggerates the potential challenges of dealing with injured patients how to buy flagyl in usa. These factors inform the attitude of some health systems that no adverse events deserve compensation and that the caregivers/organisations are the real victims.While it is encouraging to see a few large liability insurers developing CRPs and even incentivising their adoption,15 more insurers are engaging with CRPs as passive observers, with others remaining actively opposed. Insurers and attorneys will align as CRP partners only when healthcare organisations identify CRPs as a mission-critical priority.Strategy 2.

    Compel institutional leaders to recognise the critical importance of CRPsWhat how to buy flagyl in usa would persuade boards and C-suites to prioritise a CRP?. The study by Prentice et al suggests the answer lies in making institutional leaders recognise the necessity of CRPs through engagement with injured patients and their families.11Prentice and colleagues report the first truly population-based assessment of the impact of medical errors on patients. Their results highlight the continuing emotional toll that patients and how to buy flagyl in usa their families suffer from preventable injuries. On an encouraging note, they also document the potential that open and honest communication has for reducing emotional harm.

    While over half of the patients who reported experiencing medical errors 3–6 years ago described at least one emotional impact from the event, those who reported how to buy flagyl in usa the greatest degree of open communication with healthcare providers after an error were less likely to experience persisting sadness, depression or feelings of abandonment and betrayal. Open and honest communication after an error also predicted less doctor/facility avoidance.When boards and C-suites acknowledge the additional emotional harm inflicted on injured patients and their families (not to mention staff) when a CRP is not used or is poorly implemented, the mission-critical nature of CRPs will become paramount.16 17 The emotions of patients and families who have been harmed can be complex, intense and intimidating.18 It has been all too easy for board members and senior executives to look away and avoid direct involvement when their organisations harm the very patients they exist to serve. Patients and their families, of course, cannot enjoy the luxury of looking away.19While boards are sometimes made aware of selected high-value harm events, these cases represent only the tip of the iceberg. Cases of patient how to buy flagyl in usa harm that are less than catastrophic are rarely shared with boards, but represent a large reservoir of patient and family suffering as well as opportunities for learning.

    Many patients who experience injuries hesitate to complain, fearing their ongoing care may be adversely affected.20 21 Patients who have experienced serious harm may have difficulty garnering representation from a qualified plaintiff attorney especially if their claim is deemed to be worth under $500 000. Boards aware only of a few high-value how to buy flagyl in usa cases will fail to appreciate the magnitude of harm caused by substandard care and falsely believe that their organisation is responding optimally to the few they know about.Engaging a patient as soon as possible after an unplanned clinical event is a CRP hallmark. Listening, with the explicit goal of understanding the experiences of patients and families who have been harmed, is invaluable to any organisation striving for patient centricity and generates insights not available to ‘deny and defend’ adherents. Partnering with patients who have had unplanned clinical outcomes changes the way healthcare organisations value informed consent, transitions of care and communication in general.

    As patient engagement is normalised across organisations, boards and C-suites will readily recognise the importance to how to buy flagyl in usa their clinical mission and the value of the return on investment in the CRP model beyond financial gains. The accountable culture which emerges has the potential to generate other benefits unthinkable in a defensive environment. Improved staff morale with better staff retention, an open environment which values speaking up for safety, accelerated and more effective clinical outcomes and evidence-based peer review, to name a few.Strategy how to buy flagyl in usa 3. Invest in CRP implementation tools and resourcesEquating CRPs to early claims resolution predictably yields inconsistent and selective application of the model and, worse, a failure to realise its full potential for cultural improvement.22 Even as boards and C-suites accept the mission-critical status of CRPs (the ‘why’), they may not appreciate the importance of the ‘how’.

    The second CRP-related paper in this issue of BMJ Quality and Safety emphasises how how to buy flagyl in usa successful CRPs rely on the development of systems and standard work to promote consistent application.12 Mello and colleagues describe the work of the Massachusetts Alliance for Communication and Resolution after Medical Injury (MACRMI) and articulate the most important elements of their success to date. Their findings reinforce other papers that emphasize the critical nature of having the right people, processes and systems in place.23One essential element of the MACRMI model is the commitment to a process of reviewing unplanned clinical outcomes eligible for a CRP approach. Normalising a triaged review and then faithfully using the CRP for all eligible cases, regardless of whether that case might become a claim, allows the CRP to meet patient, family and caregiver needs, as well as to drive process improvements faster on a much broader group of harm events. This systematic approach to case selection also demonstrates to clinical audiences that the CRP is not premised how to buy flagyl in usa primarily on saving money, but is a norm expected within the clinical mission.The MACRMI experience also highlights the importance of devoting sufficient resources to planning and executing a CRP.

