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2. By regular mail. You may mail written comments to the following address. CMS, Office of Strategic Operations and Regulatory Affairs, Division of Regulations Development, Attention. Document Identifier/OMB Control Number.

__, Room C4-26-05, 7500 Security Boulevard, Baltimore, Maryland 21244-1850. To obtain copies of a supporting statement and any related forms for the proposed collection(s) summarized in this notice, you may make your request using one of following. 1. Access CMS' website address at website address at https://www.cms.gov/​Regulations-and-Guidance/​Legislation/​PaperworkReductionActof1995/​PRA-Listing.html. Start Further Info William N.

Parham at (410) 786-4669. End Further Info End Preamble Start Supplemental Information Contents This notice sets out a summary of the use and burden associated with the following information collections. More detailed information can be found in each collection's supporting statement and associated materials (see ADDRESSES). CMS-10280 Home Health Change of Care Notice CMS-1557 Survey Report Form for Clinical Laboratory Improvement Amendments (CLIA) and Supporting Regulations CMS-3070G-I ICF/IID Survey Report Form and Supporting Regulations Under the PRA (44 U.S.C. 3501-3520), federal agencies must obtain approval from the Office of Management and Budget (OMB) for each collection of information they conduct or sponsor.

The term “collection of information” is defined in 44 U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes agency requests or requirements that members of the public submit reports, keep records, or provide information to a third party. Section 3506(c)(2)(A) of the PRA requires federal agencies to publish a 60-day notice in the Federal Register concerning each proposed collection of information, including each proposed extension or reinstatement of an existing collection of information, before submitting the collection to OMB for approval. To comply with this requirement, CMS is publishing this notice. Information Collection 1.

Type of Information Collection Request. Extension of a currently approved collection. Title of the Information Collection. Home Health Change of Care Notice. Use.

The purpose of the Home Health Change of Care Notice (HHCCN) is to notify original Medicare beneficiaries receiving home health care benefits of plan of care changes. Home health agencies (HHAs) are required to provide written notice to Original Medicare beneficiaries under various circumstances involving the reduction or termination of items and/or services consistent with Home Health Agencies Conditions of Participation (COPs). The home health COP requirements are set forth in § 1891[42 U.S.C. 1395bbb] of the Social Security Act (the Act). The implementing regulations under 42 CFR 484.10(c) specify that Medicare patients receiving HHA services have rights.

The patient has the right to be informed, in advance about the care to be furnished, and of any changes in the care to be furnished. The HHA must advise the patient in advance of the disciplines that will furnish care, and the frequency of visits proposed to be furnished. The HHA must advise the patient in advance of any change in the plan of care before the change is made.” Notification is required for covered and non-covered services listed in the plan of care (POC). The beneficiary will use the information provided to decide whether or not to pursue alternative options to continue receiving the care noted on the HHCCN. Form Number.

CMS-10280 (OMB control number. 0938-1196). Frequency. Yearly. Affected Public.

Private Sector (Business or other for-profits, Not-for-Profit Institutions). Number of Respondents. 11,157. Total Annual Responses. 12,385,108.

Total Annual Hours. 824,848. (For policy questions regarding this collection contact Jennifer McCormick at 410-786-2852.) 2. Type of Information Collection Request. Extension of a currently approved collection.

Title of Information Collection. Survey Report Form for Clinical Laboratory Improvement Amendments (CLIA) and Supporting Regulations. Use. The form is used to report surveyor findings during a CLIA survey. For each type of survey conducted (i.e., initial certification, recertification, validation, complaint, addition/deletion of specialty/subspecialty, transfusion fatality investigation, or revisit inspections) the Survey Report Form incorporates the requirements specified in the CLIA regulations.

Form Number. CMS-1557 (OMB control number. 0938-0544). Frequency. Biennially.

Affected Public. Private sector (Business or other for-profit and Not-for-profit institutions, State, Local or Tribal Governments and Federal Government). Number of Respondents. 15,975. Total Start Printed Page 46855Annual Responses.

7,988. Total Annual Hours. 3,994. (For policy questions regarding this collection contact Kathleen Todd at 410-786-3385). 3.

Type of Information Collection Request. Revision of a currently approved collection. Title of Information Collection. ICF/IID Survey Report Form and Supporting Regulations. Use.

The information collected with forms 3070G, CMS-3070H and CMS-3070I is used by the surveyors from the State Survey Agencies (SAs) to determine the level of compliance with the ICF/IID Conditions of Participation (CoPs) necessary to participate in the Medicare/Medicaid program and to report any non-compliance with the ICF/IID CoPs to the Federal government. These forms summarize the survey team characteristics, facility characteristics, client population, and the special needs of clients. These forms are used in conjunction with the CMS regulation text and additional surveyor aids such as the CMS interpretive guidelines and probes. The CMS-3070G-I forms serves as coding worksheets, designed to facilitate data entry and retrieval into the Automated Survey Processing Environment Suite (ASPEN) in the State and at the CMS regional offices. Form Number.

CMS-3070G-I (OMB control number. 0938-0062). Frequency. Reporting—Yearly. Affected Public.

Business or other for-profits and Not-for-profit institutions. Number of Respondents. 5,758. Total Annual Responses. 5,758.

Total Annual Hours. 17,274. (For policy questions regarding this collection contact Caroline Gallaher at 410-786-8705.) Start Signature Dated. August 17, 2021. William N.

Parham, III Director, Paperwork Reduction Staff, Office of Strategic Operations and Regulatory Affairs. End Signature End Supplemental Information [FR Doc. 2021-17908 Filed 8-19-21. 8:45 am]BILLING CODE 4120-01-PStart Preamble Centers for Medicare &. Medicaid Services, Health and Human Services (HHS).

Notice. The Centers for Medicare &. Medicaid Services (CMS) is announcing an opportunity for the public to comment on CMS' intention to collect information from the public. Under the Paperwork Reduction Act of 1995 (the PRA), federal agencies are required to publish notice in the Federal Register concerning each proposed collection of information (including each proposed extension or reinstatement of an existing collection of information) and to allow 60 days for public comment on the proposed action. Interested persons are invited to send comments regarding our Start Printed Page 42842burden estimates or any other aspect of this collection of information, including the necessity and utility of the proposed information collection for the proper performance of the agency's functions, the accuracy of the estimated burden, ways to enhance the quality, utility, and clarity of the information to be collected, and the use of automated collection techniques or other forms of information technology to minimize the information collection burden.

Comments must be received by October 4, 2021. When commenting, please reference the document identifier or OMB control number. To be assured consideration, comments and recommendations must be submitted in any one of the following ways. 1. Electronically.

You may send your comments electronically to http://www.regulations.gov. Follow the instructions for “Comment or Submission” or “More Search Options” to find the information collection document(s) that are accepting comments. 2. By regular mail. You may mail written comments to the following address.

CMS, Office of Strategic Operations and Regulatory Affairs, Division of Regulations Development, Attention. Document Identifier/OMB Control Number. __, Room C4-26-05, 7500 Security Boulevard, Baltimore, Maryland 21244-1850. To obtain copies of a supporting statement and any related forms for the proposed collection(s) summarized in this notice, you may make your request using one of following. 1.

Access CMS' website address at website address at https://www.cms.gov/​Regulations-and-Guidance/​Legislation/​PaperworkReductionActof1995/​PRA-Listing.html. Start Further Info William N. Parham at (410) 786-4669. End Further Info End Preamble Start Supplemental Information Contents This notice sets out a summary of the use and burden associated with the following information collections. More detailed information can be found in each collection's supporting statement and associated materials (see ADDRESSES).

CMS-10148 HIPAA Administrative Simplification (Non-Privacy/Security) Complaint Form CMS-10784 The Home Health Care CAHPS® Survey (HHCAHPS) Mode Experiment Under the PRA (44 U.S.C. 3501-3520), federal agencies must obtain approval from the Office of Management and Budget (OMB) for each collection of information they conduct or sponsor. The term “collection of information” is defined in 44 U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes agency requests or requirements that members of the public submit reports, keep records, or provide information to a third party. Section 3506(c)(2)(A) of the PRA requires federal agencies to publish a 60-day notice in the Federal Register concerning each proposed collection of information, including each proposed extension or reinstatement of an existing collection of information, before submitting the collection to OMB for approval.

To comply with this requirement, CMS is publishing this notice. Information Collection 1. Type of Information Collection Request. Extension of a currently approved collection. Title of Information Collection.

HIPAA Administrative Simplification (Non-Privacy/Security) Complaint Form. Use. The Secretary of Health and Human Services (HHS), hereafter known as “The Secretary,” codified 45 CFR parts 160 and 164 Administrative Simplification provisions that apply to the enforcement of the Health Insurance Portability and Accountability Act of 1996 Public Law 104-191 (HIPAA). The provisions address rules relating to the investigation of non-compliance of the HIPAA Administrative Simplification code sets, unique identifiers, operating rules, and transactions. 45 CFR 160.306, Complaints to the Secretary, provides for investigations of covered entities by the Secretary.

Further, it outlines the procedures and requirements for filing a complaint against a covered entity. Anyone can file a complaint if he or she suspects a potential violation. Persons believing that a covered entity is not utilizing the adopted Administrative Simplification provisions of HIPAA are voluntarily requested to file a complaint with CMS via the Administrative Simplification Enforcement and Testing Tool (ASETT) online system, by mail, or by sending an email to the HIPAA mailbox at hipaacomplaint@cms.hhs.gov. Information provided on the standard form will be used during the investigation process to validate non-compliance of HIPAA Administrative Simplification provisions.

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What are the key cost of lasix medication features of hospitals that consistently deliver safe care on labour and delivery?. This is the primary question posed by Liberati and colleagues in this issue of BMJ Quality &. Safety.1 The authors propose a framework distilled from observations on a group of high-performing units cost of lasix medication in the UK participating in a training activity to improve patient safety. This study combined ethnography with individual interviews and focus groups and involved over 400 hours of total observations at six different maternity care sites. The seven features in their resulting For Us framework correspond well to existing theoretical as well as applied quality improvement strategies.

While we agree that their framework describes features that every labour and delivery unit should strive to include, this approach has some cost of lasix medication limitations in terms of generalisability. Specifically, Liberati and colleagues studied maternity units that are high performing, but their sample included only large-volume hospitals in what appear to be well-resourced settings. What is cost of lasix medication potentially missing is observations on underperforming units, and how these findings may or may not apply to smaller, lower resourced settings. Additionally, the structure of the UK’s National Health Service (NHS) also limits generalisability. For example, this is most analogous to employed physician models in the USA, with the potential advantage of a more organisationally oriented provider workforce.

Given that most US hospitals do not have an cost of lasix medication employed provider model, we can’t assume that these factors will have the same impact in other models of care.In the USA, the Agency for Healthcare Research and Quality (AHRQ) developed a Culture of Safety framework that delineates four key features. (1) organisations recognise that their primary activities are inherently high risk and make it their goal to operate in a reliably safe manner. (2) organisations create a safe and blame-free reporting environment. (3) interdisciplinary and interprofessional collaboration is cost of lasix medication encouraged to address safety problems. And (4) resources are deliberately allocated and made available to address safety.2 This framework, as does For Us, focuses on a healthcare-oriented conceptualisation of safety and quality, and details medical outcomes as the primary metrics by which to measure success.

Although achievement of these medical quality outcomes is cost of lasix medication imperative, we propose that there are additional domains needed to provide safe intrapartum care. (A) prioritising patient experience—including emotional safety, birthing with dignity and an expectation of person-centred care. And (B) a unit culture that values low intervention births. Let us consider these domains in more depth.Patient experience cost of lasix medication and safety are inextricable. While much work has been done to improve physician–patient communication,3 4 few have successfully targeted the perpetuation of dysfunctional behaviours grounded in healthcare professionals’ implicit and explicit biases.5 This may be in part due to the tendency to observe and look for answers from the standpoint of the healthcare system rather than patients.

Women who had recently given cost of lasix medication birth were included in the study of Liberati and colleagues, but represented only 8 of 65 individual stakeholder interviews, and were not included in focus groups. The framework thus describes a high-functioning system from primarily the healthcare system’s perspective. In general, the patient’s role in achieving safe care includes many aspects, including providing personal information to reach the correct diagnosis, providing their values and lived experience in shared decision-making discussions, choosing their provider such that their needs regarding provider experience and safe practice are met, making sure that they receive the recommended treatments in a timely manner, as well as identifying and reporting errors.6 The detriment to health outcomes among patients who have failed interactions with providers is well documented (eg, leaving against medical advice or experiencing disrespect during their care) while other harms, such as psychological trauma, often go unmeasured.7Emotional and psychological trauma are safety errors, whether or not a patient leaves the hospital physically intact.8 Research has shown that patients experience psychological trauma both as a result of an adverse outcome and as a result of how the incident was managed. In birth, patients conceptualise the meaning of safety very differently from that cost of lasix medication of the medical system, with physical and emotional safety being inextricably interwoven into a single concept.9 Psychological trauma may manifest in postpartum depression, post-traumatic stress disorder10 and, some studies suggest, reduced childbearing in patients who experience traumatic birth.11 The experience of emotional safety on the part of the patient is only knowable to the patient, and only addressable when health systems—and health services research—ask the appropriate questions. Therefore, patient-reported experience measures and critical examination of the process of patient-centred care should be at the centre of quality improvement.High-performing units prioritise patient voice and patient experience as a part of their culture.

