JAMA

Background/AimsWith a policy goal of introducing price competition into the market for biologic drugs after their period of market monopoly is over (called loss of exclusivity), policymakers created a pathway for companies to make copies of those treatments and termed them biosimilars. But unlike generic drugs, biosimilar drug copies must be studied in human trials to assure they have the same clinical effect as the original biologic products. The burden that this places on human subject participants, and the opportunity cost on the clinical trial system generally, have not been considered in detail. MethodsFor all biosimilar drugs in development, approved, or that failed to obtain approval in the US, we abstracted from clinicaltrials.gov registry the number of subjects enrolled at each phase of development. ResultsWe identified 105 clinical trials for approved or withdrawn biosimilars and another 20 studies that are either planned, ongoing or completed for biosimilars in development. These studies collectively enrolled (or plan to enroll) 38,169 human subjects. Most (28,130) are enrolled in phase 3 studies. The mean number of human subject participants per approval is 1,045, about 25% of the number required for a new drug approval on average. ConclusionsA consequential number of human subjects are required for the testing of biosimilar drugs prior to approval. The explicit and sole purpose of biosimilars is to induce competition in order to lower prices of biologic drugs after loss of exclusivity. The burden the biosimilar approval trials place on human subjects with no direct clinical benefits but definite risks, and the possibility that they rob subjects from trials that are of more scientific importance, are ones policymakers might consider. Price regulation of biologic drugs after loss of exclusivity could achieve lower prices as well, without the burdens of the current approach. Funding SourceArnold Ventures (Grant to support Drug Pricing Lab at Memorial Sloan Kettering Cancer Center)

The emerging outbreak of the 2019 novel coronavirus (2019-nCoV) originated from Wuhan poses a great challenge to healthcare system in China.1 Primary care practitioners (PCPs) have an important role in district communicable disease control.2 However, because primary health-care system in China still needs to be substantially strengthened,3,4 whether PCPs are proactive and capable in responding to the outbreak remains unclear. Using an electronic questionnaire, we surveyed a national sample of PCPs to assess their response to novel coronavirus outbreak.

BackgroundRespiratory Syncytial Virus (RSV) is associated with significant neonatal and infant morbidity and mortality. Maternal bivalent RSVpreF RSV vaccination to protect neonates and infants was approved in September 2023 for administration between 32+0 and 36+6 weeks to protect neonates and infants. This approved timeframe is narrower than the 24-36 week window evaluated in the clinical trial, due to the possible association between preterm birth and vaccine administration. Currently, data are lacking on how maternal vaccine timing within the approved window affects the transfer of antibodies from mother to fetus, critical information that could influence clinical practice. ObjectivesWe sought to examine how gestational age at vaccination and time elapsed from maternal RSV vaccination to delivery impacted transfer of maternal antibodies measured in the umbilical cord at delivery and in peripheral blood of 2-month infants. We also examined differences in maternal and cord RSV antibody levels achieved by vaccination versus natural RSV infection. Study DesignA prospective cohort study was conducted at two academic medical centers between September 20, 2023 and March 21, 2024, enrolling 124 individuals who received the RSV vaccine during pregnancy. Infant capillary blood was collected at 2 months of age from 29 of the infants. Maternal and cord IgG levels achieved by RSV vaccination were compared to those associated with maternal natural RSV infection, using banked blood from 20 maternal:cord dyads collected prior to the availability of the maternal RSV vaccine. Levels of IgG against RSV strain A2 and B fusion (F) and attachment (G) proteins and against pertussis toxin (as a comparator antigen from a vaccine routinely administered earlier in pregnancy) were measured using a Binding Antibody Multiplex Assay. Differences in titers between vaccination and natural infection were examined using Wilcoxon rank sum test. Differences in cord:maternal transfer ratios and 2-month infant antibody levels by timing of maternal vaccination were evaluated by Kruskal-Wallis testing. ResultsMaternal RSV vaccination resulted in significantly higher maternal and cord anti-F RSV antibody levels than natural infection (5.72 vs 4.82 log10MFI, p < 0.0001 maternal; 5.81 vs 5.03 log10MFI, p < 0.0001 cord). Maternal vaccination 2-3 weeks and 3-4 weeks prior to delivery was associated with significantly lower cord:maternal transfer ratios than were observed when vaccination occurred > 5 weeks prior to delivery (p = 0.03 for 2-3 weeks, p = 0.007 for 3-4 weeks), and significantly lower transfer ratios than observed for pertussis vaccination administered prior to 30 weeks gestation (p = 0.008 for 2-3 weeks, p = 0.03 for 3-4 weeks, similar at > 4 weeks). Conclusion(s)Vaccine administration earlier in the approved 32-36 week window (at least 5 weeks prior to delivery) results in the highest transplacental transfer of maternal antibodies to the neonate. These results should inform the counseling of pregnant individuals on optimal vaccination timing.

