Early Outpatient Treatment for Covid-19 with Convalescent Plasma.

BACKGROUND: Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients with recent-onset Covid-19 is uncertain. METHODS: In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion. RESULTS: Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized. CONCLUSIONS: In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).

Transfusing Convalescent Plasma as Post-Exposure Prophylaxis Against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Double-Blinded, Phase 2 Randomized, Controlled Trial.

BACKGROUND: The efficacy of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. CCP might prevent infection when administered before symptoms or laboratory evidence of infection. METHODS: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320 by Euroimmun ELISA) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed coronavirus disease 2019 (COVID-19) in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was new SARS-CoV-2 infection. RESULTS: In total, 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for screening SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) positivity. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs 25.2 days; P = .49) and COVID-19 (26.3 vs 25.9 days; P = .35) was similar for both groups. CONCLUSIONS: Administration of high-titer CCP as post-exposure prophylaxis, although appearing safe, did not prevent SARS-CoV-2 infection. CLINICAL TRIALS REGISTRATION: NCT04323800.

Transfusion reactions associated with COVID-19 convalescent plasma in outpatient clinical trials.

BACKGROUND: COVID-19 convalescent plasma (CCP) is an important therapeutic option for outpatients at high risk of hospitalization from SARS-CoV-2 infection. We assessed the safety of outpatient CCP transfusions administered during clinical trials. STUDY DESIGN AND METHODS: We analyzed data pertaining to transfusion-related reactions from two randomized controlled trials in the U.S. that evaluated the efficacy of CCP versus control plasma in various ambulatory settings. Multivariable logistic regression was used to assess whether CCP was associated with transfusion reactions, after adjusting for potential confounders. RESULTS: The combined study reported 79/1351 (5.9%) adverse events during the transfusion visit, with the majority 62/1351 (4.6%) characterized by mild, allergic-type findings of urticaria, and/or pruritus consistent with minor allergic transfusion reactions; the other reported events were attributed to the patients' underlying disease, COVID-19, or vasovagal in nature. We found no difference in the likelihood of allergic transfusion reactions between those receiving CCP versus control plasma (adjusted odds ratio [AOR], 0.75; 95% CI, 0.43-1.31). Risk of urticaria and/or pruritus increased with a pre-existing diagnosis of asthma (AOR, 2.33; 95% CI, 1.16-4.67). We did not observe any CCP-attributed antibody disease enhancement in participants with COVID-19 or increased risk of infection. There were no life-threatening severe transfusion reactions and no patients required hospitalization related to transfusion-associated complications. DISCUSSION: Outpatient plasma administration was safely performed for nearly 1400 participants. CCP is a safe therapeutic option for outpatients at risk of hospitalization from COVID-19.

A Pilot Study Of Aspirin Resistance In Obstructive Sleep Apnea Patients.

Purpose: Obstructive sleep apnea (OSA) leads to endothelial dysfunction and platelet hyperactivity, which are linked to increased risk of cardiovascular disease and implicated in the development of aspirin resistance. We hypothesized that aspirin resistance is prevalent among OSA patients and aimed to explore effects of continuous positive airway pressure (CPAP) therapy on aspirin responsiveness. Methods: In Phase 1, prevalence of aspirin resistance was determined cross-sectionally in a group of OSA patients (n=59) on daily low-dose aspirin (81 mg) taken before entering the study, for primary or secondary prevention. In Phase 2, aspirin responsiveness before and after initiation of CPAP therapy was compared and stratified by endothelial function in a cohort of aspirin-naïve patients with newly diagnosed OSA (n=18). Results: In Phase 1, prevalence of aspirin resistance was 17%; most patients (56%) were on CPAP therapy. In Phase 2, initiation of CPAP therapy was associated with significant improvement in endothelial function (p=0.03). The mean pre-CPAP aspirin resistance units (ARU) was 569 (SD=75). In subjects with endothelial dysfunction (44%), the mean decrease after initiation of CPAP therapy was 43 ARU (SD=81, p=0.18). In contrast, subjects with normal endothelial function experienced the mean decrease of 8 ARU (SD=116, p=0.83). Conclusion: Aspirin resistance may be prevalent among OSA patients. After initiation of CPAP therapy, we observed a trend towards improvement in aspirin responsiveness among patients with endothelial dysfunction. The role of endothelial dysfunction and aspirin resistance should be explored in further studies that focus on the effect of CPAP on cardiovascular outcomes.