    Many organisations focus most of their CRP efforts around training different teams to enact key steps in the CRP process. While trainings may be a necessary element, how to buy flagyl in usa reproducible workflows and simple tools are far more important. With clear leadership support, these tools and processes must be developed with and by the people in the organisation who will actually use them, rather than imposing approaches that may have worked in another system that is organised differently. Organisations should how to buy flagyl in usa understand that potential litigation is an ever-present reality.

    Sometimes, despite the CRP’s principled assessment and engagement, reasonable minds may still differ, and in a small minority of cases litigation is required. Because the motivation for CRPs is to instil the accountable culture required for continual clinical improvement, success cannot be contingent on erasing the threat of litigation altogether.Finally, a significant element of MACRMI’s success involved a shared learning community in which organisational leaders and key managers came together to discuss CRP cases supported by unfiltered patient experiences, clinical and patient safety findings and measures of implementation. The community acquired a moral how to buy flagyl in usa authority which encouraged accountability, consistent application of CRP principles, and ultimately demonstrated broad results of the favourable impact on patients, providers, system learning and liability costs.Strategy 4. Deploy CRP metrics to govern CRP and track progressMetrics matter.

    Organisations measure what they deem important.5 At present it is rare that organisations know how many unintended clinical events occurred in the previous year, how many of the affected patients and families were treated with honesty and transparency, how many of those deemed worthy of compensation actually how to buy flagyl in usa received it, how many of the affected providers received care, or how many of those cases resulted in clinical improvements. The absence of these data makes it nearly impossible to assign appropriate leadership accountabilities for CRPs and to understand how well a CRP is functioning in service to the organisational mission. Measuring mainly claims and costs signals how to buy flagyl in usa a preoccupation with money, not continual clinical improvement, and certainly not patient centricity or care for the caregiver workforce. A comprehensive suite of national CRP measures is currently being developed and refined jointly by the Collaborative for Accountability and Improvement and Ariadne Labs, and should be ready for widespread dissemination by the end of this year.ClosingHealthcare organisations exist to serve with compassion and clinical excellence the patients and their families who entrust them with their lives.

    Our society expects no less. The privilege of delivering healthcare, a practice that is intrinsically how to buy flagyl in usa dangerous, carries a heavy responsibility to minimise the risk of harm. When patients are harmed, CRPs honour patients’ trust and caregivers’ selfless dedication with honesty, transparency, best efforts at reconciliation for all and relentless determination to improve. One thing how to buy flagyl in usa is clear.

    Shedding ‘deny and defend’ in favour of a transition to an authentic CRP undoubtedly requires leadership from boards and C-suites focused on their organisations’ clinical mission. If healthcare organisations are sincere in striving to attain their clinical goals, they will insist on nothing less than elevating their CRPs to mission-critical status and using the requisite tools and resources to ensure consistent application of this model.AcknowledgmentsMany thanks to Gary S Kaplan, MD, for contributing to the concepts presented in this paper, and to Paulina H Osinska, MPH, for her assistance with manuscript preparation..

    Flagyl et grossesse

    NONE

    IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for flagyl et grossesse patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and flagyl et grossesse societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have flagyl et grossesse collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources.

    Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may flagyl et grossesse facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 flagyl et grossesse 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers.

    Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from flagyl et grossesse the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is flagyl et grossesse challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members responsible for updating the literature for a specific part of the guideline.

    Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome flagyl et grossesse to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper. Abstracts had to be written in English and were flagyl et grossesse identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care).

    Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were flagyl et grossesse excluded, as were articles that were not open access or retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was flagyl et grossesse discussed by the writing committee and, after having obtained agreement on remaining points of discussion, revised into a final draft.

    This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, the final version was presented to the paediatric and genetic associations for flagyl et grossesse approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually flagyl et grossesse occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

    In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form flagyl et grossesse of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions flagyl et grossesse and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and reports.

    If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so flagyl et grossesse any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team. After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on flagyl et grossesse the ultrasound findings and the limitations of this technique.

    The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of flagyl et grossesse information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about the flagyl et grossesse diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

    Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider flagyl et grossesse termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress flagyl et grossesse of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

    In our experience, parents appreciate having flagyl et grossesse already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 flagyl et grossesse 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array.

    It was recently estimated that flagyl et grossesse >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS. NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex flagyl et grossesse development (DSD) in the prenatal setting. A diagnostic algorithm.

    *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting.

    A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

    NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

    The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline.

    Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively. Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting.

    A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting.

    A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting.

    A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

    NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

    Conventional karyotyping can be useful. NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned.

    Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences. If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing.

    Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites. Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another.