In a recent article, Morton and Simkin12 delineate steps to promote respectful maternity care in institutions, including obtaining unit commitment to respectful care, implementing training programmes to support respectful care as the norm and, finally, instituting respectful treatment of healthcare staff and clinicians by administrators and leaders—in other words, a unit culture of mutual respect and care among the entire team enables respectful care of the patient. Liberati and colleagues address the issue of hierarchies on labour cost of lasix medication and delivery, making the key observation that high-performing units create hierarchies around expertise rather than formal titles or disciplinary silos. However, this power differential applies to patients as well. The existing hierarchy on most labour units places physicians at the top and patients at the bottom, cost of lasix medication which often acts to silence patients’ voices.13 Implicit bias and interpersonal racism and sexism contribute to this cycle of silence and mistreatment on labour and delivery units.14 Disrespect and dismissal of patient concerns have been increasingly described, but still lack quantitative measurement in association with maternal and child health outcomes.15 Interventions aimed at harm reduction are emerging,16 but more work is desperately needed in this area.Valuing low intervention is an important dimension of safety. Safety culture, as it is conceptualised by AHRQ and the current study, is ideally created to prevent or respond to harmful safety lapses.

This model is more difficult to apply to an environment where the goal is safe facilitation of a normal biological process. In this cost of lasix medication setting, interventions (that often beget more interventions) can increase complications. High rates of primary and repeat caesarean deliveries, and other invasive obstetric interventions seen in many birthing units are now widely acknowledged to be overused and overuse constitutes a patient safety risk.17 In our work in California, we have been able to demonstrate that provider attitudes, beliefs and unit culture can drive caesarean delivery overuse in ways that do not contribute to patient safety.18 19 Each intervention needs to be carefully and jointly considered for value and safety. This in no way diminishes the life-saving nature of caesarean delivery when it is medically indicated, but it sets up cost of lasix medication the expectation that safety measures, processes and procedures must be in place to actively work towards supporting vaginal birth rather than treating each labour as an emergency waiting to happen. The striking variation in obstetric intervention rates among hospitals and providers can provide critical insights.

So, what is the right balance of intervention rates and mother/baby safety outcomes?. In many instances, cost of lasix medication this may be a false dichotomy. In a study of California hospital labour practices, Lundsberg et al found that hospitals that prioritised low labour interventions and actively supported vaginal birth (eg, delaying admission until active labour onset, use of doulas, intermittent auscultation of fetal heart tones, non-pharmacological pain relief, and so on) had reduced caesarean delivery rates with well-preserved neonatal outcomes.20 It should be noted that in the USA, rates of intervention are starting at a high level so there is less danger of harm from achieving too low a rate. This may not be the case in the UK where there are now formal inquiries examining obstetric care in multiple NHS hospital trusts where poor perinatal outcomes have been linked to a systematic aversion to medical interventions even when indicated.21 Getting this balance right has been referred to as the Goldilocks quandary. Doing too little, cost of lasix medication too much or just right?.

22In conclusion, physical safety is the bare minimum of what should be expected in childbirth. Patients have a right, and healthcare cost of lasix medication providers and systems have an obligation to aim higher, to ensure patients emerge from childbirth as healthy or healthier—both physically and psychologically—than before entering the hospital. This can be best achieved by broadening the lens of what we consider essential to safety on maternity units to include prioritising patient experience, birthing with dignity and valuing low intervention rates. All of these domains need to be in balance. Good mother or baby medical outcomes at cost of lasix medication the cost of high rates of intervention and high maternal psychological trauma are not a success, nor is the opposite.

The true ‘safe’ maternity unit is one that does well on all of these dimensions, which, of course, means that we need to be able to measure each of them. Finally, all of these safety domains, including the ‘For Us’ framework proposed by Liberati and colleagues, focus on unit culture, provider behaviours and processes of care, and thus are within the reach of all maternity units no matter their level of resources..

What are the key features of hospitals that can i buy lasix online consistently deliver safe care on labour and delivery? additional info. This is the primary question posed by Liberati and colleagues in this issue of BMJ Quality &. Safety.1 The authors propose a framework distilled from observations on a group of high-performing units in the UK participating can i buy lasix online in a training activity to improve patient safety. This study combined ethnography with individual interviews and focus groups and involved over 400 hours of total observations at six different maternity care sites.

The seven features in their resulting For Us framework correspond well to existing theoretical as well as applied quality improvement strategies. While we agree that their framework describes features that every can i buy lasix online labour and delivery unit should strive to include, this approach has some limitations in terms of generalisability. Specifically, Liberati and colleagues studied maternity units that are high performing, but their sample included only large-volume hospitals in what appear to be well-resourced settings. What is potentially missing is observations on underperforming units, and how these findings may or may not apply to smaller, can i buy lasix online lower resourced settings.

Additionally, the structure of the UK’s National Health Service (NHS) also limits generalisability. For example, this is most analogous to employed physician models in the USA, with the potential advantage of a more organisationally oriented provider workforce. Given that most US hospitals do not have an employed provider model, we can’t assume that these factors will have the same impact in other models of care.In can i buy lasix online the USA, the Agency for Healthcare Research and Quality (AHRQ) developed a Culture of Safety framework that delineates four key features. (1) organisations recognise that their primary activities are inherently high risk and make it their goal to operate in a reliably safe manner.

(2) organisations create a safe and blame-free reporting environment. (3) interdisciplinary and interprofessional collaboration is can i buy lasix online encouraged to address safety problems. And (4) resources are deliberately allocated and made available to address safety.2 This framework, as does For Us, focuses on a healthcare-oriented conceptualisation of safety and quality, and details medical outcomes as the primary metrics by which to measure success. Although achievement of these medical can i buy lasix online quality outcomes is imperative, we propose that there are additional domains needed to provide safe intrapartum care.

(A) prioritising patient experience—including emotional safety, birthing with dignity and an expectation of person-centred care. And (B) a unit culture that values low intervention births. Let us consider these domains in more depth.Patient experience and safety are inextricable can i buy lasix online. While much work has been done to improve physician–patient communication,3 4 few have successfully targeted the perpetuation of dysfunctional behaviours grounded in healthcare professionals’ implicit and explicit biases.5 This may be in part due to the tendency to observe and look for answers from the standpoint of the healthcare system rather than patients.

Women who had recently given birth were included in the study of Liberati and colleagues, but represented only 8 of can i buy lasix online 65 individual stakeholder interviews, and were not included in focus groups. The framework thus describes a high-functioning system from primarily the healthcare system’s perspective. In general, the patient’s role in achieving safe care includes many aspects, including providing personal information to reach the correct diagnosis, providing their values and lived experience in shared decision-making discussions, choosing their provider such that their needs regarding provider experience and safe practice are met, making sure that they receive the recommended treatments in a timely manner, as well as identifying and reporting errors.6 The detriment to health outcomes among patients who have failed interactions with providers is well documented (eg, leaving against medical advice or experiencing disrespect during their care) while other harms, such as psychological trauma, often go unmeasured.7Emotional and psychological trauma are safety errors, whether or not a patient leaves the hospital physically intact.8 Research has shown that patients experience psychological trauma both as a result of an adverse outcome and as a result of how the incident was managed. In birth, patients conceptualise the meaning of safety very differently from that of the medical system, with physical and emotional safety being inextricably interwoven into a single concept.9 Psychological trauma may manifest in postpartum depression, post-traumatic stress disorder10 and, some studies suggest, reduced childbearing in patients can i buy lasix online who experience traumatic birth.11 The experience of emotional safety on the part of the patient is only knowable to the patient, and only addressable when health systems—and health services research—ask the appropriate questions.

Therefore, patient-reported experience measures and critical examination of the process of patient-centred care should be at the centre of quality improvement.High-performing units prioritise patient voice and patient experience as a part of their culture. In a recent article, Morton and Simkin12 delineate steps to promote respectful maternity care in institutions, including obtaining unit commitment to respectful care, implementing training programmes to support respectful care as the norm and, finally, instituting respectful treatment of healthcare staff and clinicians by administrators and leaders—in other words, a unit culture of mutual respect and care among the entire team enables respectful care of the patient. Liberati and colleagues address the issue of hierarchies on labour and delivery, making the key observation that high-performing units create hierarchies around expertise rather than formal can i buy lasix online titles or disciplinary silos. However, this power differential applies to patients as well.

The existing hierarchy on most labour units places physicians at the top and patients at the bottom, which often acts to silence patients’ voices.13 Implicit bias and interpersonal racism and sexism contribute to this cycle of silence and mistreatment on labour and delivery units.14 Disrespect and dismissal of patient concerns have been increasingly described, but still lack quantitative measurement in association with maternal and child can i buy lasix online health outcomes.15 Interventions aimed at harm reduction are emerging,16 but more work is desperately needed in this area.Valuing low intervention is an important dimension of safety. Safety culture, as it is conceptualised by AHRQ and the current study, is ideally created to prevent or respond to harmful safety lapses. This model is more difficult to apply to an environment where the goal is safe facilitation of a normal biological process. In this setting, interventions (that often beget more interventions) can increase can i buy lasix online complications.

High rates of primary and repeat caesarean deliveries, and other invasive obstetric interventions seen in many birthing units are now widely acknowledged to be overused and overuse constitutes a patient safety risk.17 In our work in California, we have been able to demonstrate that provider attitudes, beliefs and unit culture can drive caesarean delivery overuse in ways that do not contribute to patient safety.18 19 Each intervention needs to be carefully and jointly considered for value and safety. This in no way diminishes the life-saving nature of caesarean delivery when it can i buy lasix online is medically indicated, but it sets up the expectation that safety measures, processes and procedures must be in place to actively work towards supporting vaginal birth rather than treating each labour as an emergency waiting to happen. The striking variation in obstetric intervention rates among hospitals and providers can provide critical insights. So, what is the right balance of intervention rates and mother/baby safety outcomes?.

In many instances, can i buy lasix online this may be a false dichotomy. In a study of California hospital labour practices, Lundsberg et al found that hospitals that prioritised low labour interventions and actively supported vaginal birth (eg, delaying admission until active labour onset, use of doulas, intermittent auscultation of fetal heart tones, non-pharmacological pain relief, and so on) had reduced caesarean delivery rates with well-preserved neonatal outcomes.20 It should be noted that in the USA, rates of intervention are starting at a high level so there is less danger of harm from achieving too low a rate. This may not be the case in the UK where there are now formal inquiries examining obstetric care in multiple NHS hospital trusts where poor perinatal outcomes have been linked to a systematic aversion to medical interventions even when indicated.21 Getting this balance right has been referred to as the Goldilocks quandary. Doing too little, can i buy lasix online too much or just right?.

22In conclusion, physical safety is the bare minimum of what should be expected in childbirth. Patients have a right, and healthcare providers and can i buy lasix online systems have an obligation to aim higher, to ensure patients emerge from childbirth as healthy or healthier—both physically and psychologically—than before entering the hospital. This can be best achieved by broadening the lens of what we consider essential to safety on maternity units to include prioritising patient experience, birthing with dignity and valuing low intervention rates. All of these domains need to be in balance.

Good mother or baby medical outcomes at the cost of high rates of intervention and high maternal psychological trauma are not a success, nor is the opposite. The true ‘safe’ maternity unit is one that does well on all of these dimensions, which, of course, means that we need to be able to measure each of them. Finally, all of these safety domains, including the ‘For Us’ framework proposed by Liberati and colleagues, focus on unit culture, provider behaviours and processes of care, and thus are within the reach of all maternity units no matter their level of resources..

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Drawing on peer-reviewed and grey order lasix online literature, Cost of lasix at walmart Powell et al argue the dominant narrative of personal self-care during the hypertension medications lasix must be supplemented with a collectivist approach that addresses structural inequalities and fosters a more equitable society.Compliance with self-care and risk mitigation strategies to tackle hypertension medications has been chequered in the UK, fuelled partly by social media hoaxes and misinformation, lasix denialism, and policy leaders contravening their own public health messaging. Exploring individual non-compliance, and reflecting on wider societal inequities that can impact it, can help build critical normative resilience to future lasixs.From the outset, hypertension medications public health messaging was, and remains, primarily aimed at modifying individual lifestyles and behaviours to flatten the infectivity curve by following ‘common sense’ approaches captured by the hands–face–space mantra.1 A culture of practice and order lasix online new social norms of acceptable behaviour subsequently emerged,2 with concordance premised on cooperation between the public and government. However, as the lasix worsened and movement restrictions continued, norms were contested by a small but vocal segment of society.This normative contestation was founded on conflict between individual agency, government paternalism and regulatory diktat, and order lasix online echoed Kant’s epistemology of auism and the need to sacrifice individual liberties for the ‘greater good’. This conflict was exacerbated by multiple lockdowns that significantly impacted individuals’ daily lives, and dissidence within a post-Brexit body order lasix online politic characterised by distrust of politicians3 and strong personal beliefs about rights, responsibilities and sovereignty.Émile Durkeim's sociological concept of anomie, however, widens our understanding further.

Anomie characterises a dissolution or absence of established moral values, standards or mores that create a resulting normlessness.4 order lasix online 5 Discordance between personal and group norms—the absence of a shared social ethic—weakens communal bonds, impacting individual stress, frustration, anxiety, confusion and powerlessness. During hypertension medications, segments of society experienced powerlessness and loss of agency as daily routines were disrupted and further compounded by financial and mental distress order lasix online as morbidity and mortality data dominated daily news headlines.A visible minority began disregarding public health messaging, challenging norms needed to ensure a successful preventative response to the lasix (eg, hoarding of restricted supermarket items). That such behaviour was limited to a relative minority neither undermines the existence of anomie—self-interest remains juxtaposed to collective duty—nor weakens the contestation of existing dominant normative paradigms.6 Contesting ideas can reach a tipping point of popularity, establishing a new dominant social norm.7 This can trigger detrimental behaviour (eg, for rates) if the once dominant paradigm supported laudable public health messaging.In addressing this threat, it is vital to reinforce public health messaging by bolstering the underpinning social norms. Durkheim’s remedy was moral education, by which the collective consciousness—shared knowledge, ideas, beliefs and attitudes—is nurtured by supporting the collectivist tendencies of individuals,8 which can be achieved by various means.9 While using injunctions against those who transgress (eg, monetary fines) can supplement positive public health order lasix online measures, Durkheim crucially counselled that the imposition of norms does not bind individuals to the collective as strongly as consensus.