Emergency department utilization for mental health conditions before and after the COVID-19 outbreak.

INTRODUCTION: The outbreak of COVID-19 disrupted lives across the United States. Evidence shows that such a climate is deleterious to mental health and may increase demand for mental health services in emergency departments. The purpose of this study was to determine the difference in emergency department utilization for mental health diagnoses before and after the COVID-19 surge. METHODS: We conducted a cross-sectional study between January-August 2019 and January-August 2020 with emergency department encounter as the sampling unit. The primary outcome was the proportion of all emergency department encounters attributed to mental health. We performed chi-square analyses to evaluate the differences between 2019 and 2020. RESULTS: We found that overall emergency department volume declined between 2019 and 2020, while the proportion attributable to mental health conditions increased (p < 0.01). Substance abuse, anxiety, and mood disorders accounted for nearly 90% of mental health diagnoses during both periods. When stratified by sex, substance abuse was the leading mental health diagnosis for males and anxiety and substance abuse disorders combined accounted for the largest proportion for females. DISCUSSION: The emergency department is an important community resource for the identification and triage of mental health emergencies. This role is even more important during disasters and extended crises, making it imperative that emergency departments employ experienced mental health staff. This study provides a comparison of emergency department utilization for mental health diagnoses before the pandemic and during the spring 2020 surge and may serve as a useful guide for hospitals, health systems and communities in future planning.

A matched cohort study of convalescent plasma therapy for COVID-19.

INTRODUCTION: COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a public health crisis. Prior studies demonstrated successful use of convalescent plasma therapy for treatment of other viral illnesses. Our primary objective was to evaluate treatment efficacy of convalescent plasma in patients with COVID-19. MATERIALS AND METHODS: In this retrospective matched cohort study, we enrolled recipients of convalescent plasma collected from donors recovered from laboratory-confirmed SARS-CoV-2 infection under the single patient eIND process. We individually matched 35 cases with 61 controls based on age, gender, supplemental oxygen requirements, and C-reactive protein level at the time of hospital admission. We compared the outcomes of in-hospital mortality and hospital length of stay between the groups. RESULTS: In-hospital mortality was 20% among the cases and 24.6% among the controls (P = .61). A multivariable logistic regression model that included age, gender, duration of symptoms, need for mechanical ventilation, and pharmacologic interventions revealed no significant difference in mortality by study group (P = .71). The median length of stay was significantly greater among convalescent plasma recipients compared with controls, 10 (IQR, 6-17) vs 7 (IQR, 4-11) days, P < .01. The difference was not significant after controlling for covariates (P > .1). CONCLUSIONS: We did not find convalescent plasma reduced in-hospital mortality in our sample, nor did it reduce length of stay. Further investigation is warranted to determine the efficacy of this treatment in patients with COVID-19, particularly early in the disease process.

Initial review of pregnancy and neonatal outcomes of pregnant women with COVID-19 infection.

OBJECTIVES: Data regarding the pathogenesis and clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, however, there's limited data in regard to maternal and neonatal outcomes. Therefore, we conducted a retrospective analysis of all pregnant women who tested positive for SARS-CoV-2 within Nuvance Health system. METHODS: Data were abstracted from the medical records of each patient and descriptive analysis was performed. Variables included demographics, COVID testing results, symptoms, management, labor course, neonatal information, and complications. RESULTS: Total of 40 patients were identified. Average age was 29.6 years old, 35% were Hispanic, and approximately one in three patients had comorbidities. Of the patients who had repeated testing, the average number of days between first positive test and negative test was 36.8 days (± 19.9 days). Three out of four women reported symptoms. Of the 40 pregnant women who were positive for SARS-CoV-2, 25 of them delivered. About 84% of the women delivered after 37 weeks. Twelve percent of the women delivered under 33 and 6/7 weeks. Most patients had vaginal deliveries (68%) and the remaining had cesarean deliveries. Neonatal outcomes included: mean 1 and 5 min Apgar scores of 8 and 8.8, respectively and the mean birth weight was 3212 g. Twenty neonates were tested for SARS-CoV-2 and were all found to be negative. CONCLUSIONS: Overall, with routine prenatal care and preventive measures, pregnant patients and neonates in our study had good outcomes. At this time, there appears to be no evidence of vertical transmission.