    This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

    How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype.

    This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD. In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring.

    This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise. For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time.

    Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres. Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions.

    One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

    This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing.

    Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline. Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic.

    In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

    Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation. We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2.

    Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

    €œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion.

    Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92. Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected.

    Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis. For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant.

    However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

    Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

    Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study.

    Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement.

    PLoS Med 6(6). E1000097. Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons.

    Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009).

    Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

    Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations.

    Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene.

    The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

    It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer. These can be activated by high levels of KLF5 (transcriptional activator).

    Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

    P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele.

    Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry.

    There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer. We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant.

    The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

    However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

    Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs.

    It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data. This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data.

    Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS.

    Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A.

    This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

    Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans.

    This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer.

    It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.

    Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations. Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk.

    The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

    IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in how to buy flagyl in usa cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of how to buy flagyl in usa differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

    Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to how to buy flagyl in usa produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions how to buy flagyl in usa (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders.

    For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 how to buy flagyl in usa Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral.

    Transition from the prenatal to the postnatal team and from the paediatric how to buy flagyl in usa to the adult team requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with all members how to buy flagyl in usa responsible for updating the literature for a specific part of the guideline.

    Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for how to buy flagyl in usa example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

    Abstracts had how to buy flagyl in usa to be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that how to buy flagyl in usa were not open access or retrievable through institutional access.

    Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after how to buy flagyl in usa having obtained agreement on remaining points of discussion, revised into a final draft. This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline.

    After receiving and how to buy flagyl in usa incorporating their input, the final version was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex how to buy flagyl in usa and the phenotypic sex seen by ultrasound.

    In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women how to buy flagyl in usa in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus.

    However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always included in NIPT analysis and how to buy flagyl in usa reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT how to buy flagyl in usa is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

    After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings how to buy flagyl in usa and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

    And the type of information genetic testing can and cannot provide how to buy flagyl in usa. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed how to buy flagyl in usa about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

    Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands how to buy flagyl in usa. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what how to buy flagyl in usa the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided completely.

    Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our how to buy flagyl in usa experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist.

    The terminology used in communication how to buy flagyl in usa with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being how to buy flagyl in usa particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

    NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development how to buy flagyl in usa (DSD) in the prenatal setting. A diagnostic algorithm.

    *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

    NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9.

    Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition.

    Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

    The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers.

    A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively. Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process.

    Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm.

    NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting.

    A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

    AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9.

    Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting.

    A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

    Conventional karyotyping can be useful. NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype.

    Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

    If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing.

    Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites. Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another.

    This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions.

    What do laboratories report?. How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity.

    It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

    In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring.

    This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise. For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium.

    We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD.

    These should be published in widely available general medical journals and online, along with a national list of DSD centres. Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved.

    A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

    This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication.

    Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline. Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital.

    The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors.

    Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

    Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

    We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk.

    Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used. €œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”.

    No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion.

    Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92. Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected.

    For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

    For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included.

    As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

    Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis.

    Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported. Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons.

    Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

    Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement.

    PLoS Med 6(6). E1000097. Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram.

    *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study.

    Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

    The PRISMA Statement. PLoS Med 6(6). E1000097.

    Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies.

    Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene.

    Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04.

    P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

    It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

    These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21.

    P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20. P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated.

    The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele.

    Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses.

    However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

    We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer.

    For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

    However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality.

    Thus, these should be interpreted with caution. Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants.

    However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

    This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data.

    Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit.

    In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1.

    Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes.

    The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

    Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women.

    This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours.

    Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes.

    It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.

    Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

    Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

    Flagyl for h pylori

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    Date published flagyl for h pylori where can i buy metronidazole flagyl. August 26, 2020On this page Backgroundbuy antibiotics is an infectious disease caused by the antibiotics antibiotics. The World Health Organization declared a global flagyl in March 2020, and the flagyl for h pylori Minister of Health signed the Interim Order Respecting the Importation and Sale of Medical Devices for Use in Relation to buy antibiotics on March 18, 2020. The Interim Order (IO) allows us to quickly address large-scale public health emergencies.This IO allows for faster authorization of Class I-IV medical devices for buy antibiotics.This document presents the criteria for safety and effectiveness that apply to test swabs used for buy antibiotics sampling.

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    Once the sample has been taken, the swab is either placed in a preserving liquid and sent to a laboratory for testing, or placed directly in flagyl for h pylori a testing device (point-of-care).Swabs may be packaged in a variety of flagyl transport media (VTM). Specifications for individual VTMs are beyond the scope of this document. Swabs play a role in the accuracy of buy antibiotics diagnostic testing. For example, false negatives can occur in flagyl for h pylori PCR tests if.

