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Background: It remains debated whether to include resting electrocardiogram (ECG) in the routine care of human immunodeficiency virus (HIV)-infected patients.Methods: This analysis included 4518 HIV-infected patients (28% women and 29% blacks) from the Strategies for Management of Antiretroviral Therapy study, a clinical trial aimed to compare 2 HIV treatment strategies. ECG abnormalities were classified using the Minnesota Code. Cox proportional hazards analysis was used to examine the association between baseline ECG abnormalities and incident cardiovascular disease (CVD).Results: More than half of the participants (n = 2325, or 51.5%) had either minor or major ECG abnormalities. Minor ECG abnormalities (48.6%) were more common than major ECG abnormalities (7.7%). During a median follow-up of 28.7 months, 155 participants (3.4%) developed incident CVD. After adjusting for the study-treatment arms, the presence of major, minor, and either minor or major ECG abnormalities was significantly predictive of incident CVD (hazard ratio [95% confidence interval]: 2.76 [1.74-4.39], P < .001; 1.58 [1.14-2.20], P = .006; 1.57 [1.14-2.18], P = .006, respectively). However, after adjusting for demographics, CVD risk factors, and HIV characteristics (full model), presence of major ECG abnormalities were still significantly predictive of CVD (1.83 [1.12-2.97], P = .015) but not minor or major abnormalities taken together (1.26 [0.89-1.79], P = .18; 1.25 [0.89-1.76], P = .20, respectively). Individual ECG abnormalities that significantly predicted CVD in the fully adjusted model included major isolated ST-T abnormalities, major prolongation of QT interval, minor isolated ST-T, and minor isolated Q-QS abnormalities.Conclusion: Nearly 1 in 2 of the HIV-infected patients in our study had ECG abnormalities; 1 in 13 had major ECG abnormalities. Presence of ECG abnormalities, especially major ECG abnormalities, was independently predictive of incident CVD. These results suggest that the ECG could provide a convenient risk-screening tool in HIV-infected patients. [ABSTRACT FROM AUTHOR]

A few epidemiologic studies have shown an increased risk of death from external causes among men with hypertension. Previous studies were limited by small numbers of events, however, and none assessed the association of blood pressure with specific types of 'accidental' death. The authors examined data obtained from baseline interviews and 25 years of mortality follow-up (1973-1999) for 347,978 men screened for the US Multiple Risk Factor Intervention Trial. Proportional hazards regression analyses were used to quantify associations of blood pressure with all external causes of death and individual causes. There were 3,910 deaths from external causes, including 2,313 unintentional injuries, 1,248 suicides, and 349 homicides. Compared with those for men whose blood pressure status was 'normal' according to the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the multivariate-adjusted hazard ratios and 95% confidence intervals for death from external causes among men with prehypertension, stage 1 hypertension, and stage 2 hypertension were 0.91 (95% confidence interval (CI): 0.83, 1.00), 1.06 (95% CI: 0.96, 1.16), and 1.44 (95% CI: 1.28, 1.62), respectively. Men with stage 2 hypertension had multivariate-adjusted hazard ratios of 1.90 for falls (95% CI: 1.32, 2.74), 1.45 for motor vehicle injuries (95% CI: 1.14, 1.85), 1.33 for other 'accidents' (95% CI: 1.06, 1.66), 1.40 for suicide (95% CI: 1.13, 1.73), and 1.35 for homicide (95% CI: 0.92, 1.97). For men, hypertension may signal an increased risk of death from external causes. [ABSTRACT FROM AUTHOR]

Objective: To examine the long-term association of metabolic syndrome with mortality among those at high risk for cardiovascular disease (CVD).Research Design and Methods: A total of 10,950 Multiple Risk Factor Intervention Trial (MRFIT) survivors were followed for mortality an additional median 18.4 years (1980-1999). Proportional hazards models examined multivariate-adjusted risks associated with Adult Treatment Panel III-defined metabolic syndrome conditions, with BMI substituted for waist circumference.Results: At MRFIT annual visit 6, 4,588 (41.9%) men, mean age (+/-SD) 53.0 +/- 5.9 years, had metabolic syndrome and 6,362 did not. Comparing men with metabolic syndrome to men without, adjusted hazard ratios (HRs) were 1.21 (95% CI 1.13-1.29), 1.49 (1.35-1.64), and 1.51 (1.34-1.70) for 18-year total, CVD, and coronary heart disease mortality, respectively. Among men with metabolic syndrome, elevated glucose (1.54 [1.34-1.78]) and low HDL cholesterol (1.45 [1.17-1.54]) were most predictive of CVD mortality, followed by elevated BMI (1.34 [1.17-1.54]), elevated blood pressure (1.25 [0.98-1.58]), and elevated triglycerides (1.06 [0.86-1.30]). In contrast, for men without metabolic syndrome, the HR for low HDL cholesterol was 1.02 (0.86-1.22). Among metabolic syndrome men with no nonfatal CVD event, smokers with elevated LDL cholesterol showed higher CVD mortality (1.79 [1.22-2.63]) compared with nonsmokers without elevated LDL cholesterol; this additional risk was even greater for metabolic syndrome men with a nonfatal CVD event (2.11 [1.32-3.38]).Conclusions: Metabolic syndrome is associated with an increased risk of mortality. Among those with metabolic syndrome, risk is further increased by having more metabolic syndrome conditions, by cigarette smoking, and by elevated LDL cholesterol. Primary prevention of each metabolic syndrome condition should be emphasized, and presence of each condition should be treated in accordance with current guidelines. [ABSTRACT FROM AUTHOR]