A Four-Year Trend in Serum 25-Hydroxyvitamin D Levels in Western Connecticut.

OBJECTIVE: This study describes the trends in blood vitamin D levels in a regional population from 2009-2012 through a cross-sectional study design. METHODS: Over a four-year period (2009-2012), serum levels of 25-hydroxyvitamin D [25(OH)D] have been measured using an automated enzyme immunoassay with a steadily increasing number of tests performed each year. A total of 54700 tests were performed during this period, with a 90% increase in annual tests ordered. RESULTS: Mean and median serum levels of 25(OH) D showed statistically significant increases during this period. Those with 25(OH)D levels below 10 ng/mL represented 1.45% of the subjects in 2009 and 0.3% in 2012. The decrease in the proportion of subjects with 25(OH)D levels below 20 ng/mL and below 30 ng/mL was greatest out of all the proportioned subjects. Mean and median 25(OH)D levels increased with age in males and females. CONCLUSION: These results likely reflect increased health awareness in Western Connecticut compared with national surveys showing a temporal decrease in 25(OH)D levels.

Perinatal Disparities Between American Indians and Alaska Natives and Other US Populations: Comparative Changes in Fetal and First Day Mortality, 1995-2008.

To compare fetal and first day outcomes of American Indian and Alaskan Natives (AIAN) with non-AIAN populations. Singleton deliveries to AIAN and non-AIAN populations were selected from live birth-infant death cohort and fetal deaths files from 1995-1998 and 2005-2008. We examined changes over time in maternal characteristics of deliveries and disparities and changes in risks of fetal, first day (<24 h), and cause-specific deaths. We calculated descriptive statistics, odds ratios and confidence intervals, and ratio of odds ratios (RORs) to indicate changes in disparities. Along with black mothers, AIANs exhibited the highest proportion of risk factors including the highest proportion of diabetes in both time periods (4.6 and 6.5 %). Over time, late fetal death for AIANs decreased 17 % (aOR = 0.83, 95 % CI 0.72-0.97), but we noted a 47 % increased risk over time for Hispanics (aOR = 1.47, 95 % CI 1.40-1.55). Our data indicated no change over time among AIANs for first day death. For AIANs compared to whites, increased risks and disparities persisted for mortality due to congenital anomalies (ROR = 1.28, 95 % CI 1.03-1.60). For blacks compared to AIANs, the increased risks of fetal death (2005-2008: aOR = 0.60, 95 % CI 0.53-0.68) persisted. For Hispanics, lower risks compared to AIANs persisted, but protective effect declined over time. Disparities between AIAN and other groups persist, but there is variability by race/ethnicity in improvement of perinatal outcomes over time. Variability in access to care and pregnancy management should be considered in relation to health equity for fetal and early infant deaths.

Survey of developmental milestones in internal medicine among residents and faculty.

OBJECTIVES: The published Accreditation Council for Graduate Medical Education (ACGME) milestones represent a novel method of evaluation of trainees in graduate medical education. We surveyed agroup of teaching faculty and residents, regarding the new ACGME milestones project. We obtained their input on the expected timeline for the developmental milestones and compared their responses to the ACGME recommendations. METHODS: A 42-item survey questionnaire, derived from the original 142 item publication, was completed by 26 internal medicine teaching faculty and 34 internal medicine residents. RESULTS: We found statistically significant differences in the responses given by residents and faculty compared to those in the standard recommendations. The differences were more pronounced with the residents than with the faculty. CONCLUSIONS: The results of our survey showed significantly different responses as compared to the standard recommended timelines. Since this is a novel evaluation process, substantial faculty development and resident education regarding the process can help improve its implementation. Future studies should focus on how learners might better understand and refine the milestone evaluation process.

Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial.