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    US Food and Drug Administration, "Biological Indicator (BI) Premarket Notification [510(k)] Submissions," October 2007. [Online].Packaging validation Provide packaging validation data in a summary report. It should demonstrate that the swab packaging system will maintain flagyl for h pylori a sterile environment across the labelled shelf life (for example, ASTM F1980). without leakage (for example, ASTM D3078-02) with adequate seal strength (for example, ASTM F88/EN 868-5)Test packaging samples should be representative of finished swab packages that have undergone sterilization prior to testing.Biocompatibility Provide biocompatibility data in a summary report.

    It should demonstrate compliance with biocompatibility tests recommended for devices in limited contact (≤24 hrs) with mucosal membranes, as per ISO 10993-1. These include flagyl for h pylori. cytotoxicity sensitization irritation/intracutaneous reactivityThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.LabellingSwabs should be individually packaged and labelled. The application must include the flagyl for h pylori swab label, which must include.

    The name and model number of the device the term ‘sterile’, along with the sterilization method (EtO = ethylene oxide. R = gamma irradiation), if the swab is intended to be sold in a sterile condition the name and address of the manufacturer manufacturing and expiry datesIf swabs are not sterile but must be sterilized at the user facility, then the sterilization parameters and method should be clearly described in accompanying instructions for use documentation.Post-market requirementsAs stated in Section 12 of the IO, within 10 days of becoming aware of an incident in Canada, all IO authorization holders must. report the incident specify the nature of the incident specify the circumstances surrounding the incidentOn this page About flagyl for h pylori face shields Personal protective equipment (PPE) can help prevent potential exposure to infectious disease. They are considered medical devices in Canada and therefore must follow the requirements outlined in the Medical Devices Regulations.

    Medical devices are classified into 4 groups (Class I, II, III and IV) based on their risk to health and safety. Class I devices, such as gauze bandages, pose the lowest potential risk, while Class IV devices, such as flagyl for h pylori pacemakers, pose the greatest potential risk. In Canada, face shields are Class I medical devices. A face shield has a transparent window or visor that shields the face and associated mucous membranes (eyes, nose and mouth).

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    Health Canada strongly advises against the use of plastic bags as an alternative to face shields. Standards and requirements for face shields Organizations that are manufacturing face shields are advised to consult some or all of the following standards throughout the design and testing stages. ANSI/ISEA Z.87.1 (2015), American National Standard for Occupational and Educational Personal Eye and Face Protection Devices CSA Z94.3 (2020), Eye and Face Protectors CSA Z94.3.1 (2016), Guideline for Selection, flagyl for h pylori Use, and Care of Eye and Face Protectors BS EN 166 (2002), Personal Eye Protection. Specifications.

    Minimum specifications must be incorporated into the design and verification stages to ensure safe and effective face shields. Provide adequate coverage (CSA Z94.3 Sections 0.2.1/10.2.2/10.3/10.4) flagyl for h pylori. The size of the face shield is important because it must protect the face and front part of the head. This includes the eyes, forehead, cheeks, nose, mouth, and chin.

    Protection may also need to extend to the front of the neck in flagyl for h pylori situations with flying particles and sprays of hazardous liquids. Fit snugly to afford a good seal to the forehead area and to prevent slippage of the device Footnote 1. Be made of optically flagyl for h pylori clear, distortion-free, lightweight materials (CSA Z94.3.1-16 and Footnote 1). Be free of visible defects or flaws that would impede vision (ANSI Z87.1 Section 9.4).

    Be comfortable and easy to assemble, use and remove by health care professionals. Provide adequate space between the wearer’s face and the inner surface of the visor to allow for the use of ancillary equipment (for flagyl for h pylori example, medical mask, respirator, eyewear) Footnote 1. The characteristics and performance requirements of face shields must not be altered when attaching shields to other protective equipment, such as hats or caps. Display anti-fog characteristics on inside and outside of shield (CSA Z94.3.1-16).

    For face flagyl for h pylori shields that are not fog resistant, anti-fog spray must be provided. Provide user-contacting materials that have adequate material biocompatibility (skin sensitivity and cytotoxic testing) (ISO 10993-5, 10). Other items to take note of include. Face shields flagyl for h pylori used for protection in hospital settings do not have to be impact- or flame- resistant.

    If the device is specifically designed to withstand impact from sharp or fast projectiles, it must comply with set-out standards (ANSI Z87.1, sections 9.2 and 9.3, CSA Z94.3, section 10.1). For reuse, manufacturers must provide validated cleaning instructions. Sterilization procedures must not compromise the shield in any way, such as deformation or flagyl for h pylori cracking. Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from .