BackgroundAcute coronary syndrome at first contact in primary care must be recognised rapidly and safely--especially in women and in adults with diabetes, who more often present without classic chest pain and are at risk of under-triage. We synthesised evidence on symptom constellations and triage strategies--rapid electrocardiogram, high-sensitivity cardiac troponin pathways, and primary-care risk tools--that reduce missed or late recognition of acute coronary syndrome. MethodsTargeted review (Jan 1, 2007-May 31, 2025) of prospective cohorts, diagnostic or implementation studies, risk-tool derivations and validations, telephone-triage studies, and contemporary guidelines relevant to first-contact primary care (office, urgent or emergency primary care, and out-of-hours services). Prespecified outcomes were missed acute coronary syndrome, 30-day major adverse cardiac events, time to electrocardiogram, time to troponin and decision, emergency-department transfer or admission, length of stay, and diagnostic performance (sensitivity, specificity, negative and positive predictive value). Risk of bias was assessed with Quality Assessment of Diagnostic Accuracy Studies-2, Newcastle-Ottawa Scale, and Risk of Bias 2, and certainty of evidence with Grading of Recommendations, Assessment, Development and Evaluation. FindingsAcross 18 sources, symptom clusters alone were insufficient to safely rule out acute coronary syndrome; history-based rules showed heterogeneous sensitivity and are best used to structure history and trigger testing. Rapid electrocardiogram (with repeats when concern persists) and high-sensitivity cardiac troponin algorithms provided the greatest diagnostic safety. Ambulatory implementations of assay-specific strategies achieved very high negative predictive values (approximately 99-100%) for rule-out in low-risk populations and accelerated disposition; an emergency primary-care deployment of the European Society of Cardiology 0/1-hour high-sensitivity troponin pathway ruled out about 64% at 1 hour, yielded a conclusive decision for about 77% by 4 hours, and reduced length of stay by roughly 2.2 hours. Safety margins were lower in patients with known coronary artery disease (negative predictive value about 96-98%) and the rule-out fraction was smaller, supporting more conservative thresholds, brief observation, or adjunctive clinical risk scoring. Telephone and out-of-hours case-control data linked non-retrosternal descriptors and system factors to missed acute coronary syndrome, arguing for up-triage to in-person electrocardiogram and troponin testing or emergency medical services transfer. InterpretationFor adults first assessed in primary care--particularly women and people with diabetes--a protocolised pathway (electrocardiogram within minutes, serial high-sensitivity troponin using assay-specific delta thresholds, and clear escalation) offers high rule-out safety with faster, more equitable care. Known coronary artery disease is a caution zone, warranting stricter discharge thresholds or extended observation. Health systems should invest in clinic electrocardiogram access, point-of-care high-sensitivity troponin where laboratory turnaround is slow, emergency-medical-services-first scripts, and routine audit (time to electrocardiogram and troponin, rule-out at 1 and 4 hours, emergency-department transfer, and 30-day major adverse cardiac events) stratified by sex, diabetes status, and coronary artery disease. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched MEDLINE (via PubMed), Embase, and Web of Science from Jan 1, 2007, to May 31, 2025, using terms for acute coronary syndrome (ACS)/chest pain, primary care/general practice/out-of-hours services, women/sex differences, diabetes, high-sensitivity cardiac troponin (hs-cTn; 0/1-hour and very-low strategies), telephone triage, and primary-care risk scores (Marburg Heart Score, INTERCHEST, HEART/HEAR). We hand-searched guideline repositories and reference lists. Three signals consistently emerged: (1) guidelines endorse rapid electrocardiogram (ECG) and hs-cTn-based pathways; (2) symptom clusters alone--particularly in women and people with diabetes--are insufficient to rule out ACS; and (3) primary-care data are sparse and heterogeneous, with safety concerns in known coronary artery disease (CAD) when accelerated rule-out algorithms are used. Few studies linked findings to operational metrics important at the primary-care front door (time-to-ECG/hs-cTn, rule-out proportions, length of stay [LOS]). Added value of this studyWe integrate first-contact primary-care evidence across 18 sources into a single, implementable pathway centered on rapid ECG, assay-specific hs-cTn strategies (0/1-hour or single very-low when symptom onset [&ge;]3 h), and explicit escalation thresholds. We foreground women and adults with diabetes, quantify rule-out safety including the known-CAD caveat, and pair clinical accuracy with operational outcomes (time-to-test, rule-out at 1/4 h, emergency department transfers, LOS). We provide a concise summary table and figure plus an audit set that clinicians can deploy immediately, alongside formal risk-of-bias and GRADE certainty judgments. Implications of all the available evidencePrimary care can safely accelerate ACS evaluation by pairing ECG within 10 minutes and hs-cTn algorithms with conservative thresholds in known CAD and proactive escalation for non-chest presentations common in women and people with diabetes (e.g., dyspnea, epigastric discomfort, unusual fatigue). Health systems should invest in clinic ECG access, point-of-care hs-cTn where laboratory turnaround is slow, emergency medical services (EMS)-first triage scripts, and routine audit of time-to-ECG/hs-cTn, rule-out proportions, emergency department transfers, and 30-day major adverse cardiac events (MACE) stratified by sex, diabetes, and CAD. Research priorities include prospective, consecutive primary-care cohorts with adjudicated 30-day outcomes, pragmatic trials of point-of-care hs-cTn, decision support tailored to known CAD, and cluster-randomized improvements to telephone/virtual triage.