BACKGROUNDCOVID-19 convalescent plasma (CCP) virus-specific antibody levels that translate into recipient posttransfusion antibody levels sufficient to prevent disease progression are not defined.METHODSThis secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double-blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low posttransfusion antibody levels was established by 2 methods: (i) analyzing virus neutralization-equivalent anti-Spike receptor-binding domain immunoglobulin G (anti-S-RBD IgG) responses in donors or (ii) receiver operating characteristic (ROC) curve analysis.RESULTSSARS-CoV-2 anti-S-RBD IgG antibody was volume diluted 21.3-fold into posttransfusion seronegative recipients from matched donor units. Virus-specific antibody delivered was approximately 1.2 mg. The high-antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP-recipient analysis for antibody thresholds correlated to reduced hospitalizations found a statistical significant association between early transfusion and high antibodies versus all other CCP recipients (or control plasma), with antibody cutoffs established by both methods-donor-based virus neutralization cutoffs in posttransfusion recipients (0/85 [0%] versus 15/276 [5.6%]; P = 0.03) or ROC-based cutoff (0/94 [0%] versus 15/267 [5.4%]; P = 0.01).CONCLUSIONIn unvaccinated, seronegative CCP recipients, early transfusion of plasma units in the upper 30% of study donors' antibody levels reduced outpatient hospitalizations. High antibody level plasma units, given early, should be reserved for therapeutic use.TRIAL REGISTRATIONClinicalTrials.gov NCT04373460.FUNDINGDepartment of Defense (W911QY2090012); Defense Health Agency; Bloomberg Philanthropies; the State of Maryland; NIH (3R01AI152078-01S1, U24TR001609-S3, 1K23HL151826NIH); the Mental Wellness Foundation; the Moriah Fund; Octapharma; the Healthnetwork Foundation; the Shear Family Foundation; the NorthShore Research Institute; and the Rice Foundation.

Dynamics of inflammatory responses after SARS-CoV-2 infection by vaccination status in the USA: a prospective cohort study.

BACKGROUND: Cytokines and chemokines play a critical role in the response to infection and vaccination. We aimed to assess the longitudinal association of COVID-19 vaccination with cytokine and chemokine concentrations and trajectories among people with SARS-CoV-2 infection. METHODS: In this longitudinal, prospective cohort study, blood samples were used from participants enrolled in a multi-centre randomised trial assessing the efficacy of convalescent plasma therapy for ambulatory COVID-19. The trial was conducted in 23 outpatient sites in the USA. In this study, participants (aged ≥18 years) were restricted to those with COVID-19 before vaccination or with breakthrough infections who had blood samples and symptom data collected at screening (pre-transfusion), day 14, and day 90 visits. Associations between COVID-19 vaccination status and concentrations of 21 cytokines and chemokines (measured using multiplexed sandwich immunoassays) were examined using multivariate linear mixed-effects regression models, adjusted for age, sex, BMI, hypertension, diabetes, trial group, and COVID-19 waves (pre-alpha or alpha and delta). FINDINGS: Between June 29, 2020, and Sept 30, 2021, 882 participants recently infected with SARS-CoV-2 were enrolled, of whom 506 (57%) were female and 376 (43%) were male. 688 (78%) of 882 participants were unvaccinated, 55 (6%) were partly vaccinated, and 139 (16%) were fully vaccinated at baseline. After adjusting for confounders, geometric mean concentrations of interleukin (IL)-2RA, IL-7, IL-8, IL-15, IL-29 (interferon-λ), inducible protein-10, monocyte chemoattractant protein-1, and tumour necrosis factor-α were significantly lower among the fully vaccinated group than in the unvaccinated group at screening. On day 90, fully vaccinated participants had approximately 20% lower geometric mean concentrations of IL-7, IL-8, and vascular endothelial growth factor-A than unvaccinated participants. Cytokine and chemokine concentrations decreased over time in the fully and partly vaccinated groups and unvaccinated group. Log10 cytokine and chemokine concentrations decreased faster among participants in the unvaccinated group than in other groups, but their geometric mean concentrations were generally higher than fully vaccinated participants at 90 days. Days since full vaccination and type of vaccine received were not correlated with cytokine and chemokine concentrations. INTERPRETATION: Initially and during recovery from symptomatic COVID-19, fully vaccinated participants had lower concentrations of inflammatory markers than unvaccinated participants suggesting vaccination is associated with short-term and long-term reduction in inflammation, which could in part explain the reduced disease severity and mortality in vaccinated individuals. FUNDING: US Department of Defense, National Institutes of Health, Bloomberg Philanthropies, State of Maryland, Mental Wellness Foundation, Moriah Fund, Octapharma, HealthNetwork Foundation, and the Shear Family Foundation.

Outpatient COVID-19 convalescent plasma recipient antibody thresholds correlated to reduced hospitalizations within a randomized trial.