    This includes buy antibiotics. Face shields may be authorized for sale or import flagyl for h pylori into Canada through the following regulatory pathways. Pathway 1. Interim order authorization to import and sell medical devices related to buy antibiotics.

    Pathway 2 flagyl for h pylori. Expedited review and issuance of Medical Device Establishment Licences (MDEL) related to buy antibiotics. MDEL holders that import and sell face shields should take measures to ensure they are safe flagyl for h pylori and effective. Pathway 3.

    Exceptional importation and sale of certain non-compliant medical devices related to buy antibiotics. Note that a sale generally requires the transfer of ownership of a device from one party to another and does not necessitate flagyl for h pylori any transfer of money. Applicants should carefully review the pathways and select the most appropriate authorization route for their product. For more information, see Personal protective equipment (buy antibiotics).

    How to get flagyl for h pylori authorization. If you intend to manufacture 3D print face shields in response to the buy antibiotics crisis, see. 3D printing and other manufacturing of personal protective equipment in response to buy antibiotics Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J.

    Roberge, "Face shields for control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016. Related links FootnotesFootnote 1 R.

    J. Roberge, "Face shields for control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.Return to footnote 1 referrer.

    Date published how to buy flagyl in usa. August 26, 2020On this page Backgroundbuy antibiotics is an infectious disease caused by the antibiotics antibiotics. The World Health Organization declared a global flagyl in how to buy flagyl in usa March 2020, and the Minister of Health signed the Interim Order Respecting the Importation and Sale of Medical Devices for Use in Relation to buy antibiotics on March 18, 2020. The Interim Order (IO) allows us to quickly address large-scale public health emergencies.This IO allows for faster authorization of Class I-IV medical devices for buy antibiotics.This document presents the criteria for safety and effectiveness that apply to test swabs used for buy antibiotics sampling. It also provides guidance on how to meet these criteria in an application under the IO pathway.

    Diagnostic testing is a how to buy flagyl in usa key element in both. identifying cases of preventing the spread of the antibiotics A test swab may be used to collect a sample for either Polymerase Chain Reaction (PCR) laboratory testing or point-of-care testing. Point-of-care testing can be done directly in a hospital or doctor’s office. Once the sample has been taken, the swab is either placed in a preserving liquid and sent how to buy flagyl in usa to a laboratory for testing, or placed directly in a testing device (point-of-care).Swabs may be packaged in a variety of flagyl transport media (VTM). Specifications for individual VTMs are beyond the scope of this document.

    Swabs play a role in the accuracy of buy antibiotics diagnostic testing. For example, false negatives can occur in PCR tests how to buy flagyl in usa if. the swab material inhibits the test reaction or the swab design doesn’t provide enough surface area to obtain a sufficient sample Test swabs that are not safe and effective may cause or lead to harm. For example. A swab that breaks during sample collection can cause physical injury a non-sterile swab that produces an incorrect test result can lead to harmHealth Canada has how to buy flagyl in usa published a guidance document to support the preparation of applications submitted under the IO.

    It should be read in conjunction with this document. We are processing applications as quickly as possible. To avoid how to buy flagyl in usa delays, please ensure you have completed your application properly.Medical Devices Regulations (MDR) classification In the Canadian regulatory framework, Class I devices present the lowest potential risk and Class IV the highest. Swabs are classified according to their labelling and intended use. For example, if a swab is labelled for nasopharyngeal (NP) or oropharyngeal (OP) use only, it will be classified as a Class I medical device according to Classification Rule 2(2) of the MDR.

    If a swab is not exclusively for use in oral or nasal cavities, or its use is not explicitly stated, how to buy flagyl in usa it will be classified as a Class II device by Rule 2(1). These swabs belong to a higher risk class because their use in other body orifices for the collection of tissue samples (for example, to test for chlamydia or ureaplasma) is associated with greater risk. Rule 2 Subject to subrules (2) to (4), all invasive devices that penetrate the body through a body orifice or that how to buy flagyl in usa come into contact with the surface of the eye are classified as Class II. A device described in subrule (1) that is intended to be placed in the oral or nasal cavities as far as the pharynx or in the ear canal up to the ear drum is classified as Class I.Regulatory pathways for buy antibiotics devicesManufacturers of Class I swabs may seek authorization to import and sell their products under either. A Medical Device Establishment Licence (MDEL) MDEL is an establishment oversight framework that is not product-specific and not designed to assess safety and effectiveness an IO authorization information on safety and effectiveness are required as part of the application Health Canada is encouraging a sub-group of swab manufacturers to use the IO authorization pathway for Class I swabs, especially if they are.