Such a didactic approach can undermine solidarity, potentially nurturing a scapegoat culture that can exacerbate existing and historical inequities (eg, enforcing treatment uptake among ethnic minority populations).Indeed, disruption of the social order, order lasix online and the emergence of new policy prescriptions to tackle the lasix, re-exposed chronic inequalities.10 11 ‘Stay at home’ advice had different connotations to a large segment of society. Those who order lasix online were victims of domestic abuse, or struggling to pay the rent, provide for their family, or who could not afford broadband, a personal laptop or access to a garden.An effective public health strategy is a holistic one that creates an open and inclusive dialogue with diverse community groups to identify shared values. This inclusive dialogue can help create a normative system that encourages the adoption and diffusion of initiatives addressing structural inequalities and injustices.Scrutiny of the UK’s response to hypertension medications has made order lasix online the case for self-care as a public health measure to tackle communicable diseases, while also highlighting its limitations vis-à-vis individual rights and responsibilities and extant structural inequalities. These challenges have not order lasix online undermined the self-care agenda.

Rather, they have highlighted the need to reinforce it, to shore up the normative elements that underpin it to ensure success.Although the sustained adoption of health-seeking behaviours is crucial, individual self-care alone is insufficient to tackle the lasix. Societal responsibility order lasix online is also required whereby (1) individuals act in responsible and rational ways to prevent hypertension medications spread until pharmacological interventions to prevent or manage the lasix become widely available and (2) communities and governing institutions work together to build a more equal society. In the UK, the current political climate is characterised by discourse in which individuals are the order lasix online source of, and the solution to, social problems. Policies and practices order lasix online continue to focus on individual rather than collective responsibility.

Both aspects order lasix online need to be addressed when tackling national emergencies, including global lasixs. As Durkheim recognised,12 social justice and equality are necessary to sustain solidarity—they are the bond connecting individuals in society that ensures stability and social order.Key messagesSelf-care has been, and continues to be, critical to tackling the hypertension medications lasix.The concept of anomie—an uprooting, dissolution or absence of established moral values, guiding standards, or social mores, creating normlessness—cannot be overlooked when planning an integrated social response.The dominant narrative of personal self-care must be supplemented with a collectivist approach order lasix online that addresses structural inequalities for the future.Ethics statementsPatient consent for publicationNot required.AcknowledgmentsRAP's and AE-O's independent contribution to this article is supported by the National Institute for Health Research Applied Research Collaboration Northwest London. The views expressed in this publication are those of RAP and AE-O and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.The Global Burden of Disease Study reported that from 1990 to 2019, cardiovascular diseases (CVDs) emerged as a leading cause of disability-adjusted life-years (DALYs) in South Asians of both genders (15.2% of total DALYs in men and 11.9% in women).1 South Asia is largely rural with a population of approximately 1.2 billion people and projected to remain rural through to 2050, with a similar number of people.2 In 2014, the multi-country Prospective Urban Rural Epidemiology (PURE) cohort study found that rural South Asians experienced higher incidence rates for CVD mortality and morbidity (7.2 per 1000 person-years) compared with their urban counterparts (5.6 per 1000 person-years), from myocardial infarction, heart failure and stroke.3 This is despite rural South Asians having a comparatively better CVD risk profile, an INTERHEART risk score of 7.6 compared with 9.1.3 Over the past 30 years (1985–2017), the increase in age-standardised mean body mass index (BMI) in the adult rural population has outpaced urban counterparts.4 It follows that ….

Drawing on peer-reviewed and grey literature, Powell et al argue the dominant narrative of personal self-care during the hypertension medications lasix can i buy lasix online must be supplemented with a collectivist approach that addresses structural inequalities and fosters a more equitable society.Compliance with self-care and risk mitigation strategies to tackle hypertension medications has been chequered in the UK, fuelled partly by social media hoaxes and misinformation, lasix denialism, and policy leaders contravening their own public health messaging. Exploring individual non-compliance, and reflecting on wider societal inequities that can i buy lasix online can impact it, can help build critical normative resilience to future lasixs.From the outset, hypertension medications public health messaging was, and remains, primarily aimed at modifying individual lifestyles and behaviours to flatten the infectivity curve by following ‘common sense’ approaches captured by the hands–face–space mantra.1 A culture of practice and new social norms of acceptable behaviour subsequently emerged,2 with concordance premised on cooperation between the public and government. However, as the lasix worsened and movement restrictions continued, norms were contested by a small but vocal segment of society.This normative contestation was founded on conflict between individual agency, government paternalism and regulatory diktat, can i buy lasix online and echoed Kant’s epistemology of auism and the need to sacrifice individual liberties for the ‘greater good’. This conflict was exacerbated by multiple lockdowns that significantly impacted individuals’ daily lives, and dissidence within a post-Brexit body politic characterised by distrust of politicians3 and strong personal beliefs about rights, responsibilities and sovereignty.Émile Durkeim's sociological concept of can i buy lasix online anomie, however, widens our understanding further.

Anomie characterises a dissolution or absence of established moral values, standards or mores that create a resulting normlessness.4 5 Discordance between personal and group norms—the can i buy lasix online absence of a shared social ethic—weakens communal bonds, impacting individual stress, frustration, anxiety, confusion and powerlessness. During hypertension medications, segments of can i buy lasix online society experienced powerlessness and loss of agency as daily routines were disrupted and further compounded by financial and mental distress as morbidity and mortality data dominated daily news headlines.A visible minority began disregarding public health messaging, challenging norms needed to ensure a successful preventative response to the lasix (eg, hoarding of restricted supermarket items). That such behaviour was limited to a relative minority neither undermines the existence of anomie—self-interest remains juxtaposed to collective duty—nor weakens the contestation of existing dominant normative paradigms.6 Contesting ideas can reach a tipping point of popularity, establishing a new dominant social norm.7 This can trigger detrimental behaviour (eg, for rates) if the once dominant paradigm supported laudable public health messaging.In addressing this threat, it is vital to reinforce public health messaging by bolstering the underpinning social norms. Durkheim’s remedy was moral education, by which the collective consciousness—shared knowledge, ideas, beliefs and attitudes—is nurtured by supporting the collectivist tendencies of individuals,8 which can be achieved by various means.9 While using injunctions against those who can i buy lasix online transgress (eg, monetary fines) can supplement positive public health measures, Durkheim crucially counselled that the imposition of norms does not bind individuals to the collective as strongly as consensus.

Such a didactic approach can undermine solidarity, potentially can i buy lasix online nurturing a scapegoat culture that can exacerbate existing and historical inequities (eg, enforcing treatment uptake among ethnic minority populations).Indeed, disruption of the social order, and the emergence of new policy prescriptions to tackle the lasix, re-exposed chronic inequalities.10 11 ‘Stay at home’ advice had different connotations to a large segment of society. Those who were victims can i buy lasix online of domestic abuse, or struggling to pay the rent, provide for their family, or who could not afford broadband, a personal laptop or access to a garden.An effective public health strategy is a holistic one that creates an open and inclusive dialogue with diverse community groups to identify shared values. This inclusive dialogue can can i buy lasix online help create a normative system that encourages the adoption and diffusion of initiatives addressing structural inequalities and injustices.Scrutiny of the UK’s response to hypertension medications has made the case for self-care as a public health measure to tackle communicable diseases, while also highlighting its limitations vis-à-vis individual rights and responsibilities and extant structural inequalities. These challenges have not undermined can i buy lasix online the self-care agenda.

Rather, they have highlighted the need to reinforce it, to shore up the normative elements that underpin it to ensure success.Although the sustained adoption of health-seeking behaviours is crucial, individual self-care alone is insufficient to tackle the lasix. Societal responsibility is also required can i buy lasix online whereby (1) individuals act in responsible and rational ways to prevent hypertension medications spread until pharmacological interventions to prevent or manage the lasix become widely available and (2) communities and governing institutions work together to build a more equal society. In the UK, the current political climate is characterised by discourse in which individuals are the source can i buy lasix online of, and the solution to, social problems. Policies and practices continue to focus on individual rather than can i buy lasix online collective responsibility.

Both aspects can i buy lasix online need to be addressed when tackling national emergencies, including global lasixs. As Durkheim recognised,12 social justice and equality are necessary to sustain solidarity—they are the bond connecting individuals in society that ensures stability and social order.Key messagesSelf-care has been, and continues to be, critical to tackling the hypertension medications lasix.The concept of anomie—an uprooting, dissolution or absence can i buy lasix online of established moral values, guiding standards, or social mores, creating normlessness—cannot be overlooked when planning an integrated social response.The dominant narrative of personal self-care must be supplemented with a collectivist approach that addresses structural inequalities for the future.Ethics statementsPatient consent for publicationNot required.AcknowledgmentsRAP's and AE-O's independent contribution to this article is supported by the National Institute for Health Research Applied Research Collaboration Northwest London. The views expressed in this publication are those of RAP and AE-O and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.The Global Burden of Disease Study reported that from 1990 to 2019, cardiovascular diseases (CVDs) emerged as a leading cause of disability-adjusted life-years (DALYs) in South Asians of both genders (15.2% of total DALYs in men and 11.9% in women).1 South Asia is largely rural with a population of approximately 1.2 billion people and projected to remain rural through to 2050, with a similar number of people.2 In 2014, the multi-country Prospective Urban Rural Epidemiology (PURE) cohort study found that rural South Asians experienced higher incidence rates for CVD mortality and morbidity (7.2 per 1000 person-years) compared with their urban counterparts (5.6 per 1000 person-years), from myocardial infarction, heart failure and stroke.3 This is despite rural South Asians having a comparatively better CVD risk profile, an INTERHEART risk score of 7.6 compared with 9.1.3 Over the past 30 years (1985–2017), the increase in age-standardised mean body mass index (BMI) in the adult rural population has outpaced urban counterparts.4 It follows that ….

Bumex and lasix

WASHINGTON — The last time a president used an obscure law to spend billions of Medicare dollars without congressional approval, see this Republican lawmakers called it a political ploy, a technicality, a way to write a bumex and lasix “blank check” to help win an election. They launched investigations and issued subpoenas.But that was when President Obama was in charge. Now, it’s President Trump who’s using the same little-known Medicare law for a maneuver that bumex and lasix even some Republicans admit is more brazen than Obama’s attempt. And so far, Republicans are silent.Trump’s plan is to ship seniors $200 prescription drug coupons in the coming weeks, a massive, $6.6 billion initiative that he announced less than six weeks before Election Day. He is relying on the same authority that Obama used in 2010 to bolster a bumex and lasix more expensive, albeit less outwardly political, plan to direct bonus payments to high-performing insurance companies ahead of his own reelection campaign.

Republicans were outraged, and ultimately, a government watchdog recommended the Obama administration kill the program. It did not.advertisement Republican lawmakers’ silence on the administration’s use of the same authority highlights a fundamental hypocrisy in how GOP politicians bumex and lasix treat Trump. Condemnation came swiftly from Republicans outside Congress and the administration and from congressional Democrats, too, all of whom viewed the action as a clear attempt to use taxpayer cash for political gain.“It’s completely inappropriate. The timing of it reeks of a bribe to seniors before the election,” said Doug bumex and lasix Holtz-Eakin, the president of the conservative American Action Forum and a former adviser to the late Sen. John McCain’s presidential campaign, said of Trump’s plan.

€œI see no reason to bumex and lasix somehow pretend this is OK. It’s not OK.”advertisement Eliot Fishman, an Obama-era Centers for Medicare and Medicaid Services official who now works at the progressive health care group Families USA, agreed. Republicans not calling out Trump’s latest move would be “worse than conventional partisan hypocrisy,” he argued, because of the move’s long-term constitutional implications.“You’re essentially turning the Medicare program and any other program where there’s executive branch demonstration authority into an open slush fund that can be used to mail checks to key constituencies right before an election,” he said.Democratic lawmakers, too, bumex and lasix quickly cast Trump’s maneuvering as politically motivated. Sen. Ron Wyden (D-Ore.), the top Democrat on the Senate Finance Committee, referred to the move as a “taxpayer-funded bribe.” House Speaker Nancy Pelosi called it a “desperately transparent political gimmick.” Even Trump, in announcing the bumex and lasix giveaway during a Thursday address on health reform, acknowledged the move was political, telling a crowd in North Carolina.

€œJoe Biden won’t be doing this.”The Trump administration has struggled to explain the policy. During a Friday morning call with reporters, Department of Health and bumex and lasix Human Services officials said the plan was still being worked out, and that the White House would soon announce how the $200 coupons were being funded. The White House, however, had already explained. The program will rely on savings that the administration expects to generate from Trump’s separate “most favored nations” drug pricing proposal, which has not been implemented — effectively meaning that the money used to fund the coupons does not yet exist.Numerous Republican lawmakers did not immediately respond bumex and lasix to STAT’s repeated requests for comment, including the Finance Committee chairman, Sen. Chuck Grassley (Iowa), and Reps.

Kevin Brady (Texas) and Greg Walden (Ore.), respectively the top Republicans on the Ways and Means and Energy and Commerce committees bumex and lasix. Both the Obama and Trump controversies surround so-called demonstration authority, a power granted to the White House to test whether changes to Medicare to make the program run smoother or save money.Obama used that authority to change the bonuses for high-performing insurers that contract with Medicare. The plan, which was meant to test whether “stronger financial incentives and investments” would lead plans to offer better quality insurance coverage, would have doled out lucrative bonuses to 90% of private insurers.Republicans saw it as an attempt to insulate seniors from spiking insurance premiums bumex and lasix before an election. They argued that the Obama administration was robbing money from a different health program to prop up the Affordable Care Act and doling out the bonuses to make sure seniors didn’t feel the brunt of the cuts before the election.“An honest way to come to the Congress is. Look, we screwed up, we would destroy Medicare Advantage if we didn’t bail it out, so we came up with a scheme to bail bumex and lasix it out, that’s what you did,” said Rep.