The effect of SARS-CoV-2 seropositivity on the immune response to mRNA-based SARS-CoV-2 vaccines has not been well-described. Here we report longitudinal SARS-CoV-2-specific antibody responses pre- and post-vaccination among a cohort of healthcare personnel, with and without prior infection, from a large academic medical center. Our results provide preliminary evidence that prior SARS-CoV-2 infection may prime the response to the first mRNA-based SARS-CoV-2 vaccine dose. These findings could have significant impact on the allocation of mRNA-based vaccines and support the need for future research into the effect of prior infection on magnitude and durability of vaccination response.

ImportancePregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER- Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. MethodsRECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. DiscussionRECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. RegistrationNCT05172024

ObjectiveTo determine whether antibodies against the SARS-CoV-2 spike protein following BNT162B2 (Pfizer-BioNTech) COVID-19 mRNA vaccination cross-react with human syncytin-1 protein, and if BNT162B2 mRNA enters breast milk. MethodsIn this observational cohort study of female front-line workers with no history of COVID-19 infection, we amplified BNT162B2 mRNA in plasma and breast milk and assayed anti-SARS-CoV-2 neutralising antibodies and anti-human syncytin-1 binding antibodies in plasma, at early (1-4 days) and late (4-7 weeks) time points following first-dose vaccination. ResultsFifteen consented participants (mean age 40.4 years, various ethnicities) who received at least one dose of BNT162B2, including five breast-feeding women and two women who were inadvertently vaccinated in early pregnancy, were recruited. BNT162B2 mRNA, detected by amplifying part of the spike-encoding region, was detected in plasma 1-4 days following the first dose (n=13), but not 4-5 weeks later (n=2), nor was the mRNA isolated from aqueous or lipid breast milk fractions collected 0-7 days post-vaccination (n=5). Vaccine recipients demonstrated strong SARS-CoV-2 neutralising activity by at least four weeks after the first dose (n=15), including the two pregnant women. None had placental anti-syncytin-1 binding antibodies at either time-point following vaccination. ConclusionsBNT162B2-vaccinated women did not transmit vaccine mRNA to breast milk, and did not produce a concurrent humoral response to syncytin-1, suggesting that cross-reactivity to syncytin-1 on the developing trophoblast, or other adverse effects in the breast-fed infant from vaccine mRNA ingestion, are unlikely. What are the novel findings of this work?COVID-19 vaccination with BNT162B2 did not elicit a cross-reacting humoral response to human syncytin-1 despite robust neutralising activity to the SARS-CoV2 spike protein, and while vaccine mRNA was isolated from plasma, it was not found in breast milk. What are the clinical implications of this work?Our work directly addresses the fertility and breastfeeding concerns fuelling vaccine hesitancy among reproductive-age women, by suggesting that BNT162B2 vaccination is unlikely to cause adverse effects on the developing trophoblast, via cross-reacting anti-syncytin-1 antibodies, or to the breastfed neonate, via mRNA breast milk transmission.