    New to the manufacturing of swabs and manufacturing in Canada (such as a company that has re-tooled to manufacture), or using a new manufacturing process or design how to buy flagyl in usa for swabs (such as 3D printing or honeycomb design)IO applications for swabs should include the following information.Device description The device description should include. A picture and/or engineering drawing identification of all materials used in the production of the swab the intended use(s) (for example, NP swabs)Quality manufacturingManufacturers must either. demonstrate compliance with Quality Manufacturing Systems (for example, ISO 13485 certificate) applicable to the swab, or provide a clear description of the planned quality manufacturing systems that are consistent with similar existing manufacturing systemsDesign verificationProvide swab design verification (bench testing) data in a summary report. It should show that the essential minimum design characteristics are how to buy flagyl in usa met. These data should be based on test samples representative of finished swabs that have undergone sterilization prior to bench testing.Dimensions Swabs should have minimum length specifications and minimum and maximum head diameter specifications in order to be safe and effective.

    Minimum length specification for example, adult NP swabs require ≥14 cm to reach the posterior nasopharynx minimum and maximum head diameter specification for example, adult NP swabs require 1–4 mm to pass into the mid-inferior portion of the inferior turbinate and maneuver well FlexibilitySwab flexibility is assessed through. Durability for example, tolerate 20 rough repeated insertions into a 4 how to buy flagyl in usa mm inner diameter clear plastic tube curved back on itself with a curve radius of 3 cm bendability for example, bend tip and neck 90º without breaking ability to maintain initial form for example, restore to initial form following 45º bending Manufacturers may describe the test performed, the number of samples, and a summary of the results.Strength/Breakpoint (failure) To limit the potential for patient harm, the minimum breakpoint distance should be approximately 8 to 9 cm from the nasopharynx. However, no breaks or fractures should occur following reasonable manipulation. Applicants should submit a rationale for the design of the breakpoint distance from the swab tip. It should demonstrate that the breakpoint length can be accommodated by commercially available swab/media tubes.Surface propertiesThe how to buy flagyl in usa swab surface should be free of.

    processing aids (such as disinfectants) foreign materials degreasers mold release agents For injection molded swabs, no burrs, flashing, or sharp edges should be present. Design validationProvide swab validation (performance) data in a summary report that demonstrates that the swab. can acquire samples comparable to a commercially available swab control, and will not inhibit how to buy flagyl in usa the PCR reactionThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.Comparable sample acquisition to a control, and PCR compatibilityThe manufacturer should demonstrate test swab cycle threshold (Ct) recovery values (RT-PCR) that are statistically comparable to those obtained from a commercially available swab control using antibiotics (or a scientifically justified surrogate).Pass/Fail criteria. Values ≥ 2Cts indicate significantly less efficient ribonucleic acid collection and/or elution.Clinical feasibility/suitability simulationManufacturers should submit either. A clinical test report or previous clinical data Clinical test reportThe clinical test report should describe the use of the proposed finished how to buy flagyl in usa swab (sterilized) in a sufficient number of individuals by trained healthcare professionals in a minimum of 30 patients that have tested positive for antibiotics, or a scientifically justified surrogate flagyl.

    Include comparisons of the proposed swab against a flocked swab commercially available in Canada with respect to. flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Clinical testing considerations A scientifically justified surrogate flagyl may be used if buy antibiotics-positive patients are not available. Positive % agreement should not be determined using how to buy flagyl in usa high Ct samples. One-half (1/2) to two-thirds (2/3) of buy antibiotics-positive samples should have a high viral loads (Cts <. 30).

    Report agreement between control and test swabs in terms of quantitative (Ct) and qualitative (+/- test) values with appropriate how to buy flagyl in usa descriptive statistics. Include patient symptomatology for samples. For example, days from symptom onset, known vs. Suspected buy antibiotics status how to buy flagyl in usa. Use of different VTM/universal transport media (V/UTM) across buy antibiotics-positive samples may contribute to Ct variability.

    Ensure consistency by using the same media/tubes for each specimen within a clinical evaluation. Validate the how to buy flagyl in usa chosen V/UTM media/tubes to show they will not interfere with the PCR test results. For example, allowing 7 days of swab positive specimen incubation with the chosen media/vial is considered a worst-case transportation scenario to evaluate maximal leaching/interaction potential). Use a single PCR test platform throughout each clinical evaluation. The platform should have been previously authorized by HC how to buy flagyl in usa or another jurisdiction.