Darrell Issa (R-Calif.), who led the Republican investigation into the project. The Obama administration pilot prompted Republicans to order a review by the Government Accountability Office, a federal watchdog program.Both the GAO bumex and lasix and lawmakers noted that the absence of a control group made it difficult to conduct an experiment to measure the program’s effectiveness. The GAO ultimately found that the Obama administration likely exceeded its authority and recommended the demonstration be canceled.“There was clearly oversight following that demonstration,” said Jon Blum, the former Obama administration official hauled before Congress after the Obama demonstration. Blum added that he believed many of the criticisms waged bumex and lasix at the Obama demonstration, like the lack of a control group, likely could plague the Trump ploy, too. Trump’s plan is more brazen.

It’s not clear how the Trump administration might test whether the bumex and lasix payments had their intended goal if all seniors in Medicare are getting payments — or what the administration is planning to test at all.“It doesn’t pass the simple test of logic,” Holtz-Eakin said. €œI don’t see how you can send $200 to every senior and call it a demo. Doing it to everyone in the program is not a demo.”Families USA’s Fishman called the move a “completely unprecedented” abuse of Medicare waiver authority.Many of the Republicans lawmakers who used the GAO report to bumex and lasix pounce on the Obama administration have since retired, like Issa and former Sen. Orrin Hatch of Utah, the chair of the Senate Finance Committee at the time..

WASHINGTON — can i buy lasix online The last time a president used an obscure law to spend billions of Medicare dollars without congressional approval, http://carlfarrugia.com/sell-media-lightbox/ Republican lawmakers called it a political ploy, a technicality, a way to write a “blank check” to help win an election. They launched investigations and issued subpoenas.But that was when President Obama was in charge. Now, it’s President Trump who’s using the same little-known Medicare law for a maneuver that even some Republicans admit is more brazen can i buy lasix online than Obama’s attempt. And so far, Republicans are silent.Trump’s plan is to ship seniors $200 prescription drug coupons in the coming weeks, a massive, $6.6 billion initiative that he announced less than six weeks before Election Day. He is relying on the same authority that Obama used in 2010 to bolster a more expensive, albeit less outwardly political, plan to direct bonus can i buy lasix online payments to high-performing insurance companies ahead of his own reelection campaign.

Republicans were outraged, and ultimately, a government watchdog recommended the Obama administration kill the program. It did not.advertisement Republican lawmakers’ silence on the administration’s use of the same can i buy lasix online authority highlights a fundamental hypocrisy in how GOP politicians treat Trump. Condemnation came swiftly from Republicans outside Congress and the administration and from congressional Democrats, too, all of whom viewed the action as a clear attempt to use taxpayer cash for political gain.“It’s completely inappropriate. The timing can i buy lasix online of it reeks of a bribe to seniors before the election,” said Doug Holtz-Eakin, the president of the conservative American Action Forum and a former adviser to the late Sen. John McCain’s presidential campaign, said of Trump’s plan.

€œI see no reason can i buy lasix online to somehow pretend this is OK. It’s not OK.”advertisement Eliot Fishman, an Obama-era Centers for Medicare and Medicaid Services official who now works at the progressive health care group Families USA, agreed. Republicans not calling can i buy lasix online out Trump’s latest move would be “worse than conventional partisan hypocrisy,” he argued, because of the move’s long-term constitutional implications.“You’re essentially turning the Medicare program and any other program where there’s executive branch demonstration authority into an open slush fund that can be used to mail checks to key constituencies right before an election,” he said.Democratic lawmakers, too, quickly cast Trump’s maneuvering as politically motivated. Sen. Ron Wyden (D-Ore.), the top Democrat on the Senate Finance Committee, referred to the move as a “taxpayer-funded bribe.” House Speaker Nancy Pelosi called can i buy lasix online it a “desperately transparent political gimmick.” Even Trump, in announcing the giveaway during a Thursday address on health reform, acknowledged the move was political, telling a crowd in North Carolina.

€œJoe Biden won’t be doing this.”The Trump administration has struggled to explain the policy. During a can i buy lasix online Friday morning call with reporters, Department of Health and Human Services officials said the plan was still being worked out, and that the White House would soon announce how the $200 coupons were being funded. The White House, however, had already explained. The program will rely on savings that the administration expects to generate from Trump’s separate “most favored nations” drug pricing proposal, which has not been implemented — effectively meaning that the money used to fund the coupons does not yet exist.Numerous Republican lawmakers did not immediately respond can i buy lasix online to STAT’s repeated requests for comment, including the Finance Committee chairman, Sen. Chuck Grassley (Iowa), and Reps.

Kevin Brady (Texas) and Greg Walden (Ore.), respectively can i buy lasix online the top Republicans on the Ways and Means and Energy and Commerce committees. Both the Obama and Trump controversies surround so-called demonstration authority, a power granted to the White House to test whether changes to Medicare to make the program run smoother or save money.Obama used that authority to change the bonuses for high-performing insurers that contract with Medicare. The plan, which was meant to test whether “stronger financial incentives and investments” would lead plans to offer better quality insurance coverage, would have doled out lucrative bonuses to 90% of private insurers.Republicans can i buy lasix online saw it as an attempt to insulate seniors from spiking insurance premiums before an election. They argued that the Obama administration was robbing money from a different health program to prop up the Affordable Care Act and doling out the bonuses to make sure seniors didn’t feel the brunt of the cuts before the election.“An honest way to come to the Congress is. Look, we screwed up, we would destroy Medicare Advantage if we didn’t bail it out, so we came up with a scheme to bail it can i buy lasix online out, that’s what you did,” said Rep.

Darrell Issa (R-Calif.), who led the Republican investigation into the project. The Obama administration pilot prompted Republicans to order a review by the Government Accountability Office, can i buy lasix online a federal watchdog program.Both the GAO and lawmakers noted that the absence of a control group made it difficult to conduct an experiment to measure the program’s effectiveness. The GAO ultimately found that the Obama administration likely exceeded its authority and recommended the demonstration be canceled.“There was clearly oversight following that demonstration,” said Jon Blum, the former Obama administration official hauled before Congress after the Obama demonstration. Blum added that he believed many of the criticisms waged at the Obama demonstration, like the lack of a control group, likely could plague can i buy lasix online the Trump ploy, too. Trump’s plan is more brazen.

It’s not clear can i buy lasix online how the Trump administration might test whether the payments had their intended goal if all seniors in Medicare are getting payments — or what the administration is planning to test at all.“It doesn’t pass the simple test of logic,” Holtz-Eakin said. €œI don’t see how you can send $200 to every senior and call it a demo. Doing it to everyone in the program is not a demo.”Families USA’s Fishman called the move a “completely unprecedented” abuse of Medicare waiver authority.Many of the Republicans lawmakers who used the GAO report to can i buy lasix online pounce on the Obama administration have since retired, like Issa and former Sen. Orrin Hatch of Utah, the chair of the Senate Finance Committee at the time..

Buy lasix 40mg online

Participants Figure buy lasix 40mg online 1 http://www.dmpmgc.com/safe-online-pharmacy-to-buy-cialis/. Figure 1. Enrollment and buy lasix 40mg online Randomization.

The diagram represents all enrolled participants through November 14, 2020. The safety subset (those with a median of 2 months of follow-up, in accordance with application buy lasix 40mg online requirements for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date. The further procedures that one participant in the placebo group declined after dose 2 (lower right corner of the diagram) were those involving collection of blood and nasal swab samples.Table 1.

Table 1 buy lasix 40mg online. Demographic Characteristics of the Participants in the Main Safety Population. Between July 27, 2020, and November 14, 2020, a total of 44,820 persons were screened, and 43,548 persons buy lasix 40mg online 16 years of age or older underwent randomization at 152 sites worldwide (United States, 130 sites.

Argentina, 1. Brazil, 2 buy lasix 40mg online. South Africa, 4.

Germany, 6 buy lasix 40mg online. And Turkey, 9) in the phase 2/3 portion of the trial. A total of 43,448 buy lasix 40mg online participants received injections.

21,720 received BNT162b2 and 21,728 received placebo (Figure 1). At the data cut-off date of October 9, a total of 37,706 participants had a median of at least 2 months of safety data available after the second dose and contributed to the main safety data set. Among these 37,706 participants, 49% were buy lasix 40mg online female, 83% were White, 9% were Black or African American, 28% were Hispanic or Latinx, 35% were obese (body mass index [the weight in kilograms divided by the square of the height in meters] of at least 30.0), and 21% had at least one coexisting condition.

The median age was 52 years, and 42% of participants were older than 55 years of age (Table 1 and Table S2). Safety Local buy lasix 40mg online Reactogenicity Figure 2. Figure 2.

Local and Systemic Reactions Reported within 7 Days after Injection buy lasix 40mg online of BNT162b2 or Placebo, According to Age Group. Data on local and systemic reactions and use of medication were collected with electronic diaries from participants in the reactogenicity subset (8,183 participants) for 7 days after each vaccination. Solicited injection-site (local) reactions are shown in Panel buy lasix 40mg online A.

Pain at the injection site was assessed according to the following scale. Mild, does not interfere with activity buy lasix 40mg online. Moderate, interferes with activity.

Severe, prevents daily buy lasix 40mg online activity. And grade 4, emergency department visit or hospitalization. Redness and swelling were buy lasix 40mg online measured according to the following scale.

Mild, 2.0 to 5.0 cm in diameter. Moderate, >5.0 to buy lasix 40mg online 10.0 cm in diameter. Severe, >10.0 cm in diameter.

And grade 4, necrosis or exfoliative dermatitis (for redness) and necrosis (for swelling). Systemic events and medication buy lasix 40mg online use are shown in Panel B. Fever categories are designated in the key.

Medication use was buy lasix 40mg online not graded. Additional scales were as follows. Fatigue, headache, buy lasix 40mg online chills, new or worsened muscle pain, new or worsened joint pain (mild.

Does not interfere with activity. Moderate. Some interference with activity.

Or severe. Prevents daily activity), vomiting (mild. 1 to 2 times in 24 hours.

Moderate. >2 times in 24 hours. Or severe.

Requires intravenous hydration), and diarrhea (mild. 2 to 3 loose stools in 24 hours. Moderate.

4 to 5 loose stools in 24 hours. Or severe. 6 or more loose stools in 24 hours).

Grade 4 for all events indicated an emergency department visit or hospitalization. Н™¸ bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.The reactogenicity subset included 8183 participants. Overall, BNT162b2 recipients reported more local reactions than placebo recipients.

Among BNT162b2 recipients, mild-to-moderate pain at the injection site within 7 days after an injection was the most commonly reported local reaction, with less than 1% of participants across all age groups reporting severe pain (Figure 2). Pain was reported less frequently among participants older than 55 years of age (71% reported pain after the first dose. 66% after the second dose) than among younger participants (83% after the first dose.

78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), and no participant reported a grade 4 local reaction.

In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days. Systemic Reactogenicity Systemic events were reported more often by younger treatment recipients (16 to 55 years of age) than by older treatment recipients (more than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B). The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger treatment recipients.

51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger treatment recipients. 17% and 14% among older recipients). The frequency of any severe systemic event after the first dose was 0.9% or less.

Severe systemic events were reported in less than 2% of treatment recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after the second dose. Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger treatment recipients and by 11% of older recipients. Only 0.2% of treatment recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose.

Two participants each in the treatment and placebo groups reported temperatures above 40.0°C. Younger treatment recipients were more likely to use antipyretic or pain medication (28% after dose 1. 45% after dose 2) than older treatment recipients (20% after dose 1.

38% after dose 2), and placebo recipients were less likely (10 to 14%) than treatment recipients to use the medications, regardless of age or dose. Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter. Daily use of the electronic diary ranged from 90 to 93% for each day after the first dose and from 75 to 83% for each day after the second dose.

No difference was noted between the BNT162b2 group and the placebo group. Adverse Events Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3). More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related adverse event (21% and 5%).

This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by treatment recipients than by placebo recipients. Sixty-four treatment recipients (0.3%) and 6 placebo recipients (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial.

Four related serious adverse events were reported among BNT162b2 recipients (shoulder injury related to treatment administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia). Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). No deaths were considered by the investigators to be related to the treatment or placebo.

No hypertension medications–associated deaths were observed. No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of treatment.

Efficacy Table 2. Table 2. treatment Efficacy against hypertension medications at Least 7 days after the Second Dose.

Table 3. Table 3. treatment Efficacy Overall and by Subgroup in Participants without Evidence of before 7 Days after Dose 2.

Figure 3. Figure 3. Efficacy of BNT162b2 against hypertension medications after the First Dose.

Shown is the cumulative incidence of hypertension medications after the first dose (modified intention-to-treat population). Each symbol represents hypertension medications cases starting on a given day. Filled symbols represent severe hypertension medications cases.

Some symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged y axis, through 21 days. Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point.

The time period for hypertension medications case accrual is from the first dose to the end of the surveillance period. The confidence interval (CI) for treatment efficacy (VE) is derived according to the Clopper–Pearson method.Among 36,523 participants who had no evidence of existing or prior hypertension , 8 cases of hypertension medications with onset at least 7 days after the second dose were observed among treatment recipients and 162 among placebo recipients. This case split corresponds to 95.0% treatment efficacy (95% confidence interval [CI], 90.3 to 97.6.

Table 2). Among participants with and those without evidence of prior SARS CoV-2 , 9 cases of hypertension medications at least 7 days after the second dose were observed among treatment recipients and 169 among placebo recipients, corresponding to 94.6% treatment efficacy (95% CI, 89.9 to 97.3). Supplemental analyses indicated that treatment efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population (Table 3 and Table S4).

treatment efficacy among participants with hypertension was analyzed separately but was consistent with the other subgroup analyses (treatment efficacy, 94.6%. 95% CI, 68.7 to 99.9. Case split.

BNT162b2, 2 cases. Placebo, 44 cases). Figure 3 shows cases of hypertension medications or severe hypertension medications with onset at any time after the first dose (mITT population) (additional data on severe hypertension medications are available in Table S5).

Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a treatment efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the treatment, starting as soon as 12 days after the first dose.V-safe Surveillance. Local and Systemic Reactogenicity in Pregnant Persons Table 1. Table 1.

Characteristics of Persons Who Identified as Pregnant in the V-safe Surveillance System and Received an mRNA hypertension medications treatment. Table 2. Table 2.

Frequency of Local and Systemic Reactions Reported on the Day after mRNA hypertension medications Vaccination in Pregnant Persons. From December 14, 2020, to February 28, 2021, a total of 35,691 v-safe participants identified as pregnant. Age distributions were similar among the participants who received the Pfizer–BioNTech treatment and those who received the Moderna treatment, with the majority of the participants being 25 to 34 years of age (61.9% and 60.6% for each treatment, respectively) and non-Hispanic White (76.2% and 75.4%, respectively).

Most participants (85.8% and 87.4%, respectively) reported being pregnant at the time of vaccination (Table 1). Solicited reports of injection-site pain, fatigue, headache, and myalgia were the most frequent local and systemic reactions after either dose for both treatments (Table 2) and were reported more frequently after dose 2 for both treatments. Participant-measured temperature at or above 38°C was reported by less than 1% of the participants on day 1 after dose 1 and by 8.0% after dose 2 for both treatments.

Figure 1. Figure 1. Most Frequent Local and Systemic Reactions Reported in the V-safe Surveillance System on the Day after mRNA hypertension medications Vaccination.

Shown are solicited reactions in pregnant persons and nonpregnant women 16 to 54 years of age who received a messenger RNA (mRNA) hypertension disease 2019 (hypertension medications) treatment — BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) — from December 14, 2020, to February 28, 2021. The percentage of respondents was calculated among those who completed a day 1 survey, with the top events shown of injection-site pain (pain), fatigue or tiredness (fatigue), headache, muscle or body aches (myalgia), chills, and fever or felt feverish (fever).These patterns of reporting, with respect to both most frequently reported solicited reactions and the higher reporting of reactogenicity after dose 2, were similar to patterns observed among nonpregnant women (Figure 1). Small differences in reporting frequency between pregnant persons and nonpregnant women were observed for specific reactions (injection-site pain was reported more frequently among pregnant persons, and other systemic reactions were reported more frequently among nonpregnant women), but the overall reactogenicity profile was similar.

Pregnant persons did not report having severe reactions more frequently than nonpregnant women, except for nausea and vomiting, which were reported slightly more frequently only after dose 2 (Table S3). V-safe Pregnancy Registry. Pregnancy Outcomes and Neonatal Outcomes Table 3.

Table 3. Characteristics of V-safe Pregnancy Registry Participants. As of March 30, 2021, the v-safe pregnancy registry call center attempted to contact 5230 persons who were vaccinated through February 28, 2021, and who identified during a v-safe survey as pregnant at or shortly after hypertension medications vaccination.

Of these, 912 were unreachable, 86 declined to participate, and 274 did not meet inclusion criteria (e.g., were never pregnant, were pregnant but received vaccination more than 30 days before the last menstrual period, or did not provide enough information to determine eligibility). The registry enrolled 3958 participants with vaccination from December 14, 2020, to February 28, 2021, of whom 3719 (94.0%) identified as health care personnel. Among enrolled participants, most were 25 to 44 years of age (98.8%), non-Hispanic White (79.0%), and, at the time of interview, did not report a hypertension medications diagnosis during pregnancy (97.6%) (Table 3).

Receipt of a first dose of treatment meeting registry-eligibility criteria was reported by 92 participants (2.3%) during the periconception period, by 1132 (28.6%) in the first trimester of pregnancy, by 1714 (43.3%) in the second trimester, and by 1019 (25.7%) in the third trimester (1 participant was missing information to determine the timing of vaccination) (Table 3). Among 1040 participants (91.9%) who received a treatment in the first trimester and 1700 (99.2%) who received a treatment in the second trimester, initial data had been collected and follow-up scheduled at designated time points approximately 10 to 12 weeks apart. Limited follow-up calls had been made at the time of this analysis.

Table 4. Table 4. Pregnancy Loss and Neonatal Outcomes in Published Studies and V-safe Pregnancy Registry Participants.

Among 827 participants who had a completed pregnancy, the pregnancy resulted in a live birth in 712 (86.1%), in a spontaneous abortion in 104 (12.6%), in stillbirth in 1 (0.1%), and in other outcomes (induced abortion and ectopic pregnancy) in 10 (1.2%). A total of 96 of 104 spontaneous abortions (92.3%) occurred before 13 weeks of gestation (Table 4), and 700 of 712 pregnancies that resulted in a live birth (98.3%) were among persons who received their first eligible treatment dose in the third trimester. Adverse outcomes among 724 live-born infants — including 12 sets of multiple gestation — were preterm birth (60 of 636 among those vaccinated before 37 weeks [9.4%]), small size for gestational age (23 of 724 [3.2%]), and major congenital anomalies (16 of 724 [2.2%]).

No neonatal deaths were reported at the time of interview. Among the participants with completed pregnancies who reported congenital anomalies, none had received hypertension medications treatment in the first trimester or periconception period, and no specific pattern of congenital anomalies was observed. Calculated proportions of pregnancy and neonatal outcomes appeared similar to incidences published in the peer-reviewed literature (Table 4).

Adverse-Event Findings on the VAERS During the analysis period, the VAERS received and processed 221 reports involving hypertension medications vaccination among pregnant persons. 155 (70.1%) involved nonpregnancy-specific adverse events, and 66 (29.9%) involved pregnancy- or neonatal-specific adverse events (Table S4). The most frequently reported pregnancy-related adverse events were spontaneous abortion (46 cases.

37 in the first trimester, 2 in the second trimester, and 7 in which the trimester was unknown or not reported), followed by stillbirth, premature rupture of membranes, and vaginal bleeding, with 3 reports for each. No congenital anomalies were reported to the VAERS, a requirement under the EUAs.Objectives, Participants, and Oversight We conducted a randomized, placebo-controlled, observer-blinded, phase 3 trial as part of a phase 1–2–3 trial assessing BNT162b2 safety, immunogenicity, and efficacy in healthy persons 12 years of age or older. This report presents findings from 12-to-15-year-old participants enrolled in the United States, including descriptive comparisons of safety between participants in that age cohort and those who were 16 to 25 years of age and an evaluation of the noninferiority of immunogenicity in the 12-to-15-year-old cohort to that in the 16-to-25-year-old cohort.

Data were collected through the cutoff date of March 13, 2021. Eligible participants were healthy or had stable preexisting disease (including hepatitis B, hepatitis C, or human immunodeficiency lasix ). Persons with a previous clinical or virologic hypertension medications diagnosis or hypertension , previous hypertension vaccination, diagnosis of an immunocompromising or immunodeficiency disorder, or treatment with immunosuppressive therapy (including cytotoxic agents and systemic glucocorticoids) were excluded.

The ethical conduct of the trial is summarized in the Supplementary Appendix, available with the full text of this article at NEJM.org. Additional details of the trial are provided in the protocol, available at NEJM.org. Pfizer was responsible for the trial design and conduct, data collection, data analysis, data interpretation, and writing of the manuscript that was submitted.

Both Pfizer and BioNTech manufactured the treatment and placebo. BioNTech was the regulatory sponsor of the trial and contributed to data interpretation and writing of the manuscript. All data were available to the authors, who vouch for their accuracy and completeness and for the adherence of the trial to the protocol.

Procedures Randomization was conducted with the use of an interactive Web-based response system. Participants were assigned in a 1:1 ratio to receive two intramuscular injections of 30 μg of BNT162b2 or placebo (saline) 21 days apart. For evaluation of immediate treatment-associated reactions, participants were observed in the clinic for 30 minutes after vaccination.

Safety Safety objectives included the assessment of local or systemic reactogenicity events, which were recorded by the participants in an electronic diary (e-diary) for 7 days after each dose. Unsolicited adverse events (i.e., those reported by the participant without e-diary prompting) and serious adverse events were also recorded from receipt of the first dose through 1 month and 6 months after dose 2, respectively. Immunogenicity Immunogenicity assessments (hypertension serum neutralization assay and receptor-binding domain [RBD]–binding or S1-binding IgG direct Luminex immunoassays) were performed before vaccination and 1 month after dose 2, as described previously.3 The immunogenicity objective was to show noninferiority of the immune response to BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-year-old participants.

Noninferiority was assessed among participants who had no evidence of previous hypertension with the use of the two-sided 95% confidence interval for the geometric mean ratio of hypertension 50% neutralizing titers in 12-to-15-year-old participants as compared with 16-to-25-year-old participants 1 month after dose 2. BNT162b2 immunogenicity was evaluated in participants with and those without serologic or virologic evidence of previous hypertension . Corresponding end points were the geometric mean hypertension neutralizing titers at baseline (i.e., immediately before receipt of the first injection) and 1 month after dose 2 and geometric mean fold rises (GMFRs) in titers from baseline to 1 month after dose 2.

Efficacy The efficacy of BNT162b2 against confirmed hypertension medications with an onset 7 or more days after dose 2 was summarized in participants who did not have evidence of previous hypertension , as well as in all vaccinated participants. Surveillance for potential hypertension medications cases was undertaken throughout the trial. If acute respiratory illness developed in a participant, the participant was tested for hypertension.

Methods for identifying hypertension s and hypertension medications diagnoses are summarized in the Supplementary Appendix. Statistical Analysis The safety population included all participants who received at least one dose of BNT162b2 or placebo. The reactogenicity subset included all 12-to-15-year-old participants and a subset of 16-to-25-year-old participants (those who received an e-diary to record reactogenicity events).

Safety end points are presented descriptively as counts, percentages, and associated Clopper–Pearson two-sided 95% confidence intervals, with adverse events and serious adverse events described according to terms in the Medical Dictionary for Regulatory Activities, version 23.1, for each group. Immunogenicity was assessed in a random subset of participants in each age cohort with the use of a simple random-sample selection procedure. For immunogenicity assessments, all participants in both age cohorts were from U.S.

Sites. The dose 2 immunogenicity population that could be evaluated included participants who underwent randomization and received two BNT162b2 doses in accordance with the protocol, received dose 2 within the prespecified window (19 to 42 days after dose 1), had at least one valid and determinate immunogenicity result from a blood sample obtained within 28 to 42 days after dose 2, and had no major protocol deviations. Noninferiority of the immune response to BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-year-old participants was assessed on the basis of the geometric mean ratio of hypertension 50% neutralizing titers.

A sample of 225 BNT162b2 recipients who could be evaluated (or 280 BNT162b2 recipients overall) in each age cohort was estimated to provide 90.8% power for declaring noninferiority (defined as a lower limit of the 95% confidence interval for the geometric mean ratio of >0.67). A testing laboratory supply limitation of the qualified viral lot used for assay validation and clinical testing resulted in the trial having fewer participants than anticipated for the immunogenicity analyses. Calculations of the geometric mean ratios, geometric mean titers, and GMFRs are described in the Supplementary Appendix.

Although the formal evaluation of efficacy was to be based on the overall results obtained across all age cohorts, the statistical analysis plan specified that descriptive efficacy summaries would be provided for each age cohort (the stratification factor). The efficacy analysis for the 12-to-15-year-old cohort was planned as a descriptive analysis because the number of cases that would occur in the age subgroups was unknown. The efficacy population that could be evaluated included all eligible 12-to-15-year-old participants who underwent randomization and received two doses of BNT162b2 or placebo, received dose 2 within the prespecified window (19 to 42 days after dose 1), and had no major protocol deviations.

The all-available efficacy population included all participants who received one or two doses. treatment efficacy was defined as 100×(1−IRR), where IRR is the ratio of the rate of a first confirmed hypertension medications illness in the BNT162b2 group to the corresponding rate in the placebo group. Two-sided Clopper–Pearson 95% confidence intervals were calculated (not adjusted for multiple comparisons).

Because the number of participants who reported symptoms but were missing a valid polymerase-chain-reaction test result was small, data for these participants were not imputed in the analysis.The clinical picture of moderate-to-severe thrombocytopenia and thrombotic complications at unusual sites beginning approximately 1 to 2 weeks after vaccination against hypertension with ChAdOx1 nCov-19 suggests a disorder that clinically resembles severe heparin-induced thrombocytopenia, a well-known prothrombotic disorder caused by platelet-activating antibodies that recognize multimolecular complexes between cationic PF4 and anionic heparin.6 However, unlike the usual situation in heparin-induced thrombocytopenia, these vaccinated patients did not receive any heparin to explain the subsequent occurrence of thrombosis and thrombocytopenia. In recent years, it has been recognized that triggers other than heparin can cause a prothrombotic disorder that strongly resembles heparin-induced thrombocytopenia on both clinical and serologic grounds, including certain polyanionic drugs (e.g., pentosan polysulfate,7 antiangiogenic agent PI-88,8 and hypersulfated chondroitin sulfate8). Such a prothrombotic syndrome has also been observed in the absence of preceding exposure to any polyanionic medication, such as after both viral and bacterial s9,10 and knee-replacement surgery.11,12 These various clinical scenarios with apparent nonpharmacologic triggers have been classified under the term autoimmune heparin-induced thrombocytopenia.13 Unlike patients with classic heparin-induced thrombocytopenia, patients with autoimmune heparin-induced thrombocytopenia have unusually severe thrombocytopenia, an increased frequency of disseminated intravascular coagulation, and atypical thrombotic events.

Serum from these patients strongly activate platelets in the presence of heparin (0.1 to 1.0 IU per milliliter) but also in the absence of heparin (heparin-independent platelet activation). When these unusual antibodies are observed in patients who have thrombocytopenia without preceding heparin exposure, the term “spontaneous” heparin-induced thrombocytopenia syndrome13,14 has been used. Sometimes, patients in whom heparin-induced thrombocytopenia develops after exposure to heparin present with atypical clinical features, such as an onset of thrombocytopenia beginning several days after stopping heparin (delayed-onset heparin-induced thrombocytopenia15,16) or thrombocytopenia that persists for several weeks despite the discontinuation of heparin (persisting or refractory heparin-induced thrombocytopenia17,18).