BACKGROUND: The COVID-19 convalescent plasma (CCP) viral specific antibody levels that translate into recipient post-transfusion antibody levels sufficient to prevent disease progression is not defined. METHODS: This secondary analysis correlated donor and recipient antibody levels to hospitalization risk among unvaccinated, seronegative CCP recipients within the outpatient, double blind, randomized clinical trial that compared CCP to control plasma. The majority of COVID-19 CCP arm hospitalizations (15/17, 88%) occurred in this unvaccinated, seronegative subgroup. A functional cutoff to delineate recipient high versus low post-transfusion antibody levels was established by two methods: 1) analyzing virus neutralization-equivalent anti-S-RBD IgG responses in donors or 2) receiver operating characteristic (ROC) analysis. RESULTS: SARS-CoV-2 anti-S-RBD IgG antibody was diluted by a factor of 21.3 into post-transfusion seronegative recipients from matched donor units. Viral specific antibody delivered approximated 1.2 mg. The high antibody recipients transfused early (symptom onset within 5 days) had no hospitalizations. A CCP recipient analysis for antibody thresholds correlated to reduced hospitalizations found a significant association with Fisher's exact test between early and high antibodies versus all other CCP recipients (or control plasma) with antibody cutoffs established by both methods-donor virus neutralization-based cutoff: (0/85; 0% versus 15/276; 5.6%) p=0.03 or ROC based cutoff: (0/94; 0% versus 15/267; 5.4%) p=0.01. CONCLUSION: In unvaccinated, seronegative CCP recipients, early transfusion of plasma units corresponding to the upper 30% of all study donors reduced outpatient hospitalizations. These high antibody level plasma units, given early, should be reserved for therapeutic use.Trial registration: NCT04373460. FUNDING: Defense Health Agency and others.

Disparities in fetal death and first day death: the influence of risk factors in 2 time periods.

OBJECTIVES: We examined how changes in risk factors over time influence fetal, first day, and combined fetal-first day mortality and subsequent racial/ethnic disparities. METHODS: We selected deliveries to US resident non-Hispanic White and Black mothers from the linked live birth-infant death cohort and fetal deaths files (1995-1996; 2001-2002) and calculated changes over time of mortality rates, odds, and relative odds ratios (RORs) overall and among mothers with modifiable risk factors (smoking, diabetes, or hypertensive disorders). RESULTS: Adjusted odds ratios (AORs) for fetal mortality overall (AOR=0.99; 95% confidence interval [CI]=0.96, 1.01) and among Blacks (AOR=0.98; 95% CI=0.93, 1.03) indicated no change over time. Among women with modifiable risk factors, the RORs indicated no change in disparities. The ROR was not significant for fetal mortality (ROR=0.96; 95% CI=0.83, 1.01) among smokers, but there was evidence of some decline. There was evidence of increase in RORs in fetal death among mothers with diabetes and hypertensive disorders, but differences were not significant. CONCLUSIONS: Disparities in fetal, first day, and combined fetal-first day mortality have persisted and reflect discrepancies in care provision or other factors more challenging to measure.

Protein signatures from blood plasma and urine suggest changes in vascular function and IL-12 signaling in elderly with a history of chronic diseases compared with an age-matched healthy cohort.

Key processes characterizing human aging are immunosenescence and inflammaging. The capacity of the immune system to adequately respond to external perturbations (e.g., pathogens, injuries, and biochemical irritants) and to repair somatic mutations that may cause cancers or cellular senescence declines. An important goal remains to identify genetic or biochemical, predictive biomarkers for healthy aging. We recruited two cohorts in the age range 70 to 82, one afflicted by chronic illnesses (non-healthy aging, NHA) and the other in good health (healthy aging, HA). NHA criteria included major cardiovascular, neurodegenerative, and chronic pulmonary diseases, diabetes, and cancers. Quantitative analysis of forty proinflammatory cytokines in blood plasma and more than 500 proteins in urine was performed to identify candidate biomarkers for and biological pathway implications of healthy aging. Nine cytokines revealed lower quantities in blood plasma for the NHA compared with the HA groups (fold change > 1.5; p value < 0.025) including IL-12p40 and IL-12p70. We note that, sampling at two timepoints, intra-individual cytokine abundance patterns clustered in 86% of all 60 cases, indicative of person-specific, highly controlled multi-cytokine signatures in blood plasma. Twenty-three urinary proteins were differentially abundant (HA versus NHA; fold change > 1.5; p value < 0.01). Among the proteins increased in abundance in the HA cohort were glycoprotein MUC18, ephrin type-B receptor 4, matrix remodeling-associated protein 8, angiopoietin-related protein 2, K-cadherin, and plasma protease C1 inhibitor. These proteins have been linked to the extracellular matrix, cell adhesion, and vascular remodeling and repair processes. In silico network analysis identified the regulation of coagulation, antimicrobial humoral immune responses, and the IL-12 signaling pathway as enriched GO terms. To validate links of these preliminary biomarkers and IL-12 signaling with healthy aging, clinical studies using larger cohorts and functional characterization of the genes/proteins in cellular models of aging need to be conducted.