    Location (for example, left vs right nostril) and order of sampling (for example, control vs. Test swab) can affect specimen quality and results variability. Location and swab sampling order should be randomized.For how to buy flagyl in usa additional information on collecting, handling, and testing buy antibiotics specimens, please refer to the Centers for Disease Control and Prevention (CDC) Interim Guidelines for Collecting, Handling, and Testing Clinical Specimens for buy antibiotics.Previous clinical dataPreviously obtained clinical data may be submitted in lieu of clinical testing. Those data should demonstrate the safe and effective use of a swab of identical design and materials in human subjects. The proposed swab should be compared against how to buy flagyl in usa a flocked swab commercially available in Canada with respect to.

    flexibility fit ability to navigate to the nasopharynx (or other areas specified in the indications) ability to collect a specimen/respiratory epithelial cells for example, using the RNase P housekeeping gene test results agreement for example, ≥ 90% positive % agreement) using a composite control (positive % agreement calculation that includes all positive findings from control and test swabs) Sterility Provide sterilization validation data in a summary report. It should demonstrate that the chosen sterilization method will achieve a minimum Sterility Assurance Level (SAL) of 10-6 for the proposed swab, using an appropriate biological indicator (BI) organism (see below). If the swab will be sterilized using an ethylene oxide (EtO) method, how to buy flagyl in usa you should demonstrate that EtO and ethylene chlorohydrin (ECH) residuals meet the tolerable contact limits (TCL) specified in ISO 10993-7. Commonly used swab materials, compatible sterilization methods, and appropriate biological indicators are described below. Sterilization Method Swab Materials EtO(for example, ISO 11135) Gamma Irradiation(ISO 11137) Polystyrene handle, polyester bicomponent fiber tipFootnote * X(for example, Puritan 25-3316-H/U) Not applicable Polystyrene handle, nylon flocked fiber tipFootnote * X(for example, Copan 503CS01) X(for example, BD 220252) Footnote * The CDC provides guidance on the types of swabs that should be used for optimal specimen collection for PCR testing.

    They include swabs how to buy flagyl in usa that are made of polyester (for example, Dacron), rayon, or nylon-flocked. Cotton-tipped or calcium alginate swabs are not acceptable because residues present in those materials inhibit the PCR reaction. Return to footnote * referrer Appropriate BIIf ionizing radiation will be used to sterilize the swab. Bacillus pumilus spores are recommended how to buy flagyl in usa for doses of 25 kGy Bacillus cereus or Bacillus sphaericus spores are recommended for doses of >. 25 kGy (World Health Organization, The International Pharmacopoeia, 9th Ed., 2019) Sterilization Process Spore (Indicator Organism) Steam Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Dry Heat Bacillus atrophaeus (formerly Bacillus subtilis var.

    Niger) Ethlylene Oxide Bacillus atrophaeus (formerly Bacillus subtilis var. Niger) Hydrogen Peroxide Geobacillus stearothermophilus(formerly Bacillus stearothermophilus) Source how to buy flagyl in usa. US Food and Drug Administration, "Biological Indicator (BI) Premarket Notification [510(k)] Submissions," October 2007. [Online].Packaging validation Provide packaging validation data in a summary report. It should demonstrate that the swab packaging system will maintain a sterile environment across the labelled shelf how to buy flagyl in usa life (for example, ASTM F1980).

    without leakage (for example, ASTM D3078-02) with adequate seal strength (for example, ASTM F88/EN 868-5)Test packaging samples should be representative of finished swab packages that have undergone sterilization prior to testing.Biocompatibility Provide biocompatibility data in a summary report. It should demonstrate compliance with biocompatibility tests recommended for devices in limited contact (≤24 hrs) with mucosal membranes, as per ISO 10993-1. These include how to buy flagyl in usa. cytotoxicity sensitization irritation/intracutaneous reactivityThese data should be based on test samples representative of finished swabs that have undergone sterilization prior to testing.LabellingSwabs should be individually packaged and labelled. The application how to buy flagyl in usa must include the swab label, which must include.

    The name and model number of the device the term ‘sterile’, along with the sterilization method (EtO = ethylene oxide. R = gamma irradiation), if the swab is intended to be sold in a sterile condition the name and address of the manufacturer manufacturing and expiry datesIf swabs are not sterile but must be sterilized at the user facility, then the sterilization parameters and method should be clearly described in accompanying instructions for use documentation.Post-market requirementsAs stated in Section 12 of the IO, within 10 days of becoming aware of an incident in Canada, all IO authorization holders must. report the incident specify the nature of the incident specify the how to buy flagyl in usa circumstances surrounding the incidentOn this page About face shields Personal protective equipment (PPE) can help prevent potential exposure to infectious disease. They are considered medical devices in Canada and therefore must follow the requirements outlined in the Medical Devices Regulations. Medical devices are classified into 4 groups (Class I, II, III and IV) based on their risk to health and safety.