BackgroundThe COVID-19 pandemic has been characterized by ongoing evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with concomitant variation in viral transmissibility and morbidity. Within specific timeframes and geographic areas, multiple SARS-CoV-2 variants have coexisted in the human population, each characterized by distinct biologic and clinical features, such as varying susceptibility to neutralizing monoclonal antibodies (nMAbs), a major frontline treatment. As part of an observational real-world data study of the effectiveness of nMAbs for treatment of COVID-19, SARS-CoV-2 viral samples were obtained from patients under treatment, generating paired clinical and genomics data. This paper describes the processing pipeline and findings from the genomics portion of this combined data set. MethodsSARS-CoV-2 sequences were generated from 14,796 diagnostic samples from four large U.S. health systems between July 2020 and March 2022. Among nMAbs-treated patients, samples were collected on the same day as, or prior to, treatment with nMAbs. Thus, these samples represent a snapshot of SARS-CoV-2 variants circulating in the respective patient groups, as opposed to variants that arose in response to specific treatments. Health systems collected viral samples and performed library creation and sequencing according to local protocols, using tiled ARTIC amplicon primers. FASTQ files were submitted to a study data platform and processed through a common pipeline. This pipeline enabled a unified approach to quality control, assembly, and production of genomics features for downstream analysis. ResultsAlpha and pre-Alpha SARS-CoV-2 lineages were predominant in the data set prior to June 2021. From June 2021 through November 2021, Delta was the dominant variant. Beginning in December 2021, Omicron was dominant. A variety of mutations associated with decreased nMAbs binding to the spike protein in vitro were detected, including lineage-defining mutations and non-lineage-defining mutations such as E340A, G446V, and S494P. Distinct patterns of sequence gaps and ambiguous base calls were associated with distinct variants. ConclusionsThe distribution of SARS-CoV-2 variants, per WHO nomenclature, across epochs in this data set matched concurrent CDC genomic surveillance results across the U.S. Detection of putative nMAbs escape mutations within clinical samples was consistent with FDA decisions to amend EUAs as variants emerged. This genomics data set provides an opportunity to examine associations between SARS-CoV-2 genomic variation and clinical outcomes in the associated EHR data set. The expansion of real-world data sets such as this to study the relationship between viral sequence and treatment outcomes could provide the foundation for future efforts to achieve near-real-time understanding of clinical outcomes related to genomic variation over time, and evidence to update treatment decisions more rapidly and to greater effect during ongoing and future pandemics.

BackgroundCarotid artery stenosis is a notable risk factor for ischemic stroke. In 2021, the U.S. Preventive Services Task Force (USPSTF) published an updated evidence review on screening for asymptomatic carotid artery stenosis (ACAS). At the request of the Japan Preventive Services Task Force, we conducted a systematic review to adapt and update the USPSTF review by incorporating recent international evidence and Japanese-language literature. MethodsFollowing the USPSTF analytic framework, we evaluated the evidence on screening effectiveness, harms of screening or confirmatory testing, the incremental benefit of revascularization beyond current medical therapy, and harms of surgical interventions in asymptomatic individuals. The International Medical Information Center conducted literature searches in PubMed, the Cochrane Library, and Ichushi-Web. Searches were limited to English and Japanese studies. Two reviewers independently performed study selection, data extraction, and risk of bias assessment, with disagreements resolved by consensus. Newly identified studies were qualitatively synthesized with the 2021 USPSTF findings. ResultsNo eligible studies directly assessing the benefits and harms of screening for ACAS were identified. One RCT evaluated the benefits of revascularization, and harms were assessed in that RCT and five observational studies. The RCT (SPACE-2; n=513), which investigated the incremental benefit of revascularization, was terminated prematurely and had substantial methodological limitations. In five registry- or claims-based observational studies, the 30-day incidence of stroke or death following revascularization was 2.5% to 2.8%. Perioperative stroke, death, and myocardial infarction occurred in 0.9% to 2.3%, 0.3% to 0.9%, and 0.3% to 0.9% of patients, respectively, consistent with the 2021 USPSTF review. ConclusionsThere is no direct evidence evaluating the effectiveness and harms of screening for asymptomatic carotid artery stenosis. Evidence on the benefits and harms of adding revascularization to optimal medical therapy was limited by early trial termination and methodological concerns, reducing the internal validity of the available data.