Serum from these patients also shows the phenomenon of heparin-independent platelet-activating properties. These clinical features that resemble those of autoimmune heparin-induced thrombocytopenia were observed in the patients with treatment-induced immune thrombotic thrombocytopenia. The serum usually showed strong reactivity on the PF4–heparin ELISA.

Moreover, serum showed variable degrees of platelet activation in the presence of buffer that was in most cases greatly enhanced in the presence of PF4 (Figure 1A and 1B). More strikingly, most serum showed inhibition, rather than increased activation, in the presence of low-dose low-molecular-weight heparin (0.2 U per milliliter of anti–factor Xa). In addition, antibodies from two patients, which were affinity purified on either immobilized PF4 or immobilized PF4–heparin, strongly activated platelets but only in the presence of PF4.

Enhancement of platelet activation by PF4 is also a feature of heparin-induced thrombocytopenia19,20 and has been used to enhance detection of platelet-activating antibodies in diagnostic testing for this adverse drug reaction.21 Whether these antibodies are autoantibodies against PF4 induced by the strong inflammatory stimulus of vaccination or antibodies induced by the treatment that cross-react with PF4 and platelets requires further study. Although we found enhanced reactivity of patient serum with platelets in the presence of ChAdOx1 nCov-19, this is likely to be an in vitro artifact. It is well known that adenolasix binds to platelets22 and causes platelet activation.22,23 Furthermore, the amount of adenolasix in a 500-microliter treatment injection administered 1 or 2 weeks earlier would seem unlikely to contribute to subsequent platelet activation observed in these patients.

However, interactions between the treatment and platelets or between the treatment and PF4 could play a role in pathogenesis. One possible trigger of these PF4-reactive antibodies could be free DNA in the treatment. We have previously shown that DNA and RNA form multimolecular complexes with PF4, which bind antibodies from patients with heparin-induced thrombocytopenia and also induce antibodies against PF4–heparin in a murine model.24 Unfortunately, other hypertension medications treatments were not available to us for testing.

Our findings have several important clinical implications. First, clinicians should be aware that in some patients, venous or arterial thrombosis can develop at unusual sites such as the brain or abdomen, which becomes clinically apparent approximately 5 to 20 days after vaccination. If such a reaction is accompanied by thrombocytopenia, it can represent an adverse effect of the preceding hypertension medications vaccination.

To date, this reaction has been reported only with the ChAdOx1 nCov-19 treatment, which has been used in approximately 25% of treatment recipients in Germany and in 30% of those in Austria. Second, ELISA to detect PF4–heparin antibodies in patients with heparin-induced thrombocytopenia is widely available and can be used to investigate patients for potential postvaccination thrombocytopenia or thrombosis associated with antibodies against PF4.25 A strongly positive ELISA result that is obtained in a patient who has not been recently exposed to heparin would be a striking abnormality. Third, we have shown that these antibodies recognize PF4 and that the addition of PF4 greatly enhances their detectability in a platelet-activation assay.

Since vaccination of millions of persons will be complicated by a background of thrombotic events unrelated to vaccination, a PF4-dependent ELISA or a PF4-enhanced platelet-activation assay may be used to confirm the diagnosis of treatment-induced immune thrombotic thrombocytopenia through this novel mechanism of postvaccination formation of platelet-activating antibodies against PF4. Although treatment decisions such as administering intravenous immune globulin and starting anticoagulation do not need to await laboratory diagnosis, detection of these unusual platelet-activating antibodies will be highly relevant for case identification and future risk–benefit assessment of this and other treatments. Figure 2.

Figure 2. Potential Diagnostic and Therapeutic Strategies for Management of Suspected treatment-Induced Immune Thrombotic Thrombocytopenia. Shown is a decision tree for the evaluation and treatment of patients who have symptoms of thrombocytopenia or thrombosis within 20 days after receiving the ChAdOx1 nCov-19 treatment and who have had no heparin exposure.

The diagnostic and therapeutic strategies in such patients differ from those in patients with autoimmune heparin-induced thrombocytopenia (HIT).13 DIC denotes disseminated intravascular coagulation, INR international normalized ratio, PF4 platelet factor 4, and PTT partial thromboplastin time.Figure 2 shows a potential diagnostic and therapeutic strategy for managing this novel prothrombotic thrombocytopenic disorder. One consideration is to administer high-dose intravenous immune globulin to inhibit Fcγ receptor–mediated platelet activation. This recommendation parallels emerging experience in the treatment of severe autoimmune heparin-induced thrombocytopenia in which high-dose intravenous immune globulin has resulted in rapid increases in platelet count and de-escalation of hypercoagulability.12,26 We found that the addition of immune globulin in doses that are readily achieved clinically was effective in inhibiting platelet activation by patients’ antibodies.

Clinician reluctance to start anticoagulation may be tempered by administering high-dose intravenous immune globulin to raise the platelet count, especially when a patient presents with severe thrombocytopenia and thrombosis, such as cerebral venous thrombosis. Given the parallels with autoimmune heparin-induced thrombocytopenia, anticoagulant options should include nonheparin anticoagulants used for the management of heparin-induced thrombocytopenia,27 unless a functional test has excluded heparin-dependent enhancement of platelet activation. Finally, we suggest naming this novel entity treatment-induced immune thrombotic thrombocytopenia (VITT) to avoid confusion with heparin-induced thrombocytopenia.To the Editor.

Rare thromboembolic events have been observed during the vaccination rollout, which have prompted cautionary pauses in vaccinations by some regulatory authorities, including the South Africa Health Products Regulatory Authority.1,2 Here, we report interim safety data from the first 288,368 participants who were vaccinated with Ad26.COV2.S in the Sisonke study — an open label, single-group, phase 3b implementation study to monitor the effectiveness of the single-dose Ad26.COV2.S treatment among 500,000 health care workers in South Africa (ClinicalTrials.gov number, NCT04838795). Enrollment in the study began on February 17, 2021, and as of April 12, 2021, a total of 288,368 health care workers had received the Ad26.COV2.S treatment, among whom 5898 (2%) reported adverse events. The majority (81%) of adverse events reported were expected mild-to-moderate reactogenicity events.

Fifty health care workers had adverse events that met the criteria of being serious or of special interest3,4. A full list of these events is provided in Table 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org. Among these 50 workers, 12 (24%) had hypertension disease 2019 (hypertension medications), which occurred within 28 days after vaccination.

12 (24%) had allergic reactions, of which one met the criteria for anaphylaxis. And 6 (12%) had neurologic conditions, including a 40-year-old man who received a diagnosis of Guillain–Barré syndrome and a 53-year-old woman with Bell’s palsy. Five arterial, venous thrombotic, or embolic events were reported in 5 health care workers with known risk factors for thromboembolism (1.7 events per 100,000 participants).

One case of pulmonary embolus occurred 23 days after vaccination in a 63-year-old woman who was overweight and had hypertension, diabetes mellitus, and a history of venous thrombosis. This event was fatal. A second case occurred in a 64-year-old woman who received a diagnosis of cor pulmonale 17 days after vaccination.

This case had features consistent with chronic and recurrent pulmonary emboli. Two cerebrovascular accidents (infarcts on imaging) were reported — one case involved a 45-year-old woman who had underlying rheumatic heart disease and a history of human immunodeficiency lasix , cerebrovascular accident, and aortic valve replacement, in whom left-sided weakness developed the day after vaccination, and the other case involved a 38-year-old woman who had given birth to twins 9 months before vaccination and presented with features of transient ischemic attack 8 days after vaccination. A 65-year-old woman with chronic diabetes mellitus had deterioration and blurring of vision 8 days after vaccination and received a diagnosis of retinal vein occlusion and macular hemorrhage.

To date, no case of treatment-induced immune thrombotic thrombocytopenia has been documented. In South Africa, since the start of the lasix, hypertension medications has been reported in 1.58 million persons, including more than 55,000 health care workers. The rate of adverse events with vaccination is low, and thromboembolic events have occurred mainly in persons with risk factors for thromboembolism.

Simbarashe Takuva, M.B., Ch.B.Azwidhwi Takalani, M.B., Ch.B.Fred Hutchinson Cancer Research Center, Seattle, WA [email protected]Nigel Garrett, M.B., B.S., Ph.D.Centre for the AIDS Programme of Research in South Africa, Durban, South AfricaAmeena Goga, M.B., Ch.B., Ph.D.South African Medical Research Council, Cape Town, South AfricaJonny Peter, M.B., Ch.B., Ph.D.Vernon Louw, M.B., Ch.B., Ph.D.Jessica Opie, M.B., Ch.B.University of Cape Town, Cape Town, South AfricaBarry Jacobson, M.B., Ch.B., Ph.D.University of the Witwatersrand, Johannesburg, South AfricaIan Sanne, M.B., Ch.B.Right to Care, Johannesburg, South AfricaLinda Gail-Bekker, M.B., Ch.B., Ph.D.University of Cape Town, Cape Town, South AfricaGlenda Gray, M.B., Ch.B., D.Sc.South African Medical Research Council, Cape Town, South Africa Supported by Janssen treatments and Prevention and the South African Medical Research Council. Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on June 2, 2021, at NEJM.org.4 References.

Participants Figure can i buy lasix online his comment is here 1. Figure 1. Enrollment and can i buy lasix online Randomization. The diagram represents all enrolled participants through November 14, 2020.

The safety subset (those with a median of 2 months of follow-up, in accordance with application requirements can i buy lasix online for Emergency Use Authorization) is based on an October 9, 2020, data cut-off date. The further procedures that one participant in the placebo group declined after dose 2 (lower right corner of the diagram) were those involving collection of blood and nasal swab samples.Table 1. Table 1 can i buy lasix online. Demographic Characteristics of the Participants in the Main Safety Population.

Between July 27, 2020, and November 14, 2020, a total of 44,820 persons were screened, and can i buy lasix online 43,548 persons 16 years of age or older underwent randomization at 152 sites worldwide (United States, 130 sites. Argentina, 1. Brazil, 2 can i buy lasix online. South Africa, 4.

Germany, 6 can i buy lasix online. And Turkey, 9) in the phase 2/3 portion of the trial. A total can i buy lasix online of 43,448 participants received injections. 21,720 received BNT162b2 and 21,728 received placebo (Figure 1).

At the data cut-off date of October 9, a total of 37,706 participants had a median of at least 2 months of safety data available after the second dose and contributed to the main safety data set. Among these 37,706 participants, 49% were female, 83% were White, 9% were Black or African American, 28% were Hispanic or Latinx, 35% were obese (body mass index [the weight in kilograms divided by the square of the height in meters] of at least 30.0), and 21% can i buy lasix online had at least one coexisting condition. The median age was 52 years, and 42% of participants were older than 55 years of age (Table 1 and Table S2). Safety Local Reactogenicity Figure can i buy lasix online 2.

Figure 2. Local and Systemic can i buy lasix online Reactions Reported within 7 Days after Injection of BNT162b2 or Placebo, According to Age Group. Data on local and systemic reactions and use of medication were collected with electronic diaries from participants in the reactogenicity subset (8,183 participants) for 7 days after each vaccination. Solicited injection-site can i buy lasix online (local) reactions are shown in Panel A.

Pain at the injection site was assessed according to the following scale. Mild, does not interfere with activity can i buy lasix online. Moderate, interferes with activity. Severe, prevents can i buy lasix online daily activity.

And grade 4, emergency department visit or hospitalization. Redness and swelling were measured according to can i buy lasix online the following scale. Mild, 2.0 to 5.0 cm in diameter. Moderate, >5.0 can i buy lasix online to 10.0 cm in diameter.

Severe, >10.0 cm in diameter. And grade 4, necrosis or exfoliative dermatitis (for redness) and necrosis (for swelling). Systemic events and medication use are shown can i buy lasix online in Panel B. Fever categories are designated in the key.

Medication use was not graded can i buy lasix online. Additional scales were as follows. Fatigue, headache, can i buy lasix online chills, new or worsened muscle pain, new or worsened joint pain (mild. Does not interfere with activity.

Moderate. Some interference with activity. Or severe. Prevents daily activity), vomiting (mild.

1 to 2 times in 24 hours. Moderate. >2 times in 24 hours. Or severe.

Requires intravenous hydration), and diarrhea (mild. 2 to 3 loose stools in 24 hours. Moderate. 4 to 5 loose stools in 24 hours.

Or severe. 6 or more loose stools in 24 hours). Grade 4 for all events indicated an emergency department visit or hospitalization. Н™¸ bars represent 95% confidence intervals, and numbers above the 𝙸 bars are the percentage of participants who reported the specified reaction.The reactogenicity subset included 8183 participants.

Overall, BNT162b2 recipients reported more local reactions than placebo recipients. Among BNT162b2 recipients, mild-to-moderate pain at the injection site within 7 days after an injection was the most commonly reported local reaction, with less than 1% of participants across all age groups reporting severe pain (Figure 2). Pain was reported less frequently among participants older than 55 years of age (71% reported pain after the first dose. 66% after the second dose) than among younger participants (83% after the first dose.

78% after the second dose). A noticeably lower percentage of participants reported injection-site redness or swelling. The proportion of participants reporting local reactions did not increase after the second dose (Figure 2A), and no participant reported a grade 4 local reaction. In general, local reactions were mostly mild-to-moderate in severity and resolved within 1 to 2 days.

Systemic Reactogenicity Systemic events were reported more often by younger treatment recipients (16 to 55 years of age) than by older treatment recipients (more than 55 years of age) in the reactogenicity subset and more often after dose 2 than dose 1 (Figure 2B). The most commonly reported systemic events were fatigue and headache (59% and 52%, respectively, after the second dose, among younger treatment recipients. 51% and 39% among older recipients), although fatigue and headache were also reported by many placebo recipients (23% and 24%, respectively, after the second dose, among younger treatment recipients. 17% and 14% among older recipients).