The relationship between 12-month CD4(+) cell count response and clinical outcome (AIDS-defining event or death) in a subset of 228 patients with a human immunodeficiency virus load >400 copies/mL despite receiving combination antiretroviral therapy as part of a larger randomized trial was defined by use of Cox models. The 12-month CD4(+) cell count responses were divided into 5 categories, ranging from decrease or no change (29% of patients) to a > or =100-cell/mm(3) increase (27% of patients). There was a lower risk of clinical progression for each incremental increase in CD4(+) cell count response. A 25-cell/mm(3) increase in CD4(+) cell count was associated with a 21% reduction in the risk of an AIDS-defining event or death (P<.0001). Copyright © 2005 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Background: Weight loss and increased physical exercise reduce the risk for diabetes in people with impaired glucose tolerance. Randomized trial evidence on the effect of these interventions on people without impaired glucose tolerance is lacking.Objective: To examine the influence of a comprehensive intervention program on the risk for developing diabetes in men without impaired glucose tolerance and in a post hoc subgroup analysis by baseline cigarette smoking status.Design: Randomized, controlled trial.Setting: 22 clinical centers for the Multiple Risk Factor Intervention Trial (MRFIT).Participants: 12,866 men age 35 to 57 years at risk for cardiovascular disease were randomly assigned to either a special intervention or usual care group and followed for 6 to 7 years; this report focuses on 11,827 men without diabetes or impaired glucose tolerance at entry for whom follow-up glucose measurements were available.Measurements: Cardiovascular disease risk factors, fasting blood glucose levels, and diabetes medication history were assessed before randomization and annually.Intervention: Men in the special intervention group were counseled to change diet (reduce saturated fat, cholesterol, and calorie intake), to stop smoking, and to increase physical activity. Blood pressure was treated more intensively in the special intervention group than in the usual care group.Results: 11.5% of the special intervention group and 10.8% of the usual care group developed diabetes over 6 years of follow-up (hazard ratio, 1.08 [95% CI, 0.96 to 1.20]). The special intervention-usual care hazard ratio for diabetes was 1.26 (CI, 1.10 to 1.45) among smokers (63%) and 0.82 (CI, 0.68 to 0.98) among nonsmokers (37%). These estimates differed significantly (P = 0.0003). Weight gain after smoking cessation and the use of antihypertensive drugs may have counterbalanced the beneficial effect of the lifestyle intervention for the special intervention group smokers, while the lifestyle intervention was beneficial among nonsmokers.Limitations: Principal findings are based on a post hoc subgroup analysis.Conclusions: In nonsmokers, an intervention program that included nutrition counseling to produce reductions in weight, serum cholesterol, and (along with antihypertensive medication) blood pressure reduced the risk for diabetes. [ABSTRACT FROM AUTHOR]

Context: The sixth Joint National Committee (JNC-VI) classification system of blood pressure emphasizes both systolic blood pressure (SBP) and diastolic blood pressure (DBP) for cardiovascular disease risk assessment. Pulse pressure may also be a valuable risk assessment tool.Objective: To compare relationships of SBP, DBP, and pulse pressure, separately and jointly, with cardiovascular disease-related mortality in men.Design and Setting: Data from the Multiple Risk Factor Intervention Trial (MRFIT), which screened men aged 35 to 57 years from 1973 through 1975 at 22 US centers, was used to assess cardiovascular disease-related mortality through 1996.Participants: A total of 342 815 men without diabetes or a history of myocardial infarction were divided into 2 groups based on their age at MRFIT screening (35- to 44-year-olds and 45- to 57-year olds). Participant blood pressure levels were classified into a JNC-VI blood pressure category based on SBP and DBP (optimal, normal but not optimal, high normal, stage 1 hypertension, stage 2-3 hypertension), and pulse pressure was calculated.Main Outcome Measure: Cardiovascular disease-related mortality.Results: There were 25 721 cardiovascular disease-related deaths. Levels of SBP and DBP were more strongly related to cardiovascular disease than pulse pressure. Relationships of SBP, DBP, and pulse pressure to cardiovascular disease-related mortality varied within JNC-VI category. Concordant elevations of SBP and DBP were associated with a greater risk of cardiovascular disease-related mortality for both age groups of men. Among men aged 45 to 57 years, higher SBP and lower DBP (discordant elevations) also yielded a greater risk of cardiovascular disease-related mortality.Conclusion: In both age groups, cardiovascular disease risk assessment was improved by considering both SBP and DBP, not just SBP, DBP, or pulse pressure separately. [ABSTRACT FROM AUTHOR]

Background: Studies of underlying differences in adult mortality between black and white individuals in the USA have been constrained by limitations of data or small study size. We investigated the extent to which differences in socioeconomic position between black and white men contribute to differences in all-cause and cause-specific mortality.Methods: 361,662 men were screened for the Multiple Risk Factor Intervention Trial between 1973 and 1975, in 22 sites. Median family income of households by zipcode (postal) area of residence was available for 20,224 black and 300,685 white men as well as data on age, cigarette smoking, blood pressure, serum cholesterol, previous heart attack, and treatment for diabetes. We classified deaths during 16 years of follow-up into specific causes and compared differences in death rates between black men and white men, before and after adjustment for differences in income and other risk factors.Findings: Age-adjusted relative risk of death (black vs white) was 1.47 (95% CI 1.42-1.53). Adjustment for diastolic blood pressure, serum cholesterol, cigarette smoking, medication for diabetes, and previous admission to hospital for heart attack decreased the relative risk to 1.40 (1.35-1.46). Adjustment for income but not the other risk factors decreased the risk to 1.19 (1.14-1.24) and adjustment for other risk factors did not alter this estimate. For cardiovascular death, relative risk on adjustment for income was decreased from 1.36 to 1.09; for cancer from 1.47 to 1.25; and for non-cardiovascular and non-cancer deaths from 1.71 to 1.26. For some specific causes of death, including prostate cancer, myeloma, and hypertensive heart disease, the higher death rates among black men did not seem to reflect differences in income. Rates of death for suicide and melanoma were lower among black than white men, as were those for coronary heart disease after adjustment for income.Interpretation: Socioeconomic position is the major contributor to differences in death rates between black and white men. Differentials in mortality from some specific causes do not simply reflect differences in income, however, and more detailed investigations are needed of how differences are influenced by environmental exposures, lifetime socioeconomic conditions, lifestyle, racism, and other sociocultural and biological factors. [ABSTRACT FROM AUTHOR]

Objective: - To compare long-term plasma lipid changes among 6 antihypertensive treatment interventions for stage I (mild) hypertension.Design: - Multicenter, randomized, double-blind, parallel-group clinical trial.Setting: - Four academic clinical research units in the United States.Participants: - A total of 902 men and women, aged 45 to 69 years, with stage I diastolic hypertension (diastolic blood pressure <100 mm Hg), recruited from 11914 persons screened in their communities.Interventions: - Participants were randomized to 1 of 6 treatment groups: (1) placebo, (2) beta-blocker (acebutolol), (3) calcium antagonist (amlodipine), (4) diuretic (chlorthalidone), (5) alpha1-antagonist (doxazosin), and (6) angiotensin-converting enzyme inhibitor (enalapril). All groups received intensive lifestyle counseling to achieve weight loss, dietary sodium and alcohol reduction, and increased physical activity.Main Outcome Measures: - Changes in plasma total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides from baseline to annual visits through 4 years.Results: - Mean changes in all plasma lipids were favorable in all groups. The degree of weight loss with fat-modified diet and exercise was significantly related to favorable lipid changes. Significant differences (P<.01) among groups for average changes during follow-up in each lipid were observed. Decreases in plasma total cholesterol and LDL cholesterol were greater with doxazosin and acebutolol (for plasma total cholesterol, 0.36 and 0.30 mmol/L [13.8 and 11.7 mg/dL], respectively), less with chlorthalidone and placebo (0.12 and 0.13 mmol/L [4.5 and 5.1 mg/dL], respectively). Decreases in triglycerides were greater with doxazosin and enalapril, least with acebutolol. Increases in HDL cholesterol were greater with enalapril and doxazosin, least with acebutolol. Significant relative increases in plasma total cholesterol with chlorthalidone compared with placebo at 12 months were no longer present at 24 months and beyond, when mean plasma total cholesterol for the chlorthalidone group fell below baseline. Analyses of participants continuing to receive chlorthalidone throughout the 4 years of follow-up indicated this was not due solely to an increasing percentage of participants changing or discontinuing use of medication during follow-up.Conclusions: - Weight loss with a fat-modified diet plus increased exercise produces favorable long-term effects on blood pressure and all plasma lipid fractions of adults with stage I hypertension; blood pressure reduction is enhanced to a similar degree by addition of a drug from any one of 5 classes of antihypertensive medication. These drugs differ quantitatively in influencing the degree of long-term favorable effects on blood lipids obtained with nutritional-hygienic treatment. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis," by F. M. Islam and colleagues in the September 2012 issue.