Randomized controlled trial transfusing convalescent plasma as post-exposure prophylaxis against SARS-CoV-2 infection.

BACKGROUND: The efficacy of SARS-CoV-2 convalescent plasma (CCP) for preventing infection in exposed, uninfected individuals is unknown. We hypothesized that CCP might prevent infection when administered before symptoms or laboratory evidence of infection. METHODS: This double-blinded, phase 2 randomized, controlled trial (RCT) compared the efficacy and safety of prophylactic high titer (≥1:320) CCP with standard plasma. Asymptomatic participants aged ≥18 years with close contact exposure to a person with confirmed COVID-19 in the previous 120 hours and negative SARS-CoV-2 test within 24 hours before transfusion were eligible. The primary outcome was development of SARS-CoV-2 infection. RESULTS: 180 participants were enrolled; 87 were assigned to CCP and 93 to control plasma, and 170 transfused at 19 sites across the United States from June 2020 to March 2021. Two were excluded for SARS-CoV-2 RT-PCR positivity at screening. Of the remaining 168 participants, 12/81 (14.8%) CCP and 13/87 (14.9%) control recipients developed SARS-CoV-2 infection; 6 (7.4%) CCP and 7 (8%) control recipients developed COVID-19 (infection with symptoms). There were no COVID-19-related hospitalizations in CCP and 2 in control recipients. There were 28 adverse events in CCP and 58 in control recipients. Efficacy by restricted mean infection free time (RMIFT) by 28 days for all SARS-CoV-2 infections (25.3 vs. 25.2 days; p=0.49) and COVID-19 (26.3 vs. 25.9 days; p=0.35) were similar for both groups. CONCLUSION: In this trial, which enrolled persons with recent exposure to a person with confirmed COVID-19, high titer CCP as post-exposure prophylaxis appeared safe, but did not prevent SARS-CoV-2 infection. TRIAL REGISTRATION: Clinicaltrial.gov number NCT04323800 .

Randomized Controlled Trial of Early Outpatient COVID-19 Treatment with High-Titer Convalescent Plasma.

BACKGROUND: The efficacy of polyclonal high titer convalescent plasma to prevent serious complications of COVID-19 in outpatients with recent onset of illness is uncertain. METHODS: This multicenter, double-blind randomized controlled trial compared the efficacy and safety of SARS-CoV-2 high titer convalescent plasma to placebo control plasma in symptomatic adults ≥18 years positive for SARS-CoV-2 regardless of risk factors for disease progression or vaccine status. Participants with symptom onset within 8 days were enrolled, then transfused within the subsequent day. The measured primary outcome was COVID-19-related hospitalization within 28 days of plasma transfusion. The enrollment period was June 3, 2020 to October 1, 2021. RESULTS: A total of 1225 participants were randomized and 1181 transfused. In the pre-specified modified intention-to-treat analysis that excluded those not transfused, the primary endpoint occurred in 37 of 589 (6.3%) who received placebo control plasma and in 17 of 592 (2.9%) participants who received convalescent plasma (relative risk, 0.46; one-sided 95% upper bound confidence interval 0.733; P=0.004) corresponding to a 54% risk reduction. Examination with a model adjusting for covariates related to the outcome did not change the conclusions. CONCLUSION: Early administration of high titer SARS-CoV-2 convalescent plasma reduced outpatient hospitalizations by more than 50%. High titer convalescent plasma is an effective early outpatient COVID-19 treatment with the advantages of low cost, wide availability, and rapid resilience to variant emergence from viral genetic drift in the face of a changing pandemic. Trial Registration: ClinicalTrials.gov number, NCT04373460.