The frequency of any severe systemic event after the first dose was 0.9% or less. Severe systemic events were reported in less than 2% of treatment recipients after either dose, except for fatigue (in 3.8%) and headache (in 2.0%) after the second dose. Fever (temperature, ≥38°C) was reported after the second dose by 16% of younger treatment recipients and by 11% of older recipients. Only 0.2% of treatment recipients and 0.1% of placebo recipients reported fever (temperature, 38.9 to 40°C) after the first dose, as compared with 0.8% and 0.1%, respectively, after the second dose.

Two participants each in the treatment and placebo groups reported temperatures above 40.0°C. Younger treatment recipients were more likely to use antipyretic or pain medication (28% after dose 1. 45% after dose 2) than older treatment recipients (20% after dose 1. 38% after dose 2), and placebo recipients were less likely (10 to 14%) than treatment recipients to use the medications, regardless of age or dose.

Systemic events including fever and chills were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter. Daily use of the electronic diary ranged from 90 to 93% for each day after the first dose and from 75 to 83% for each day after the second dose. No difference was noted between the BNT162b2 group and the placebo group. Adverse Events Adverse event analyses are provided for all enrolled 43,252 participants, with variable follow-up time after dose 1 (Table S3).

More BNT162b2 recipients than placebo recipients reported any adverse event (27% and 12%, respectively) or a related adverse event (21% and 5%). This distribution largely reflects the inclusion of transient reactogenicity events, which were reported as adverse events more commonly by treatment recipients than by placebo recipients. Sixty-four treatment recipients (0.3%) and 6 placebo recipients (<0.1%) reported lymphadenopathy. Few participants in either group had severe adverse events, serious adverse events, or adverse events leading to withdrawal from the trial.

Four related serious adverse events were reported among BNT162b2 recipients (shoulder injury related to treatment administration, right axillary lymphadenopathy, paroxysmal ventricular arrhythmia, and right leg paresthesia). Two BNT162b2 recipients died (one from arteriosclerosis, one from cardiac arrest), as did four placebo recipients (two from unknown causes, one from hemorrhagic stroke, and one from myocardial infarction). No deaths were considered by the investigators to be related to the treatment or placebo. No hypertension medications–associated deaths were observed.

No stopping rules were met during the reporting period. Safety monitoring will continue for 2 years after administration of the second dose of treatment. Efficacy Table 2. Table 2.

treatment Efficacy against hypertension medications at Least 7 days after the Second Dose. Table 3. Table 3. treatment Efficacy Overall and by Subgroup in Participants without Evidence of before 7 Days after Dose 2.

Figure 3. Figure 3. Efficacy of BNT162b2 against hypertension medications after the First Dose. Shown is the cumulative incidence of hypertension medications after the first dose (modified intention-to-treat population).

Each symbol represents hypertension medications cases starting on a given day. Filled symbols represent severe hypertension medications cases. Some symbols represent more than one case, owing to overlapping dates. The inset shows the same data on an enlarged y axis, through 21 days.

Surveillance time is the total time in 1000 person-years for the given end point across all participants within each group at risk for the end point. The time period for hypertension medications case accrual is from the first dose to the end of the surveillance period. The confidence interval (CI) for treatment efficacy (VE) is derived according to the Clopper–Pearson method.Among 36,523 participants who had no evidence of existing or prior hypertension , 8 cases of hypertension medications with onset at least 7 days after the second dose were observed among treatment recipients and 162 among placebo recipients. This case split corresponds to 95.0% treatment efficacy (95% confidence interval [CI], 90.3 to 97.6.

Table 2). Among participants with and those without evidence of prior SARS CoV-2 , 9 cases of hypertension medications at least 7 days after the second dose were observed among treatment recipients and 169 among placebo recipients, corresponding to 94.6% treatment efficacy (95% CI, 89.9 to 97.3). Supplemental analyses indicated that treatment efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the overall population (Table 3 and Table S4). treatment efficacy among participants with hypertension was analyzed separately but was consistent with the other subgroup analyses (treatment efficacy, 94.6%.

95% CI, 68.7 to 99.9. Case split. BNT162b2, 2 cases. Placebo, 44 cases).

Figure 3 shows cases of hypertension medications or severe hypertension medications with onset at any time after the first dose (mITT population) (additional data on severe hypertension medications are available in Table S5). Between the first dose and the second dose, 39 cases in the BNT162b2 group and 82 cases in the placebo group were observed, resulting in a treatment efficacy of 52% (95% CI, 29.5 to 68.4) during this interval and indicating early protection by the treatment, starting as soon as 12 days after the first dose.V-safe Surveillance. Local and Systemic Reactogenicity in Pregnant Persons Table 1. Table 1.

Characteristics of Persons Who Identified as Pregnant in the V-safe Surveillance System and Received an mRNA hypertension medications treatment. Table 2. Table 2. Frequency of Local and Systemic Reactions Reported on the Day after mRNA hypertension medications Vaccination in Pregnant Persons.

From December 14, 2020, to February 28, 2021, a total of 35,691 v-safe participants identified as pregnant. Age distributions were similar among the participants who received the Pfizer–BioNTech treatment and those who received the Moderna treatment, with the majority of the participants being 25 to 34 years of age (61.9% and 60.6% for each treatment, respectively) and non-Hispanic White (76.2% and 75.4%, respectively). Most participants (85.8% and 87.4%, respectively) reported being pregnant at the time of vaccination (Table 1). Solicited reports of injection-site pain, fatigue, headache, and myalgia were the most frequent local and systemic reactions after either dose for both treatments (Table 2) and were reported more frequently after dose 2 for both treatments.

Participant-measured temperature at or above 38°C was reported by less than 1% of the participants on day 1 after dose 1 and by 8.0% after dose 2 for both treatments. Figure 1. Figure 1. Most Frequent Local and Systemic Reactions Reported in the V-safe Surveillance System on the Day after mRNA hypertension medications Vaccination.

Shown are solicited reactions in pregnant persons and nonpregnant women 16 to 54 years of age who received a messenger RNA (mRNA) hypertension disease 2019 (hypertension medications) treatment — BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna) — from December 14, 2020, to February 28, 2021. The percentage of respondents was calculated among those who completed a day 1 survey, with the top events shown of injection-site pain (pain), fatigue or tiredness (fatigue), headache, muscle or body aches (myalgia), chills, and fever or felt feverish (fever).These patterns of reporting, with respect to both most frequently reported solicited reactions and the higher reporting of reactogenicity after dose 2, were similar to patterns observed among nonpregnant women (Figure 1). Small differences in reporting frequency between pregnant persons and nonpregnant women were observed for specific reactions (injection-site pain was reported more frequently among pregnant persons, and other systemic reactions were reported more frequently among nonpregnant women), but the overall reactogenicity profile was similar. Pregnant persons did not report having severe reactions more frequently than nonpregnant women, except for nausea and vomiting, which were reported slightly more frequently only after dose 2 (Table S3).

V-safe Pregnancy Registry. Pregnancy Outcomes and Neonatal Outcomes Table 3. Table 3. Characteristics of V-safe Pregnancy Registry Participants.

As of March 30, 2021, the v-safe pregnancy registry call center attempted to contact 5230 persons who were vaccinated through February 28, 2021, and who identified during a v-safe survey as pregnant at or shortly after hypertension medications vaccination. Of these, 912 were unreachable, 86 declined to participate, and 274 did not meet inclusion criteria (e.g., were never pregnant, were pregnant but received vaccination more than 30 days before the last menstrual period, or did not provide enough information to determine eligibility). The registry enrolled 3958 participants with vaccination from December 14, 2020, to February 28, 2021, of whom 3719 (94.0%) identified as health care personnel. Among enrolled participants, most were 25 to 44 years of age (98.8%), non-Hispanic White (79.0%), and, at the time of interview, did not report a hypertension medications diagnosis during pregnancy (97.6%) (Table 3).

Receipt of a first dose of treatment meeting registry-eligibility criteria was reported by 92 participants (2.3%) during the periconception period, by 1132 (28.6%) in the first trimester of pregnancy, by 1714 (43.3%) in the second trimester, and by 1019 (25.7%) in the third trimester (1 participant was missing information to determine the timing of vaccination) (Table 3). Among 1040 participants (91.9%) who received a treatment in the first trimester and 1700 (99.2%) who received a treatment in the second trimester, initial data had been collected and follow-up scheduled at designated time points approximately 10 to 12 weeks apart. Limited follow-up calls had been made at the time of this analysis. Table 4.

Table 4. Pregnancy Loss and Neonatal Outcomes in Published Studies and V-safe Pregnancy Registry Participants. Among 827 participants who had a completed pregnancy, the pregnancy resulted in a live birth in 712 (86.1%), in a spontaneous abortion in 104 (12.6%), in stillbirth in 1 (0.1%), and in other outcomes (induced abortion and ectopic pregnancy) in 10 (1.2%). A total of 96 of 104 spontaneous abortions (92.3%) occurred before 13 weeks of gestation (Table 4), and 700 of 712 pregnancies that resulted in a live birth (98.3%) were among persons who received their first eligible treatment dose in the third trimester.

Adverse outcomes among 724 live-born infants — including 12 sets of multiple gestation — were preterm birth (60 of 636 among those vaccinated before 37 weeks [9.4%]), small size for gestational age (23 of 724 [3.2%]), and major congenital anomalies (16 of 724 [2.2%]). No neonatal deaths were reported at the time of interview. Among the participants with completed pregnancies who reported congenital anomalies, none had received hypertension medications treatment in the first trimester or periconception period, and no specific pattern of congenital anomalies was observed. Calculated proportions of pregnancy and neonatal outcomes appeared similar to incidences published in the peer-reviewed literature (Table 4).

Adverse-Event Findings on the VAERS During the analysis period, the VAERS received and processed 221 reports involving hypertension medications vaccination among pregnant persons. 155 (70.1%) involved nonpregnancy-specific adverse events, and 66 (29.9%) involved pregnancy- or neonatal-specific adverse events (Table S4). The most frequently reported pregnancy-related adverse events were spontaneous abortion (46 cases. 37 in the first trimester, 2 in the second trimester, and 7 in which the trimester was unknown or not reported), followed by stillbirth, premature rupture of membranes, and vaginal bleeding, with 3 reports for each.

No congenital anomalies were reported to the VAERS, a requirement under the EUAs.Objectives, Participants, and Oversight We conducted a randomized, placebo-controlled, observer-blinded, phase 3 trial as part of a phase 1–2–3 trial assessing BNT162b2 safety, immunogenicity, and efficacy in healthy persons 12 years of age or older. This report presents findings from 12-to-15-year-old participants enrolled in the United States, including descriptive comparisons of safety between participants in that age cohort and those who were 16 to 25 years of age and an evaluation of the noninferiority of immunogenicity in the 12-to-15-year-old cohort to that in the 16-to-25-year-old cohort. Data were collected through the cutoff date of March 13, 2021. Eligible participants were healthy or had stable preexisting disease (including hepatitis B, hepatitis C, or human immunodeficiency lasix ).

Persons with a previous clinical or virologic hypertension medications diagnosis or hypertension , previous hypertension vaccination, diagnosis of an immunocompromising or immunodeficiency disorder, or treatment with immunosuppressive therapy (including cytotoxic agents and systemic glucocorticoids) were excluded. The ethical conduct of the trial is summarized in the Supplementary Appendix, available with the full text of this article at NEJM.org. Additional details of the trial are provided in the protocol, available at NEJM.org. Pfizer was responsible for the trial design and conduct, data collection, data analysis, data interpretation, and writing of the manuscript that was submitted.

Both Pfizer and BioNTech manufactured the treatment and placebo. BioNTech was the regulatory sponsor of the trial and contributed to data interpretation and writing of the manuscript. All data were available to the authors, who vouch for their accuracy and completeness and for the adherence of the trial to the protocol. Procedures Randomization was conducted with the use of an interactive Web-based response system.

Participants were assigned in a 1:1 ratio to receive two intramuscular injections of 30 μg of BNT162b2 or placebo (saline) 21 days apart. For evaluation of immediate treatment-associated reactions, participants were observed in the clinic for 30 minutes after vaccination. Safety Safety objectives included the assessment of local or systemic reactogenicity events, which were recorded by the participants in an electronic diary (e-diary) for 7 days after each dose. Unsolicited adverse events (i.e., those reported by the participant without e-diary prompting) and serious adverse events were also recorded from receipt of the first dose through 1 month and 6 months after dose 2, respectively.

Immunogenicity Immunogenicity assessments (hypertension serum neutralization assay and receptor-binding domain [RBD]–binding or S1-binding IgG direct Luminex immunoassays) were performed before vaccination and 1 month after dose 2, as described previously.3 The immunogenicity objective was to show noninferiority of the immune response to BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-year-old participants. Noninferiority was assessed among participants who had no evidence of previous hypertension with the use of the two-sided 95% confidence interval for the geometric mean ratio of hypertension 50% neutralizing titers in 12-to-15-year-old participants as compared with 16-to-25-year-old participants 1 month after dose 2. BNT162b2 immunogenicity was evaluated in participants with and those without serologic or virologic evidence of previous hypertension . Corresponding end points were the geometric mean hypertension neutralizing titers at baseline (i.e., immediately before receipt of the first injection) and 1 month after dose 2 and geometric mean fold rises (GMFRs) in titers from baseline to 1 month after dose 2.

Efficacy The efficacy of BNT162b2 against confirmed hypertension medications with an onset 7 or more days after dose 2 was summarized in participants who did not have evidence of previous hypertension , as well as in all vaccinated participants. Surveillance for potential hypertension medications cases was undertaken throughout the trial. If acute respiratory illness developed in a participant, the participant was tested for hypertension. Methods for identifying hypertension s and hypertension medications diagnoses are summarized in the Supplementary Appendix.