Background: In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]).We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis.Methods and Findings: Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p < 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively.Conclusions: IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation. [ABSTRACT FROM AUTHOR]

Background: Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV).Methods: We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease.Results: A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1).Conclusions: Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy. (ClinicalTrials.gov number, NCT00027352 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Background: There is a clinical need for therapeutics for COVID-19 patients with acute hypoxemic respiratory failure whose 60-day mortality remains at 30-50%. Aviptadil, a lung-protective neuropeptide, and remdesivir, a nucleotide prodrug of an adenosine analog, were compared with placebo among patients with COVID-19 acute hypoxaemic respiratory failure., Methods: TESICO was a randomised trial of aviptadil and remdesivir versus placebo at 28 sites in the USA. Hospitalised adult patients were eligible for the study if they had acute hypoxaemic respiratory failure due to confirmed SARS-CoV-2 infection and were within 4 days of the onset of respiratory failure. Participants could be randomly assigned to both study treatments in a 2 × 2 factorial design or to just one of the agents. Participants were randomly assigned with a web-based application. For each site, randomisation was stratified by disease severity (high-flow nasal oxygen or non-invasive ventilation vs invasive mechanical ventilation or extracorporeal membrane oxygenation [ECMO]), and four strata were defined by remdesivir and aviptadil eligibility, as follows: (1) eligible for randomisation to aviptadil and remdesivir in the 2 × 2 factorial design; participants were equally randomly assigned (1:1:1:1) to intravenous aviptadil plus remdesivir, aviptadil plus remdesivir matched placebo, aviptadil matched placebo plus remdesvir, or aviptadil placebo plus remdesivir placebo; (2) eligible for randomisation to aviptadil only because remdesivir was started before randomisation; (3) eligible for randomisation to aviptadil only because remdesivir was contraindicated; and (4) eligible for randomisation to remdesivir only because aviptadil was contraindicated. For participants in strata 2-4, randomisation was 1:1 to the active agent or matched placebo. Aviptadil was administered as a daily 12-h infusion for 3 days, targeting 600 pmol/kg on infusion day 1, 1200 pmol/kg on day 2, and 1800 pmol/kg on day 3. Remdesivir was administered as a 200 mg loading dose, followed by 100 mg daily maintenance doses for up to a 10-day total course. For participants assigned to placebo for either agent, matched saline placebo was administered in identical volumes. For both treatment comparisons, the primary outcome, assessed at day 90, was a six-category ordinal outcome: (1) at home (defined as the type of residence before hospitalisation) and off oxygen (recovered) for at least 77 days, (2) at home and off oxygen for 49-76 days, (3) at home and off oxygen for 1-48 days, (4) not hospitalised but either on supplemental oxygen or not at home, (5) hospitalised or in hospice care, or (6) dead. Mortality up to day 90 was a key secondary outcome. The independent data and safety monitoring board recommended stopping the aviptadil trial on May 25, 2022, for futility. On June 9, 2022, the sponsor stopped the trial of remdesivir due to slow enrolment. The trial is registered with ClinicalTrials.gov, NCT04843761., Findings: Between April 21, 2021, and May 24, 2022, we enrolled 473 participants in the study. For the aviptadil comparison, 471 participants were randomly assigned to aviptadil or matched placebo. The modified intention-to-treat population comprised 461 participants who received at least a partial infusion of aviptadil (231 participants) or aviptadil matched placebo (230 participants). For the remdesivir comparison, 87 participants were randomly assigned to remdesivir or matched placebo and all received some infusion of remdesivir (44 participants) or remdesivir matched placebo (43 participants). 85 participants were included in the modified intention-to-treat analyses for both agents (ie, those enrolled in the 2 x 2 factorial). For the aviptadil versus placebo comparison, the median age was 57 years (IQR 46-66), 178 (39%) of 461 participants were female, and 246 (53%) were Black, Hispanic, Asian or other (vs 215 [47%] White participants). 431 (94%) of 461 participants were in an intensive care unit at baseline, with 271 (59%) receiving high-flow nasal oxygen or non-invasive ventiliation, 185 (40%) receiving invasive mechanical ventilation, and five (1%) receiving ECMO. The odds ratio (OR) for being in a better category of the primary efficacy endpoint for aviptadil versus placebo at day 90, from a model stratified by baseline disease severity, was 1·11 (95% CI 0·80-1·55; p=0·54). Up to day 90, 86 participants in the aviptadil group and 83 in the placebo group died. The cumulative percentage who died up to day 90 was 38% in the aviptadil group and 36% in the placebo group (hazard ratio 1·04, 95% CI 0·77-1·41; p=0·78). The primary safety outcome of death, serious adverse events, organ failure, serious infection, or grade 3 or 4 adverse events up to day 5 occurred in 146 (63%) of 231 patients in the aviptadil group compared with 129 (56%) of 230 participants in the placebo group (OR 1·40, 95% CI 0·94-2·08; p=0·10)., Interpretation: Among patients with COVID-19-associated acute hypoxaemic respiratory failure, aviptadil did not significantly improve clinical outcomes up to day 90 when compared with placebo. The smaller than planned sample size for the remdesivir trial did not permit definitive conclusions regarding safety or efficacy., Funding: National Institutes of Health., Competing Interests: Declaration of interests SMB reports funding from the National Institutes of Health during the conduct of the study and chairing a Data and Safety Monitoring Board (DSMB) for Hamilton Ventilators, outside of the study. CEB reports funding from the National Institutes of Health (NIH) for the Aviptadil study, during the conduct of the study. BG reports grants from the NIH, during the conduct of the study. SS reports a grant from the NIH, during the conduct of the study. ANP reports grants from the Wellcome Trust, the National Institute for Health and Care Research, UK Research and Innovation (UKRI), and the Bill & Melinda Gates Foundation, and consulting fees from the Bill & Melinda Gates Foundation, outside of the submitted work. IDP reports funding from NIH and the National Institute of General Medical Sciences, during the conduct of the study, a grant from Janssen for a study of influenza patient reported outcomes, and a contract with Regeneron for a COVID-19 therapy trial, outside of the submitted work. JRB reports a grant from the NIH, during the conduct of the study, grants from the NIH, Quantum Leap Healthcare Collaborative, and Sedana Medical, consulting fees from Sedana Medical, Biomarck, and Global Blood Therapeutics, and compensation from Hamilton Medical for participation as a medical monitor, outside of the submitted work. ESHa reports study materials from NeuroRx and Gilead through a National Heart, Lung, and Blood Institute (NHLBI) subcontract, during the conduct of the study, subcontracts with Bristol Meyers Squibb (BMS), Allergan, Gilead, and Janssen for the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-1) clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the Therapeutics for Inpatients with COVID-19 (TICO) clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the Novel Experimental COVID-19 Therapies Affecting Host Response (NECTAR) clinical trial, outside of the submitted work. EAM reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and additional subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. MAGB reports study materials from NeuroRx and Gilead through an NHLBI subcontract, during the conduct of the study, subcontracts with BMS, Allergan, Gilead, and Janssen for the ACTIV-1 clinical trial, subcontracts with AstraZeneca, Brii Biosciences, Vir Biotechnology, and Eli Lilly for the TICO clinical trial, and subcontracts with Rigel, APEIRON Biologics, and Trevena for the NECTAR clinical trial, outside of the submitted work. KSM reports grants and contracts from NIH, NHLBI, and the Society for Critical Care Medicine, participation as a steering committee member for Roivant-Kinevant Sciences, and employment as a clinical research physician at Chiesi USA, outside of submitted work. JM reports receiving study materials and funding from the Albert Einstein College of Medicine for the study protocol, during the conduct of the study. CH reports funding from the National Institute of Allergy and Infectious Diseases (NIAID) in the form of per-patient payments for A Multicenter, Adaptive, Randomized, Blinded Controlled Trial of the Safety and Efficacy of Investigational Therapeutics for Hospitalized Patients with Acute Respiratory Distress Syndrome Associated with COVID-19, during the conduct of the study. AK reports grants from Eli Lilly, AstraZeneca, 4D Medical, United Therapeutics, Regeneron Pharmaceuticals, and Dompe Pharmaceuticals and consulting fees from Dompe Pharmaceuticals for clinical trial design, outside of the submitted work. AD reports grants from NHLBI Prevention and Early Treatment of Acute Lung Injury network and the US Centers for Disease Control and Prevention (CDC) and data safety monitoring board (DSMB) or advisory board participation for Alung Technologies, outside of the submitted work. SD reports a grant from Chest Sonosite Ultrasound to study the incidence of deep vein thrombosis in patients with COVID-19, during the conduct of the study. AJG reports payment from Sound Pharmaceuticals for participation as a medical monitor for a COVID therapeutic trial, outside of the submitted work. USS reports consulting fees from Shionogi, Paratek, and ViiV Healthcare for participation on advisory boards and speaking fees from Shionogi and Paratek, outside of the submitted work. NJJ reports grants from the CDC, the US Department of Defense (DOD), and NIH and participation on a DSMB for the Legacy Health System, outside of the submitted work. MAM reports grants from NIH and NIAID, during the conduct of the study. NRA reports funding from NIH, during the conduct of the study. JDC reports grants from NIH and DOD, outside of the submitted work. DDM reports funding from the Danish National Research Foundation (DNRF126), during the conduct of study. AAG reports funding from NIH, during the conduct of the study, grants or contracts from NIH, DOD, CDC, Faron Pharmaceuticals, and Abbvie, and participation on a DSMB or advisory board for NIH, outside of the submitted work. WHS reports funding from NIH and NIAID, during the conduct of the study. CFO reports contracts with NIH and NHLBI, outside of the submitted work. BTT reports a grant from NHLBI, consulting fees from Bayer, Genetec, and Novartis, and participation on a DSMB or advisory board for Aperion, outside of the submitted work. During a portion of this research, BTT had a financial interest in Direct Biologics, a developer and manufacturer of regenerative biologic products, including an investigational treatment of COVID-19-associated ARDS. BTT's interests were reviewed and are managed by Massachusetts General Hospital and Mass General Brigham in accordance with their conflict of interest policies, and had no relationship to the agents studied. VK reports subcontracts with University of Minnesota, NIAID, and NIH for the TICO and Therapeutics for Severely Ill Inpatients with COVID-19 platform trials, outside of the submitted work. AGB reports a grant from University of Minnesota, during the conduct of the study, grants from the Medical Reserve Corps and UKRI, payment from NIAID for participation on a COVID-19 Vaccines DSMB, and participation on the WHO Trial Data and Safety Monitoring Committee, outside of the submitted work. JDN reports grants from NIAID, NIH, and Leidos Biomedical, outside of the submitted work. HCL reports employment from NIAID, during the conduct of the study. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