Introduction: Preeclampsia (PE) is a leading cause of maternal and neonatal morbidity and mortality, and low-dose aspirin (LDA) prophylaxis is the cornerstone of evidence-based prevention. Despite guideline recommendations, LDA adherence remains poor, with 10-25% of moderate-risk patients taking aspirin. Objective personalized risk stratification using biomarkers has been shown to motivate behavior change in other disease contexts. Survey data suggest that patients are more motivated to take aspirin if informed by an objective predictive test. Here, we report real-world LDA adherence among patients who received a high-risk result from a cell-free RNA (cfRNA) PE risk prediction test. Methods: This retrospective, observational survey study included asymptomatic patients of advanced maternal age (AMA; [&ge;] 35 years at delivery) with singleton pregnancies without USPSTF-defined preexisting high-risk conditions for PE who received the cfRNA PE risk prediction test. Patients who opted in to receive text message surveys were asked about LDA use following receipt of test results. High adherence was defined as reporting LDA use on at least 6 of 7 days per week at least 85% of the time surveyed. The primary analysis included patients with a high-risk test result and at least one LDA frequency survey response following receipt of test result. The observed proportion of adherent patients was compared to a baseline estimate of 25% using an exact binomial test. Results: Of 166 patients who received a cfRNA PE risk prediction test result, 48 (28.9%) received a high-risk result. Of these, 29 (60%) opted in and responded to at least one survey, constituting the primary analysis population. Twenty-seven of the 29 (93.1%; 95% CI: 78.0-98.1%) were classified as highly adherent, significantly higher than the 25% baseline adherence estimate for moderate-risk patients (p < 0.0001). Conclusion: Among surveyed patients who received a high-risk cfRNA PE test result, the proportion classified as highly adherent to LDA (93%) substantially exceeded published estimates of adherence in a similar patient population and met the clinically meaningful threshold of [&ge;] 80% associated with reduced risk of preterm preeclampsia. These findings indicate that objective and personalized biomarker risk testing may be a powerful driver of behavior change that current guidelines have failed to produce.

Smoking Cessation Efforts for Patients with Asthma and COPD IntroductionSmoking cessation can alter the natural history of both COPD and asthma by reducing the frequency and severity of exacerbations and slowing disease progression. Accordingly, the Global Initiative for Asthma and the Global Initiative for Chronic Obstructive Lung Disease recommend that clinicians address smoking cessation at every visit using counseling and pharmacotherapy. MethodsThe Mount Sinai Health System includes seven hospitals and more than 400 outpatient locations in the New York metropolitan area, all using a unified electronic medical record (Epic). De-identified data from calendar year 2024 were extracted for individuals identified as current smokers via the EMR smoking status tool. Patients with asthma and/or COPD were identified using ICD-10 codes. Tobacco treatment was defined as receipt of counseling or pharmacotherapy, including varenicline, bupropion, or nicotine replacement therapy. ResultsAmong 961,997 patients, 58,566 (6.1%) were identified as current cigarette smokers. Across all health system encounters, 32.6% of smokers with both asthma and COPD were given any treatment, followed by 26.7% of smokers with COPD, 13.0% of smokers with asthma, and 9.9% of cigarette smokers without these conditions. Smokers seen in pulmonary clinics were the most likely to be given treatment (17.4%), followed next by primary care (6.6%).The most commonly used treatment for all cohorts and all treatment settings was nicotine with the exception of the pulmonary clinic where varenicline predominated. DiscussionDespite higher treatment rates among smokers with asthma and COPD, only one-third of those with either condition received cessation treatment over a full year, underscoring the need for sustained system-wide quality improvement efforts.