Statistical Analysis The safety population included all participants who received at least one dose of BNT162b2 or placebo. The reactogenicity subset included all 12-to-15-year-old participants and a subset of 16-to-25-year-old participants (those who received an e-diary to record reactogenicity events). Safety end points are presented descriptively as counts, percentages, and associated Clopper–Pearson two-sided 95% confidence intervals, with adverse events and serious adverse events described according to terms in the Medical Dictionary for Regulatory Activities, version 23.1, for each group. Immunogenicity was assessed in a random subset of participants in each age cohort with the use of a simple random-sample selection procedure.

For immunogenicity assessments, all participants in both age cohorts were from U.S. Sites. The dose 2 immunogenicity population that could be evaluated included participants who underwent randomization and received two BNT162b2 doses in accordance with the protocol, received dose 2 within the prespecified window (19 to 42 days after dose 1), had at least one valid and determinate immunogenicity result from a blood sample obtained within 28 to 42 days after dose 2, and had no major protocol deviations. Noninferiority of the immune response to BNT162b2 in 12-to-15-year-old participants as compared with that in 16-to-25-year-old participants was assessed on the basis of the geometric mean ratio of hypertension 50% neutralizing titers.

A sample of 225 BNT162b2 recipients who could be evaluated (or 280 BNT162b2 recipients overall) in each age cohort was estimated to provide 90.8% power for declaring noninferiority (defined as a lower limit of the 95% confidence interval for the geometric mean ratio of >0.67). A testing laboratory supply limitation of the qualified viral lot used for assay validation and clinical testing resulted in the trial having fewer participants than anticipated for the immunogenicity analyses. Calculations of the geometric mean ratios, geometric mean titers, and GMFRs are described in the Supplementary Appendix. Although the formal evaluation of efficacy was to be based on the overall results obtained across all age cohorts, the statistical analysis plan specified that descriptive efficacy summaries would be provided for each age cohort (the stratification factor).

The efficacy analysis for the 12-to-15-year-old cohort was planned as a descriptive analysis because the number of cases that would occur in the age subgroups was unknown. The efficacy population that could be evaluated included all eligible 12-to-15-year-old participants who underwent randomization and received two doses of BNT162b2 or placebo, received dose 2 within the prespecified window (19 to 42 days after dose 1), and had no major protocol deviations. The all-available efficacy population included all participants who received one or two doses. treatment efficacy was defined as 100×(1−IRR), where IRR is the ratio of the rate of a first confirmed hypertension medications illness in the BNT162b2 group to the corresponding rate in the placebo group.

Two-sided Clopper–Pearson 95% confidence intervals were calculated (not adjusted for multiple comparisons). Because the number of participants who reported symptoms but were missing a valid polymerase-chain-reaction test result was small, data for these participants were not imputed in the analysis.The clinical picture of moderate-to-severe thrombocytopenia and thrombotic complications at unusual sites beginning approximately 1 to 2 weeks after vaccination against hypertension with ChAdOx1 nCov-19 suggests a disorder that clinically resembles severe heparin-induced thrombocytopenia, a well-known prothrombotic disorder caused by platelet-activating antibodies that recognize multimolecular complexes between cationic PF4 and anionic heparin.6 However, unlike the usual situation in heparin-induced thrombocytopenia, these vaccinated patients did not receive any heparin to explain the subsequent occurrence of thrombosis and thrombocytopenia. In recent years, it has been recognized that triggers other than heparin can cause a prothrombotic disorder that strongly resembles heparin-induced thrombocytopenia on both clinical and serologic grounds, including certain polyanionic drugs (e.g., pentosan polysulfate,7 antiangiogenic agent PI-88,8 and hypersulfated chondroitin sulfate8). Such a prothrombotic syndrome has also been observed in the absence of preceding exposure to any polyanionic medication, such as after both viral and bacterial s9,10 and knee-replacement surgery.11,12 These various clinical scenarios with apparent nonpharmacologic triggers have been classified under the term autoimmune heparin-induced thrombocytopenia.13 Unlike patients with classic heparin-induced thrombocytopenia, patients with autoimmune heparin-induced thrombocytopenia have unusually severe thrombocytopenia, an increased frequency of disseminated intravascular coagulation, and atypical thrombotic events.

Serum from these patients strongly activate platelets in the presence of heparin (0.1 to 1.0 IU per milliliter) but also in the absence of heparin (heparin-independent platelet activation). When these unusual antibodies are observed in patients who have thrombocytopenia without preceding heparin exposure, the term “spontaneous” heparin-induced thrombocytopenia syndrome13,14 has been used. Sometimes, patients in whom heparin-induced thrombocytopenia develops after exposure to heparin present with atypical clinical features, such as an onset of thrombocytopenia beginning several days after stopping heparin (delayed-onset heparin-induced thrombocytopenia15,16) or thrombocytopenia that persists for several weeks despite the discontinuation of heparin (persisting or refractory heparin-induced thrombocytopenia17,18). Serum from these patients also shows the phenomenon of heparin-independent platelet-activating properties.

These clinical features that resemble those of autoimmune heparin-induced thrombocytopenia were observed in the patients with treatment-induced immune thrombotic thrombocytopenia. The serum usually showed strong reactivity on the PF4–heparin ELISA. Moreover, serum showed variable degrees of platelet activation in the presence of buffer that was in most cases greatly enhanced in the presence of PF4 (Figure 1A and 1B). More strikingly, most serum showed inhibition, rather than increased activation, in the presence of low-dose low-molecular-weight heparin (0.2 U per milliliter of anti–factor Xa).

In addition, antibodies from two patients, which were affinity purified on either immobilized PF4 or immobilized PF4–heparin, strongly activated platelets but only in the presence of PF4. Enhancement of platelet activation by PF4 is also a feature of heparin-induced thrombocytopenia19,20 and has been used to enhance detection of platelet-activating antibodies in diagnostic testing for this adverse drug reaction.21 Whether these antibodies are autoantibodies against PF4 induced by the strong inflammatory stimulus of vaccination or antibodies induced by the treatment that cross-react with PF4 and platelets requires further study. Although we found enhanced reactivity of patient serum with platelets in the presence of ChAdOx1 nCov-19, this is likely to be an in vitro artifact. It is well known that adenolasix binds to platelets22 and causes platelet activation.22,23 Furthermore, the amount of adenolasix in a 500-microliter treatment injection administered 1 or 2 weeks earlier would seem unlikely to contribute to subsequent platelet activation observed in these patients.

However, interactions between the treatment and platelets or between the treatment and PF4 could play a role in pathogenesis. One possible trigger of these PF4-reactive antibodies could be free DNA in the treatment. We have previously shown that DNA and RNA form multimolecular complexes with PF4, which bind antibodies from patients with heparin-induced thrombocytopenia and also induce antibodies against PF4–heparin in a murine model.24 Unfortunately, other hypertension medications treatments were not available to us for testing. Our findings have several important clinical implications.

First, clinicians should be aware that in some patients, venous or arterial thrombosis can develop at unusual sites such as the brain or abdomen, which becomes clinically apparent approximately 5 to 20 days after vaccination. If such a reaction is accompanied by thrombocytopenia, it can represent an adverse effect of the preceding hypertension medications vaccination. To date, this reaction has been reported only with the ChAdOx1 nCov-19 treatment, which has been used in approximately 25% of treatment recipients in Germany and in 30% of those in Austria. Second, ELISA to detect PF4–heparin antibodies in patients with heparin-induced thrombocytopenia is widely available and can be used to investigate patients for potential postvaccination thrombocytopenia or thrombosis associated with antibodies against PF4.25 A strongly positive ELISA result that is obtained in a patient who has not been recently exposed to heparin would be a striking abnormality.

Third, we have shown that these antibodies recognize PF4 and that the addition of PF4 greatly enhances their detectability in a platelet-activation assay. Since vaccination of millions of persons will be complicated by a background of thrombotic events unrelated to vaccination, a PF4-dependent ELISA or a PF4-enhanced platelet-activation assay may be used to confirm the diagnosis of treatment-induced immune thrombotic thrombocytopenia through this novel mechanism of postvaccination formation of platelet-activating antibodies against PF4. Although treatment decisions such as administering intravenous immune globulin and starting anticoagulation do not need to await laboratory diagnosis, detection of these unusual platelet-activating antibodies will be highly relevant for case identification and future risk–benefit assessment of this and other treatments. Figure 2.

Figure 2. Potential Diagnostic and Therapeutic Strategies for Management of Suspected treatment-Induced Immune Thrombotic Thrombocytopenia. Shown is a decision tree for the evaluation and treatment of patients who have symptoms of thrombocytopenia or thrombosis within 20 days after receiving the ChAdOx1 nCov-19 treatment and who have had no heparin exposure. The diagnostic and therapeutic strategies in such patients differ from those in patients with autoimmune heparin-induced thrombocytopenia (HIT).13 DIC denotes disseminated intravascular coagulation, INR international normalized ratio, PF4 platelet factor 4, and PTT partial thromboplastin time.Figure 2 shows a potential diagnostic and therapeutic strategy for managing this novel prothrombotic thrombocytopenic disorder.

One consideration is to administer high-dose intravenous immune globulin to inhibit Fcγ receptor–mediated platelet activation. This recommendation parallels emerging experience in the treatment of severe autoimmune heparin-induced thrombocytopenia in which high-dose intravenous immune globulin has resulted in rapid increases in platelet count and de-escalation of hypercoagulability.12,26 We found that the addition of immune globulin in doses that are readily achieved clinically was effective in inhibiting platelet activation by patients’ antibodies. Clinician reluctance to start anticoagulation may be tempered by administering high-dose intravenous immune globulin to raise the platelet count, especially when a patient presents with severe thrombocytopenia and thrombosis, such as cerebral venous thrombosis. Given the parallels with autoimmune heparin-induced thrombocytopenia, anticoagulant options should include nonheparin anticoagulants used for the management of heparin-induced thrombocytopenia,27 unless a functional test has excluded heparin-dependent enhancement of platelet activation.

Finally, we suggest naming this novel entity treatment-induced immune thrombotic thrombocytopenia (VITT) to avoid confusion with heparin-induced thrombocytopenia.To the Editor. Rare thromboembolic events have been observed during the vaccination rollout, which have prompted cautionary pauses in vaccinations by some regulatory authorities, including the South Africa Health Products Regulatory Authority.1,2 Here, we report interim safety data from the first 288,368 participants who were vaccinated with Ad26.COV2.S in the Sisonke study — an open label, single-group, phase 3b implementation study to monitor the effectiveness of the single-dose Ad26.COV2.S treatment among 500,000 health care workers in South Africa (ClinicalTrials.gov number, NCT04838795). Enrollment in the study began on February 17, 2021, and as of April 12, 2021, a total of 288,368 health care workers had received the Ad26.COV2.S treatment, among whom 5898 (2%) reported adverse events. The majority (81%) of adverse events reported were expected mild-to-moderate reactogenicity events.

Fifty health care workers had adverse events that met the criteria of being serious or of special interest3,4. A full list of these events is provided in Table 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org. Among these 50 workers, 12 (24%) had hypertension disease 2019 (hypertension medications), which occurred within 28 days after vaccination. 12 (24%) had allergic reactions, of which one met the criteria for anaphylaxis.

And 6 (12%) had neurologic conditions, including a 40-year-old man who received a diagnosis of Guillain–Barré syndrome and a 53-year-old woman with Bell’s palsy. Five arterial, venous thrombotic, or embolic events were reported in 5 health care workers with known risk factors for thromboembolism (1.7 events per 100,000 participants). One case of pulmonary embolus occurred 23 days after vaccination in a 63-year-old woman who was overweight and had hypertension, diabetes mellitus, and a history of venous thrombosis. This event was fatal.

A second case occurred in a 64-year-old woman who received a diagnosis of cor pulmonale 17 days after vaccination. This case had features consistent with chronic and recurrent pulmonary emboli. Two cerebrovascular accidents (infarcts on imaging) were reported — one case involved a 45-year-old woman who had underlying rheumatic heart disease and a history of human immunodeficiency lasix , cerebrovascular accident, and aortic valve replacement, in whom left-sided weakness developed the day after vaccination, and the other case involved a 38-year-old woman who had given birth to twins 9 months before vaccination and presented with features of transient ischemic attack 8 days after vaccination. A 65-year-old woman with chronic diabetes mellitus had deterioration and blurring of vision 8 days after vaccination and received a diagnosis of retinal vein occlusion and macular hemorrhage.

To date, no case of treatment-induced immune thrombotic thrombocytopenia has been documented. In South Africa, since the start of the lasix, hypertension medications has been reported in 1.58 million persons, including more than 55,000 health care workers. The rate of adverse events with vaccination is low, and thromboembolic events have occurred mainly in persons with risk factors for thromboembolism. Simbarashe Takuva, M.B., Ch.B.Azwidhwi Takalani, M.B., Ch.B.Fred Hutchinson Cancer Research Center, Seattle, WA [email protected]Nigel Garrett, M.B., B.S., Ph.D.Centre for the AIDS Programme of Research in South Africa, Durban, South AfricaAmeena Goga, M.B., Ch.B., Ph.D.South African Medical Research Council, Cape Town, South AfricaJonny Peter, M.B., Ch.B., Ph.D.Vernon Louw, M.B., Ch.B., Ph.D.Jessica Opie, M.B., Ch.B.University of Cape Town, Cape Town, South AfricaBarry Jacobson, M.B., Ch.B., Ph.D.University of the Witwatersrand, Johannesburg, South AfricaIan Sanne, M.B., Ch.B.Right to Care, Johannesburg, South AfricaLinda Gail-Bekker, M.B., Ch.B., Ph.D.University of Cape Town, Cape Town, South AfricaGlenda Gray, M.B., Ch.B., D.Sc.South African Medical Research Council, Cape Town, South Africa Supported by Janssen treatments and Prevention and the South African Medical Research Council.

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. This letter was published on June 2, 2021, at NEJM.org.4 References.

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