BACKGROUNDAntibody-based therapies for respiratory viruses are of increasing importance. The INSIGHT 006 trial administered anti-influenza hyperimmune intravenous immunoglobulin (Flu-IVIG) to patients hospitalized with influenza. Flu-IVIG treatment improved outcomes in patients with influenza B but showed no benefit for influenza A.METHODSTo probe potential mechanisms of Flu-IVIG utility, sera collected from patients hospitalized with influenza A or B viruses (IAV or IBV) were analyzed for antibody isotype/subclass and Fcγ receptor (FcγR) binding by ELISA, bead-based multiplex, and NK cell activation assays.RESULTSInfluenza-specific FcγR-binding antibodies were elevated in Flu-IVIG-infused IBV- and IAV-infected patients. In IBV-infected participants (n = 62), increased IgG3 and FcγR binding were associated with more favorable outcomes. Flu-IVIG therapy also improved the odds of a more favorable outcome in patients with low levels of anti-IBV Fc-functional antibody. Higher FcγR-binding antibody was associated with less favorable outcomes in IAV-infected patients (n = 50), and Flu-IVIG worsened the odds of a favorable outcome in participants with low levels of anti-IAV Fc-functional antibody.CONCLUSIONThese detailed serological analyses provide insights into antibody features and mechanisms required for a successful humoral response against influenza, suggesting that IBV-specific, but not IAV-specific, antibodies with Fc-mediated functions may assist in improving influenza outcome. This work will inform development of improved influenza immunotherapies.TRIAL REGISTRATIONClinicalTrials.gov NCT02287467.FUNDINGFunding for this research was provided by subcontract 13XS134 under Leidos Biomedical Research Prime Contract HHSN261200800001E and HHSN261201500003I, NCI/NIAID.