    Class I devices, such how to buy flagyl in usa as gauze bandages, pose the lowest potential risk, while Class IV devices, such as pacemakers, pose the greatest potential risk. In Canada, face shields are Class I medical devices. A face shield has a transparent window or visor that shields the face and associated mucous membranes (eyes, nose and mouth). It protects the wearer against exposure from splashes and how to buy flagyl in usa sprays of body fluids. Face shields are made of shatterproof plastic, fit over the face and are held in place by head straps or caps.

    They may be made of polycarbonate, propionate, acetate, polyvinyl chloride, or polyethylene terephthalate. They are usually worn with other PPE, such as a medical mask, respirator how to buy flagyl in usa or eyewear. Health Canada strongly advises against the use of plastic bags as an alternative to face shields. Standards and requirements for face shields Organizations that are manufacturing face shields are advised to consult some or all of the following standards throughout the design and testing stages. ANSI/ISEA Z.87.1 (2015), American National Standard for Occupational and Educational Personal Eye and Face Protection Devices CSA Z94.3 (2020), Eye and Face Protectors CSA Z94.3.1 (2016), Guideline for Selection, Use, and Care of Eye and Face Protectors BS EN 166 (2002), Personal Eye Protection how to buy flagyl in usa.

    Specifications. Minimum specifications must be incorporated into the design and verification stages to ensure safe and effective face shields. Provide adequate how to buy flagyl in usa coverage (CSA Z94.3 Sections 0.2.1/10.2.2/10.3/10.4). The size of the face shield is important because it must protect the face and front part of the head. This includes the eyes, forehead, cheeks, nose, mouth, and chin.

    Protection may also need to extend to the front of the neck in situations with flying particles and sprays of hazardous liquids how to buy flagyl in usa. Fit snugly to afford a good seal to the forehead area and to prevent slippage of the device Footnote 1. Be made how to buy flagyl in usa of optically clear, distortion-free, lightweight materials (CSA Z94.3.1-16 and Footnote 1). Be free of visible defects or flaws that would impede vision (ANSI Z87.1 Section 9.4). Be comfortable and easy to assemble, use and remove by health care professionals.

    Provide adequate space between how to buy flagyl in usa the wearer’s face and the inner surface of the visor to allow for the use of ancillary equipment (for example, medical mask, respirator, eyewear) Footnote 1. The characteristics and performance requirements of face shields must not be altered when attaching shields to other protective equipment, such as hats or caps. Display anti-fog characteristics on inside and outside of shield (CSA Z94.3.1-16). For face shields that are not how to buy flagyl in usa fog resistant, anti-fog spray must be provided. Provide user-contacting materials that have adequate material biocompatibility (skin sensitivity and cytotoxic testing) (ISO 10993-5, 10).

    Other items to take note of include. Face shields used for protection in hospital settings do not have to be impact- how to buy flagyl in usa or flame- resistant. If the device is specifically designed to withstand impact from sharp or fast projectiles, it must comply with set-out standards (ANSI Z87.1, sections 9.2 and 9.3, CSA Z94.3, section 10.1). For reuse, manufacturers must provide validated cleaning instructions. Sterilization procedures must not compromise the shield in any way, such as deformation or cracking how to buy flagyl in usa.

    Regulatory authorization Most PPE, including face shields, are Class I medical devices if they are manufactured, sold or represented for use for reducing the risk of or preventing the user from . This includes buy antibiotics. Face shields may be authorized for sale or import into Canada through the following how to buy flagyl in usa regulatory pathways. Pathway 1. Interim order authorization to import and sell medical devices related to buy antibiotics.

    Pathway 2 how to buy flagyl in usa. Expedited review and issuance of Medical Device Establishment Licences (MDEL) related to buy antibiotics. MDEL holders that import how to buy flagyl in usa and sell face shields should take measures to ensure they are safe and effective. Pathway 3. Exceptional importation and sale of certain non-compliant medical devices related to buy antibiotics.

    Note that a sale generally requires the transfer of ownership of a device how to buy flagyl in usa from one party to another and does not necessitate any transfer of money. Applicants should carefully review the pathways and select the most appropriate authorization route for their product. For more information, see Personal protective equipment (buy antibiotics). How to how to buy flagyl in usa get authorization. If you intend to manufacture 3D print face shields in response to the buy antibiotics crisis, see.

    3D printing and other manufacturing of personal protective equipment in response to buy antibiotics Feedback If you have any questions or comments about this notice, contact the Medical Devices Directorate at hc.meddevices-instrumentsmed.sc@canada.ca R. J. Roberge, "Face shields for control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.

    Related links FootnotesFootnote 1 R. J. Roberge, "Face shields for control. A review," Journal of Occupational and Environmental Hygiene, pp. 235-242, 2016.Return to footnote 1 referrer.

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