Rapid, widespread COVID-19 vaccination is critical to pandemic mitigation and recovery. To help policymakers interested in further enhancing primary care delivery of COVID-19 vaccines, it is important to estimate the absolute number of vaccination opportunities, and identify how these opportunities may fall disproportionately among different communities given the unequal way that COVID-19 falls upon communities of color, low-income, and rural communities. To quantify the potential benefits of greater primary care engagement in vaccination efforts, we estimated the number of potential vaccination opportunities (PVOs) in primary care in the remaining calendar months of year 2021, and the possible uptake if we supplied enough vaccine to primary care practices to fulfill their opportunities. To estimate how many potential vaccination opportunities (PVOs) may occur in primary care, we used three sets of data, analyzing the latest available waves of the following: (i) the National Ambulatory Medical Care Survey (NAMCS, 2016, N = 677 providers); (ii) the National Health Interview Survey (NHIS, 2018, N = 29,839 individuals in 29,839 households); and (iii) the Medical Expenditure Panel Survey (MEPS, 2018, N = 40,025 individuals in 14,500 households). Per the NAMCS data, which provide a nationally-representative sample of ambulatory care visits, primary care physicians normally provide 40.2 million primary care visits per month. The majority of the primary care utilization is absorbed by those aged 16 to 64 years old who are not otherwise priority groups (i.e., not having chronic diseases as defined by ACIP) but the second large group of visits are those with a chronic disease (27.2% of all visits). As compared to the NAMCS data providing an estimate of care from the perspective of providers, the overall sample in NHIS provides a view of primary care access and utilization from a population perspective. Per NHIS, 34% of the civilian US population saw a generalist physician in the prior calendar year, or 109.8 million people. Overall, we would estimate that over the latter half of calendar year 2021, approximately 15 million potential vaccine opportunities per month would be available through US primary care practices.

Recently it was shown that blood hemoglobin concentration could be predicted from retinal fundus photographs by deep learning models. However, it is unclear whether the models were quantifying current blood hemoglobin level, or estimating based on subjects pretest probability of having anemia. Here, we conducted an observational study with 14 volunteers who donated blood at an on site blood drive held by the local blood center (ie, at which time approximately 10% of their blood was removed). When the deep learning model was applied to retinal fundus photographs taken before and after blood donation, it detected a decrease in blood hemoglobin concentration within each subject at 2-3 days after donation, suggesting that the model was quantifying subacute hemoglobin changes instead of predicting subjects risk. Additional randomized or controlled studies can further validate this finding.

ObjectiveSomatic mutations in UBA1 cause the recently described systemic auto-inflammatory syndrome, VEXAS. Study of this disease has largely been limited to highly symptomatic patients. We sought to determine the prevalence of VEXAS-associated somatic mutations and their disease penetrance in a diverse, unselected population. MethodsWe analyzed clinical-grade whole genome sequencing data from 245,368 individuals in the All of Us Research Program. We compared persons with canonical VEXAS-associated mutations to ten age, sex, and ancestry matched controls across the domains of diagnoses, medications, and laboratory values. Results74 persons were identified with a VEXAS-defining somatic mutation at c.121A>C (p.Met41Leu) in UBA1. The variant allele fraction ranged from 4.5% to 33%. No other canonical VEXAS-associated mutations were identified. Of the 74 persons, 62 (84%) were women, 20 (27%) were African American, and 14 (19%) were American Admixed / Latino. There was no statistically significant association between case/control status and any diagnosis code, medication prescription, or laboratory value. ConclusionWe report the largest cohort to date of persons with the VEXAS-associated p.Met41Leu mutation. This cohort differed substantially from reported cohorts of patients with clinical VEXAS, having a higher proportion of persons who were young, female, and of diverse ancestry. Variant allele fractions of p.Met41Leu mutations were lower than reported in clinical VEXAS and none of the patients had bioinformatically apparent VEXAS syndrome. The p.Met41Leu UBA1 variant displayed incomplete penetrance for VEXAS. Further study is needed to determine the natural history of VEXAS-associated mutations in the pre-disease phase.