Background Cardiovascular disease risk prediction models underestimate CVD risk in people living with HIV (PLWH). Our goal is to derive a risk score based on protein biomarkers that could be used to predict CVD in PLWH. Methods and Results In a matched case-control study, we analyzed normalized protein expression data for participants enrolled in 1 of 4 trials conducted by INSIGHT (International Network for Strategic Initiatives in Global HIV Trials). We used dimension reduction, variable selection and resampling methods, and multivariable conditional logistic regression models to determine candidate protein biomarkers and to generate a protein score for predicting CVD in PLWH. We internally validated our findings using bootstrap. A protein score that was derived from 8 proteins (including HGF [hepatocyte growth factor] and interleukin-6) was found to be associated with an increased risk of CVD after adjustment for CVD and HIV factors (odds ratio: 2.17 [95% CI: 1.58-2.99]). The protein score improved CVD prediction when compared with predicting CVD risk using the individual proteins that comprised the protein score. Individuals with a protein score above the median score were 3.10 (95% CI, 1.83-5.41) times more likely to develop CVD than those with a protein score below the median score. Conclusions A panel of blood biomarkers may help identify PLWH at a high risk for developing CVD. If validated, such a score could be used in conjunction with established factors to identify CVD at-risk individuals who might benefit from aggressive risk reduction, ultimately shedding light on CVD pathogenesis in PLWH.

Background: Minimal data exist on pregnancy following recovery from Ebola in people of child-bearing potential (females aged roughly 18-45 years). The aim of this study was to assess viral persistence or reactivation in pregnancy, the frequency of placental transfer of anti-Ebola IgG antibodies, and pregnancy outcomes in this population., Methods: In this observational cohort study, we studied self-reported pregnancies in two groups: seropositive people who had recovered from Ebola virus disease (seropositive group) and seronegative people who had close contact with people with Ebola (seronegative group). Participants had enrolled in the PREVAIL III longitudinal study and were exposed during the 2014-2016 Liberian Ebola outbreak. The primary outcome was pregnancy result. We assessed rates of livebirths and other pregnancy results in both study groups, and presence of Ebola RNA by PCR in samples of placenta, maternal and cord blood, breastmilk, and vaginal secretions from people who had recovered from Ebola who conceived a median of 14 months after acute Ebola virus disease. Mixed-model logistic regression evaluated associations between first-reported pregnancy outcome, age, and study group. Growth and neurodevelopment in the infants born to people in the seropositive group were assessed at 6-month intervals for 2 years. Data were accrued by PREVAIL III study staff., Findings: 1566 participants were enrolled between June 17, 2015, and Dec 14, 2017, of whom 639 became pregnant (215 seropositive, 424 seronegative) and 589 reported pregnancy outcomes (206 seropositive, 383 seronegative). 105 infants born to 98 mothers in the seropositive group were enrolled in the birth cohort. Ebola RNA was not detected in 205 samples of placenta, cord blood, or maternal blood taken at birth from 54 mothers in the seropositive group, nor in 367 vaginal swabs. Viral RNA was found in two of 354 longitudinal breastmilk samples. All but one of 57 infants born during these 54 births were seropositive for anti-Ebola antibodies. Neonates showed high concentrations of anti-Ebola IgG, which declined after 6 months. Odds of adverse pregnancy outcome among the two groups were indistinguishable (OR 1·13, 95% CI 0·71-1·79). Compared with WHO standards, infants born to those in the seropositive group had lower median weight and length, and larger median head circumference over 2 years. Compared with a cohort from the USA accrual of gross motor developmental milestones was similar, whereas attainment of pincer grasp and early vocalisation were mildly delayed., Interpretation: The risks of Ebola virus reactivation in the peripartum and postpartum period and of adverse birth outcomes are low in those who have recovered from Ebola virus disease and become pregnant approximately 1 year after acute Ebola virus disease. The implication for clinical practice is that care of people who are pregnant and who have recovered from Ebola can be offered without risks to health-care providers or stigmatisation of the mothers and their offspring. The implication for prospective mothers is that safe pregnancies are entirely possible after recovery from Ebola., Funding: National Institute of Allergy and Infectious Diseases and Liberia Ministry of Health., Competing Interests: Declaration of interests SGK reports support from the National Institute of Allergy and Infectious Diseases for travel to Liberia, to serve as site physician between May and June, 2015, and to attend the annual meeting in March, 2016. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Seasonal influenza vaccination rates remain low, and contribute to preventable influenza cases, hospitalizations, and deaths in the US. While numerous interventions have been implemented to increase vaccine uptake, there is a need to determine which interventions contribute most to vaccine willingness, particularly among age groups with vaccination rates that have plateaued at suboptimal levels. This study aimed to quantify the relative effect of multiple interventions on vaccine willingness to receive influenza vaccine in three age groups using a series of hypothetical situations with different behavioral interventions. We assessed the relative impact of four categories of interventions: source of vaccine messages, type of vaccination messages, vaccination incentives, and ease of vaccine access using a discrete choice experiment. Within each category, we investigated the role of four different attributes to measure their relative contribution to willingness to be vaccinated by removing one option from each of the intervention categories. Among the 1,763 Minnesota residents who volunteered for our study, participants expressed vaccine willingness in over 80% of the scenarios presented. Easy access to drop-in vaccination sites had the greatest impact on vaccine willingness in all age groups. Among the younger age group, small financial incentives also contributed to high vaccine willingness. Our results suggest that public health programs and vaccination campaigns may improve their chances of successfully increasing vaccine willingness if they offer interventions preferred by adults, including facilitating convenient access to vaccination and offering small monetary incentives, particularly for young adults., Competing Interests: The authors declare that the funders had no role in the role in the design of the study or in the analysis and interpretation of data., (© 2023 The Authors.)