Clinical Outcomes With the Use of Prophylactic Versus Therapeutic Anticoagulation in Coronavirus Disease 2019.

OBJECTIVES: To determine the impact of anticoagulation on inhospital mortality among coronavirus disease 2019-positive patients with the a priori hypothesis that there would be a lower risk of inhospital mortality with use of preemptive therapeutic over prophylactic dose enoxaparin or heparin. DESIGN SETTING: Retrospective cohort study from April 1, 2020, to April 25, 2020. The date of final follow-up was June 12, 2020 Two large, acute-care hospitals in Western Connecticut. PATIENTS: Five hundred and one inpatients were identified after discharge as 18 years or older and positive for severe acute respiratory syndrome coronavirus 2. The final sample size included 374 patients after applying exclusion criteria. Demographic variables were collected via hospital billing inquiries, whereas the clinical variables were abstracted from patients' medical records. EXPOSURE: Preemptive enoxaparin or heparin at a therapeutic or prophylactic dose. MAIN RESULTS: When comparing treatments through multivariable analysis, risk of inhospital mortality was 2.3 times greater in patients receiving preemptive therapeutic anticoagulation (95% CI = 1.0-4.9; p = 0.04). Additionally, the average treatment effects were higher (ß = 0.11, p = 0.01) in the therapeutic group. CONCLUSIONS: An increase in inhospital mortality was observed among patients on preemptive therapeutic anticoagulation. Thus, in the management of coronavirus disease 2019 and its complications, we recommend further research and cautious use of preemptive therapeutic over prophylactic anticoagulation.

Estimation of the contribution of non-assisted reproductive technology ovulation stimulation fertility treatments to US singleton and multiple births.

Infertility treatments that include ovulation stimulation, both assisted reproductive technologies (ARTs) and non-ART ovulation stimulation, are associated with increased risks of multiple birth and concomitant sequelae and adverse outcomes, even among singletons. While a US surveillance system for ART-induced births is ongoing, no population-based tracking system exists for births resulting from non-ART treatments. The authors developed a multistage model to estimate the uncertain proportion of US infants born in 2005 who were conceived by using non-ART ovulation treatments. Using published surveillance data, they estimated proportions of US multiple births conceived naturally and by ART and assumed that the remainder were conceived with non-ART treatments. They used Bayesian meta-analyses to summarize published clinical studies on the multiple-gestation risk associated with non-ART ovulation treatments, applied a fetal survival factor, and used this multiple-birth risk estimate and their own estimate of the proportion of US multiple births attributable to non-ART ovulation stimulation to estimate the total (and, through subtraction, singleton) proportion of infants conceived with such treatments. On the basis of the model, the authors estimate that 4.6% of US infants born in 2005 (95% uncertainty range: 2.8%-7.1%) resulted from non-ART ovulation treatments. Notably, this figure is 4 times greater than the ART contribution.

Increased risk of adverse neurological development for late preterm infants.

OBJECTIVE: To assess the risks of moderate prematurity for cerebral palsy (CP), developmental delay/mental retardation (DD/MR), and seizure disorders in early childhood. STUDY DESIGN: Retrospective cohort study using hospitalization and outpatient databases from the Northern California Kaiser Permanente Medical Care Program. Data covered 141 321 children > or =30 weeks born between Jan 1, 2000, and June 30, 2004, with follow-up through June 30, 2005. Presence of CP, DD/MR, and seizures was based on International Classification of Diseases, Ninth Revision codes identified in the encounter data. Separate Cox proportional hazard models were used for each of the outcomes, with crude and adjusted hazard ratios calculated for each gestational age group. RESULTS: Decreasing gestational age was associated with increased incidence of CP and DD/MR, even for those born at 34 to 36 weeks gestation. Children born late preterm were >3 times as likely (hazard ratio, 3.39; 95% CI, 2.54-4.52) as children born at term to be diagnosed with CP. A modest association with DD/MR was found for children born at 34 to 36 weeks (hazard ratio, 1.25; 95% CI, 1.01-1.54), but not for children in whom seizures were diagnosed. CONCLUSIONS: Prematurity is associated with long-term neurodevelopmental consequences, with risks increasing as gestation decreases, even in infants born at 34 to 36 weeks.