Although there have been many studies on antibody responses to SARS-CoV-2 in breastmilk, very few have looked at the fate of these in the baby. We carried out a study in 22 mother/baby pairs (mothers who breastfed and who were SARS-CoV-2 vaccinated before or after delivery) looking at mother blood, mother milk, baby blood, baby nose, and baby stool. Breastfed infants only acquired systemic anti-SARS-CoV-2 IgG antibodies if their mothers were vaccinated antepartum. None of the infants had SARS-CoV-2-specific IgA in the blood, but surprisingly, half of the infants in the Antepartum group had high titer SARS-CoV-2-specific IgA in the nose that exceeded titers found in breastmilk. Vaccination antepartum followed by breastfeeding appears to be the best way to provide systemic and local anti-SARS-CoV-2 antibodies for infants.

Influenza H3N2 subclade K (J.2.4.1) is a genetic branch of H3N2 with 11 mutations in hemagglutinin and currently represents the dominant circulating influenza strain. We evaluated antibody responses to H3N2 subclade K before and after influenza vaccination in 46 healthy individuals. Our data show that baseline antibody responses to two H3N2 subclade K variants were lower than to other H1N1 and H3N2 strains and that antibody responses following vaccination were also less robust to the H3N2 subclade K variants. These data indicate that the H3N2 subclade K strain partially evades both prior H3N2 immunity and the current inactivated influenza vaccine.

This study assessed racial and ethnic disparities in severe maternal mortality during delivery through 6 weeks postpartum, before and during the COVID pandemic, in a statewide Medicaid population. This retrospective, population-based, cohort study used Medicaid claims data linked to birth certificates from the Michigan Department of Health and Human Services Health Services Data Warehouse that included all individuals giving birth between January 1, 2017, and October 31, 2021, in Michigan who had Medicaid insurance during the month of childbirth. The SMM rate increased more during the COVID pandemic for Black (1.36 [1.26-1.46]) compared to White individuals (1.17 [1.09-1.26], p-value<0.01 Black vs White). The Black-White and Hispanic-White disparities in severe maternal morbidity, already high in the Medicaid population, widened during the COVID pandemic. Multilevel interventions are needed to reduce disparities in maternal morbidity and mortality. Conflict of interest disclosureNo conflicts to disclose.

ObjectiveWe report secondary histologic and high-risk HPV (hrHPV) outcomes from the Acceptability and Feasibility of Combination Treatment for Cervical Precancer Among South African Women Living with HIV (ACT 2) Trial. MethodsWe conducted a double-blind Phase 2b feasibility trial of loop electrosurgical excision procedure (LEEP) combined with adjuvant intravaginal 5-fluorouracil (5FU) cream. Women living with HIV (WLWH) and cervical intraepithelial neoplasia (CIN) 2/3 underwent LEEP and were randomly assigned (1:1) to receive 8 doses of 5FU or placebo cream. Our secondary outcomes were (a) regression of cervical disease and (b) clearance of hrHPV. ResultsFrom March 2023 to January 2025, 180 participants underwent LEEP and were randomized to 5FU or placebo cream. Median age was 41 years (IOR: 35-45), 29% had HPV16, 18% had HPV18/45; 99% of women were virologically suppressed (<200 copies/mL) and median CD4 count was 636 cells/uL (IOR: 376-873). 172 participants (95.6%) completed follow-up. At week 24, 96.3% (78/81) in the 5FU group and 82.0% (73/89) in the placebo group regressed to CIN1 or normal histology (PD 14.3%, CI 5.3%, 23.3%). Among participants with positive LEEP margins at week 0, 88.0% (22/25) in the 5FU versus 61.3% (19/31) in the placebo group regressed to CIN1 or normal (PD 26.7%, CI 5.4%, 48.1%). Genotype-specific hrHPV clearance was similar in both groups (5FU: 58.0%, 40/69; Placebo: 53.8%, 43/80; PD 4.2%, CI -11.7%, 20.2%). ConclusionClinical outcomes from our Phase 2b trial demonstrates that intravaginal 5FU post-LEEP may be a beneficial adjuvant treatment for CIN2/3. Clinical Trial RegistrationNCT05413811