Background: For people with HIV and CD4 + counts >500 cells/mm 3 , early initiation of antiretroviral therapy (ART) reduces serious AIDS and serious non-AIDS (SNA) risk compared with deferral of treatment until CD4 + counts are <350 cells/mm 3 . Whether excess risk of AIDS and SNA persists once ART is initiated for those who defer treatment is uncertain., Methods: The Strategic Timing of AntiRetroviral Treatment (START) trial, as previously reported, randomly assigned 4684 ART-naive HIV-positive adults with CD4 + counts .500 cells/mm 3 to immediate treatment initiation after random assignment (n = 2325) or deferred treatment (n= 2359). In 2015, a 57% lower risk of the primary end point (AIDS, SNA, or death) for the immediate group was reported, and the deferred group was offered ART. This article reports the follow-up that continued to December 31, 2021. Cox proportional-hazards models were used to compare hazard ratios for the primary end point from randomization through December 31, 2015, versus January 1, 2016, through December 31, 2021., Results: Through December 31, 2015, approximately 7 months after the cutoff date from the previous report, the median CD4 + count was 648 and 460 cells/mm 3 in the immediate and deferred groups, respectively, at treatment initiation. The percentage of follow-up time spent taking ART was 95% and 36% for the immediate and deferred groups, respectively, and the time-averaged CD4 + difference was 199 cells/mm 3 . After January 1, 2016, the percentage of follow-up time on treatment was 97.2% and 94.1% for the immediate and deferred groups, respectively, and the CD4 + count difference was 155 cells/mm 3 . After January 1, 2016, a total of 89 immediate and 113 deferred group participants experienced a primary end point (hazard ratio of 0.79 [95% confidence interval, 0.60 to 1.04] versus hazard ratio of 0.47 [95% confidence interval, 0.34 to 0.65; P<0.001]) before 2016 (P=0.02 for hazard ratio difference)., Conclusions: Among adults with CD4 + counts >500 cells/mm 3 , excess risk of AIDS and SNA associated with delaying treatment initiation was diminished after ART initiation, but persistent excess risk remained. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Competing Interests: We declare no competing interests.

Background: Levels of plasma SARS-CoV-2 nucleocapsid (N) antigen may be an important biomarker in patients with COVID-19 and enhance our understanding of the pathogenesis of COVID-19., Objective: To evaluate whether levels of plasma antigen can predict short-term clinical outcomes and identify clinical and viral factors associated with plasma antigen levels in hospitalized patients with SARS-CoV-2., Design: Cross-sectional study of baseline plasma antigen level from 2540 participants enrolled in the TICO (Therapeutics for Inpatients With COVID-19) platform trial from August 2020 to November 2021, with additional data on day 5 outcome and time to discharge., Setting: 114 centers in 10 countries., Participants: Adults hospitalized for acute SARS-CoV-2 infection with 12 days or less of symptoms., Measurements: Baseline plasma viral N antigen level was measured at a central laboratory. Delta variant status was determined from baseline nasal swabs using reverse transcriptase polymerase chain reaction. Associations between baseline patient characteristics and viral factors and baseline plasma antigen levels were assessed using both unadjusted and multivariable modeling. Association between elevated baseline antigen level of 1000 ng/L or greater and outcomes, including worsening of ordinal pulmonary scale at day 5 and time to hospital discharge, were evaluated using logistic regression and Fine-Gray regression models, respectively., Results: Plasma antigen was below the level of quantification in 5% of participants at enrollment, and 1000 ng/L or greater in 57%. Baseline pulmonary severity of illness was strongly associated with plasma antigen level, with mean plasma antigen level 3.10-fold higher among those requiring noninvasive ventilation or high-flow nasal cannula compared with room air (95% CI, 2.22 to 4.34). Plasma antigen level was higher in those who lacked antispike antibodies (6.42 fold; CI, 5.37 to 7.66) and in those with the Delta variant (1.73 fold; CI, 1.41 to 2.13). Additional factors associated with higher baseline antigen level included male sex, shorter time since hospital admission, decreased days of remdesivir, and renal impairment. In contrast, race, ethnicity, body mass index, and immunocompromising conditions were not associated with plasma antigen levels. Plasma antigen level of 1000 ng/L or greater was associated with a markedly higher odds of worsened pulmonary status at day 5 (odds ratio, 5.06 [CI, 3.41 to 7.50]) and longer time to hospital discharge (median, 7 vs. 4 days; subhazard ratio, 0.51 [CI, 0.45 to 0.57]), with subhazard ratios similar across all levels of baseline pulmonary severity., Limitations: Plasma samples were drawn at enrollment, not hospital presentation. No point-of-care test to measure plasma antigen is currently available., Conclusion: Elevated plasma antigen is highly associated with both severity of pulmonary illness and clinically important patient outcomes. Multiple clinical and viral factors are associated with plasma antigen level at presentation. These data support a potential role of ongoing viral replication in the pathogenesis of SARS-CoV-2 in hospitalized patients., Primary Funding Source: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.

Rationale: Uncertainty regarding the natural history of coronavirus disease (COVID-19) led to difficulty in efficacy endpoint selection for therapeutic trials. Capturing outcomes that occur after hospital discharge may improve assessment of clinical recovery among hospitalized patients with COVID-19. Objectives: Evaluate 90-day clinical course of patients hospitalized with COVID-19, comparing three distinct definitions of recovery. Methods: We used pooled data from three clinical trials of neutralizing monoclonal antibodies to compare: 1 ) the hospital discharge approach; 2 ) the TICO (Therapeutics for Inpatients with COVID-19) trials sustained recovery approach; and 3 ) a comprehensive approach. At the time of enrollment, all patients were hospitalized in a non-ICU setting without organ failure or major extrapulmonary manifestations of COVID-19. We defined discordance as a difference between time to recovery. Measurements and Main Results: Discordance between the hospital discharge and comprehensive approaches occurred in 170 (20%) of 850 enrolled participants, including 126 hospital readmissions and 24 deaths after initial hospital discharge. Discordant participants were older (median age, 68 vs. 59 years; P  < 0.001) and more had a comorbidity (84% vs. 70%; P  < 0.001). Of 170 discordant participants, 106 (62%) had postdischarge events captured by the TICO approach. Conclusions: Among patients hospitalized with COVID-19, 20% had clinically significant postdischarge events within 90 days after randomization in patients who would be considered "recovered" using the hospital discharge approach. Using the TICO approach balances length of follow-up with practical limitations. However, clinical trials of COVID-19 therapeutics should use follow-up times up to 90 days to assess clinical recovery more accurately.

Background: Ensovibep (MP0420) is a designed ankyrin repeat protein, a novel class of engineered proteins, under investigation as a treatment of SARS-CoV-2 infection., Objective: To investigate if ensovibep, in addition to remdesivir and other standard care, improves clinical outcomes among patients hospitalized with COVID-19 compared with standard care alone., Design: Double-blind, randomized, placebo-controlled, clinical trial. (ClinicalTrials.gov: NCT04501978)., Setting: Multinational, multicenter trial., Participants: Adults hospitalized with COVID-19., Intervention: Intravenous ensovibep, 600 mg, or placebo., Measurements: Ensovibep was assessed for early futility on the basis of pulmonary ordinal scores at day 5. The primary outcome was time to sustained recovery through day 90, defined as 14 consecutive days at home or place of usual residence after hospital discharge. A composite safety outcome that included death, serious adverse events, end-organ disease, and serious infections was assessed through day 90., Results: An independent data and safety monitoring board recommended that enrollment be halted for early futility after 485 patients were randomly assigned and received an infusion of ensovibep ( n  = 247) or placebo ( n  = 238). The odds ratio (OR) for a more favorable pulmonary outcome in the ensovibep (vs. placebo) group at day 5 was 0.93 (95% CI, 0.67 to 1.30; P  = 0.68; OR > 1 would favor ensovibep). The 90-day cumulative incidence of sustained recovery was 82% for ensovibep and 80% for placebo (subhazard ratio [sHR], 1.06 [CI, 0.88 to 1.28]; sHR > 1 would favor ensovibep). The primary composite safety outcome at day 90 occurred in 78 ensovibep participants (32%) and 70 placebo participants (29%) (HR, 1.07 [CI, 0.77 to 1.47]; HR < 1 would favor ensovibep)., Limitation: The trial was prematurely stopped because of futility, limiting power for the primary outcome., Conclusion: Compared with placebo, ensovibep did not improve clinical outcomes for hospitalized participants with COVID-19 receiving standard care, including remdesivir; no safety concerns were identified., Primary Funding Source: National Institutes of Health.

The protection provided by natural versus hybrid immunity from COVID-19 is unclear. We reflect on the challenges from trying to conduct a randomized post-SARS-CoV-2 infection vaccination trial study with rapidly evolving scientific data, vaccination guidelines, varying international policies, difficulties with vaccine availability, vaccine hesitancy, and a constantly evolving virus., Competing Interests: Declaration of interests D.L.B is on the advisory boards of Gilead, MerckSharpe & Dohme, Pfizer, and ViiV, and receives travel grants from ViiV Healthcare. G.M. receives research grants from Gilead, AbbvieInc., ViiV Healthcare, and Janssen, and is on the advisory boards of Gileadand AstraZeneca. The other authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to assess the prevalence of cytomegalovirus (CMV) viremia in HIV-positive patients starting antiretroviral therapy (ART) and to evaluate its impact on clinical outcomes., Design: A retrospective analysis of four clinical trials (INSIGHT FIRST, SMART, START, and ANRS REFLATE TB)., Methods: Stored plasma samples from participants were used to measure CMV viremia at baseline prior to initiating ART and at visits through 1 year of follow-up after ART initiation. CMV viremia was measured centrally using a quantitative PCR assay. Within FIRST, associations of CMV viremia at baseline and through 8 months of ART were examined with a composite clinical outcome of AIDS, serious non-AIDS events, or death using Cox proportional hazards regression., Results: Samples from a total of 3176 participants, 1169 from FIRST, 137 from ANRS REFLATE TB, 54 from SMART, and 1816 from START were available with baseline CMV viremia prevalence of 17, 26, 0, and 1%, respectively. Pooled across trials, baseline CMV viremia was associated with low CD4 + T-cell counts and high HIV RNA levels. In FIRST, CMV viremia was detected in only 5% of participants between baseline and month 8. After adjustment for CD4 + T-cell count and HIV RNA levels, hazard ratios for risk of clinical outcomes was 1.15 (0.86-1.54) and 2.58 (1.68-3.98) in FIRST participants with baseline and follow-up CMV viremia, respectively., Conclusion: Baseline CMV viremia in HIV-positive patients starting ART is associated with advanced infection and only persistent CMV viremia after ART initiation is associated with a higher risk of morbidity and mortality., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: There is a critical need to identify the drivers of willingness to receive new vaccines against emerging and epidemic diseases. A discrete choice experiment is the ideal approach to evaluating how individuals weigh multiple attributes simultaneously. We assessed the degree to which six attributes were associated with willingness to be vaccinated among university students in Uganda., Methods: We conducted a single-profile discrete choice experiment at Makerere University in 2019. Participants were asked whether or not they would be vaccinated in 8 unique scenarios where attributes varied by disease risk, disease severity, advice for or against vaccination from trusted individuals, recommendations from influential figures, whether the vaccine induced indirect protection, and side effects. We calculated predicted probabilities of vaccination willingness using mixed logistic regression models, comparing health professional students with all other disciplines., Findings: Of the 1576 participants, 783 (49.8%) were health professional students and 685 (43.5%) were female. Vaccination willingness was high (78%), and higher among health students than other students. We observed the highest vaccination willingness for the most severe disease outcomes and the greatest exposure risks, along with the Minister of Health's recommendation or a vaccine that extended secondary protection to others. Mild side effects and recommendations against vaccination diminished vaccination willingness., Interpretation: Our results can be used to develop evidence-based messaging to encourage uptake for new vaccines. Future vaccination campaigns, such as for COVID-19 vaccines in development, should consider acknowledging individual risk of exposure and disease severity and incorporate recommendations from key health leaders., Competing Interests: The authors have declared that no competing interests exist.

BackgroundThe value of the soluble receptor for advanced glycation end-products (sRAGE) as a biomarker in COVID-19 is not well understood. We tested the association between plasma sRAGE and illness severity, viral burden, and clinical outcomes in hospitalized patients with COVID-19 who were not mechanically ventilated.MethodsBaseline sRAGE was measured among participants enrolled in the ACTIV-3/TICO trial of bamlanivimab for hospitalized patients with COVID-19. Spearman's rank correlation was used to assess the relationship between sRAGE and other plasma biomarkers, including viral nucleocapsid antigen. Fine-Gray models adjusted for baseline supplemental oxygen requirement, antigen level, positive endogenous anti-nucleocapsid antibody response, sex, age, BMI, diabetes mellitus, renal impairment, corticosteroid treatment, and log2-transformed IL-6 level were used to assess the association between baseline sRAGE and time to sustained recovery. Cox regression adjusted for the same factors was used to assess the association between sRAGE and mortality.ResultsAmong 277 participants, baseline sRAGE was strongly correlated with viral plasma antigen concentration (ρ = 0.57). There was a weaker correlation between sRAGE and biomarkers of systemic inflammation, such as IL-6 (ρ = 0.36) and CRP (ρ = 0.20). Participants with plasma sRAGE in the highest quartile had a significantly lower rate of sustained recovery (adjusted recovery rate ratio, 0.64 [95% CI, 0.43-0.90]) and a higher unadjusted risk of death (HR, 4.70 [95% CI, 2.01-10.99]) compared with participants in the lower quartiles.ConclusionElevated plasma sRAGE in hospitalized, nonventilated patients with COVID-19 was an indicator of both clinical illness severity and plasma viral load. Plasma sRAGE in the highest quartile was associated with a lower likelihood of sustained recovery and higher unadjusted risk of death. These findings, which we believe to be novel, indicate that plasma sRAGE may be a promising biomarker for COVID-19 prognostication and clinical trial enrichment.Trial RegistrationClinicalTrials.gov NCT04501978.FundingNIH (5T32GM008440-24, 18X107CF6, HHSN261201500003I, R35HL140026, and OT2HL156812).