BackgroundChildren and adolescents in England were offered BNT162b2 as part of the national COVID-19 vaccine roll out from September 2021. We assessed the safety and effectiveness of first and second dose BNT162b2 COVID-19 vaccination in children and adolescents in England. MethodsWith the approval of NHS England, we conducted an observational study in the OpenSAFELY-TPP database, including a) adolescents aged 12-15 years, and b) children aged 5-11 years and comparing individuals receiving i) first vaccination with unvaccinated controls and ii) second vaccination to single-vaccinated controls. We matched vaccinated individuals with controls on age, sex, region, and other important characteristics. Outcomes were positive SARS-CoV-2 test (adolescents only); COVID-19 A&E attendance; COVID-19 hospitalisation; COVID-19 critical care admission; COVID-19 death, with non-COVID-19 death and fractures as negative control outcomes and A&E attendance, unplanned hospitalisation, pericarditis, and myocarditis as safety outcomes. ResultsAmongst 820,926 previously unvaccinated adolescents, the incidence rate ratio (IRR) for positive SARS-CoV-2 test comparing vaccination with no vaccination was 0.74 (95% CI 0.72-0.75), although the 20-week risks were similar. The IRRs were 0.60 (0.37-0.97) for COVID-19 A&E attendance, 0.58 (0.38-0.89) for COVID-19 hospitalisation, 0.99 (0.93-1.06) for fractures, 0.89 (0.87-0.91) for A&E attendances and 0.88 (0.81-0.95) for unplanned hospitalisation. Amongst 441,858 adolescents who had received first vaccination IRRs comparing second dose with first dose only were 0.67 (0.65-0.69) for positive SARS-CoV-2 test, 1.00 (0.20-4.96) for COVID-19 A&E attendance, 0.60 (0.26-1.37) for COVID-19 hospitalisation, 0.94 (0.84-1.05) for fractures, 0.93 (0.89-0.98) for A&E attendance and 0.99 (0.86-1.13) for unplanned hospitalisation. Amongst 283,422 previously unvaccinated children and 132,462 children who had received a first vaccine dose, COVID-19-related outcomes were too rare to allow IRRs to be estimated precisely. A&E attendance and unplanned hospitalisation were slightly higher after first vaccination (IRRs versus no vaccination 1.05 (1.01-1.10) and 1.10 (0.95-1.26) respectively) but slightly lower after second vaccination (IRRs versus first dose 0.95 (0.86-1.05) and 0.78 (0.56-1.08) respectively). There were no COVID-19-related deaths in any group. Fewer than seven (exact number redacted) COVID-19-related critical care admissions occurred in the adolescent first dose vs unvaccinated cohort. Among both adolescents and children, myocarditis and pericarditis were documented only in the vaccinated groups, with rates of 27 and 10 cases/million after first and second doses respectively. ConclusionBNT162b2 vaccination in adolescents reduced COVID-19 A&E attendance and hospitalisation, although these outcomes were rare. Protection against positive SARS-CoV-2 tests was transient.

Recently, multiple novel strains of SARS-CoV-2 have been found to share the same deletion of amino acids H69 and V70 in the virus S gene. This includes strain B.1.1.7 / SARS-CoV-2 VUI 202012/01, which has been found to be more infectious than other strains of SARS-CoV-2, and its increasing presence has resulted in new lockdowns in and travel restrictions leaving the UK. Here, we analyze 2 million RT-PCR SARS-CoV-2 tests performed at Helix to identify the rate of S gene dropout, which has been recently shown to occur in tests from individuals infected with strains of SARS-CoV-2 that carry the H69del/V70del mutation. We observe a rise in S gene dropout in the US starting in early October, with 0.25% of our daily SARS-CoV-2-positive tests exhibiting this pattern during the first week. The rate of positive samples with S gene dropout has grown slowly over time, with last week exhibiting the highest level yet, at 0.5%. Focusing on the 14 states for which we have sufficient sample size to assess the frequency of this rare event (n>1000 SARS-CoV-2-positive samples), we see a recent expansion in the Eastern part of the US, concentrated in MA, OH, and FL. However, we cannot say from these data whether the S gene dropout samples we observe here represent the B.1.1.7. strain. Only with an expansion of genomic surveillance sequencing in the US will we know for certain the prevalence of the B.1.1.7 strain in the US.