Background: Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality in recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). In retrospective single center analyses, severe disease and relapse are common. We undertook an international, prospective cohort study to estimate the response to physician determined antibiotic treatment for CDI in patients with SOT and HSCT., Methods: Adults with a first episode of CDI within the first 2 years of SOT or HSCT were enrolled. Demographics, comorbidities, and medication history were collected, and over 90 days of follow-up clinical cure, recurrences, and complications were assessed. Logistic regression was used to study associations of baseline predictors of clinical cure and recurrence. Odds ratios (ORs) and 95% confidence intervals (CIs) are cited., Results: A total of 132 patients, 81 SOT and 51 HSCT (32 allogeneic), were enrolled with a median age of 56 years; 82 (62%) were males and 128 (97%) were hospitalized at enrollment. One hundred and six (80.3%) were diagnosed by DNA assay. CDI occurred at a median of 20 days post-transplant (interquartile range, IQR: 6-133). One hundred and eight patients (81.8%) were on proton pump inhibitors; 126 patients (95.5%) received antibiotics within the 6 weeks before CDI. The most common initial CDI treatments prescribed, on or shortly before enrollment, were oral vancomycin alone (50%) and metronidazole alone (36%). Eighty-three percent (95% CI: 76, 89) of patients had clinical cure; 18% (95% CI: 12, 27) of patients had recurrent CDI; global clinical cure occurred in 65.2%. Of the 11 patients who died, two (1.5% of total) were related to CDI. In multivariable logistic regression analyses, the type of initial treatment was associated with clinical cure (p = .009) and recurrence (p = .014). A history of cytomegalovirus (CMV) after transplant was associated with increased risk of recurrence (44% with versus 13% without CMV history; OR: 5.7, 95% CI: 1.5, 21.3; p = .01)., Conclusions: Among adults who develop CDI after SOT or HSCT, despite their immunosuppressed state, the percentage with clinical cure was high and the percentage with recurrence was low. Clinical cure and recurrence varied by type of initial treatment, and CMV viremia/disease was associated with an increased risk of recurrence., (© 2021 Wiley Periodicals LLC.)

Background/aims: Safe and effective therapies for COVID-19 are urgently needed. In order to meet this need, the Accelerating COVID-19 Therapeutic Interventions and Vaccines public-private partnership initiated the Therapeutics for Inpatients with COVID-19. Therapeutics for Inpatients with COVID-19 is a multi-arm, multi-stage platform master protocol, which facilitates the rapid evaluation of the safety and efficacy of novel candidate antiviral therapeutic agents for adults hospitalized with COVID-19. Five agents have so far entered the protocol, with rapid answers already provided for three of these. Other agents are expected to enter the protocol throughout 2021. This protocol contains a number of key design and implementation features that, along with challenges faced by the protocol team, are presented and discussed., Methods: Three clinical trial networks, encompassing a global network of clinical sites, participated in the protocol development and implementation. Therapeutics for Inpatients with COVID-19 utilizes a multi-arm, multi-stage design with an agile and robust approach to futility and safety evaluation at 300 patients enrolled, with subsequent expansion to full sample size and an expanded target population if the agent shows an acceptable safety profile and evidence of efficacy. Rapid recruitment to multiple agents is enabled through the sharing of placebo, the confining of agent-specific information to protocol appendices, and modular consent forms. In collaboration with the Food and Drug Administration, a thorough safety data collection and Data and Safety Monitoring Board schedule was developed for the study of potential therapeutic agents with limited in-human data in hospitalized patients with COVID-19., Results: As of 8 August 2021, five agents have entered the Therapeutics for Inpatients with COVID-19 master protocol and a total of 1909 participants have been randomized to one of these agents or matching placebo. There were a number of challenges faced by the study team that needed to be overcome in order to successfully implement Therapeutics for Inpatients with COVID-19 across a global network of sites. These included ensuring drug supply and reliable recruitment allowing for changing infection rates across the global network of sites, the need to balance the collection of data and samples without overburdening clinical staff and obtaining regulatory approvals across a global network of sites., Conclusion: Through a robust multi-network partnership, the Therapeutics for Inpatients with COVID-19 protocol has been successfully used across a global network of sites for rapid generation of efficacy data on multiple novel antiviral agents. The protocol design and implementation features used in this protocol, and the approaches to address challenges, will have broader applicability. Mechanisms to facilitate improved communication and harmonization among country-specific regulatory bodies are required to achieve the full potential of this approach in dealing with a global outbreak.

Background: In a randomized, placebo-controlled, clinical trial, bamlanivimab, a SARS-CoV-2-neutralizing monoclonal antibody, given in combination with remdesivir, did not improve outcomes among hospitalized patients with COVID-19 based on an early futility assessment., Objective: To evaluate the a priori hypothesis that bamlanivimab has greater benefit in patients without detectable levels of endogenous neutralizing antibody (nAb) at study entry than in those with antibodies, especially if viral levels are high., Design: Randomized, placebo-controlled trial. (ClinicalTrials.gov: NCT04501978)., Setting: Multicenter trial., Patients: Hospitalized patients with COVID-19 without end-organ failure., Intervention: Bamlanivimab (7000 mg) or placebo., Measurements: Antibody, antigen, and viral RNA levels were centrally measured on stored specimens collected at baseline. Patients were followed for 90 days for sustained recovery (defined as discharge to home and remaining home for 14 consecutive days) and a composite safety outcome (death, serious adverse events, organ failure, or serious infections)., Results: Among 314 participants (163 receiving bamlanivimab and 151 placebo), the median time to sustained recovery was 19 days and did not differ between the bamlanivimab and placebo groups (subhazard ratio [sHR], 0.99 [95% CI, 0.79 to 1.22]; sHR > 1 favors bamlanivimab). At entry, 50% evidenced production of anti-spike nAbs; 50% had SARS-CoV-2 nucleocapsid plasma antigen levels of at least 1000 ng/L. Among those without and with nAbs at study entry, the sHRs were 1.24 (CI, 0.90 to 1.70) and 0.74 (CI, 0.54 to 1.00), respectively (nominal P for interaction = 0.018). The sHR (bamlanivimab vs. placebo) was also more than 1 for those with plasma antigen or nasal viral RNA levels above median level at entry and was greatest for those without antibodies and with elevated levels of antigen (sHR, 1.48 [CI, 0.99 to 2.23]) or viral RNA (sHR, 1.89 [CI, 1.23 to 2.91]). Hazard ratios for the composite safety outcome (<1 favors bamlanivimab) also differed by serostatus at entry: 0.67 (CI, 0.37 to 1.20) for those without and 1.79 (CI, 0.92 to 3.48) for those with nAbs., Limitation: Subgroup analysis of a trial prematurely stopped because of futility; small sample size; multiple subgroups analyzed., Conclusion: Efficacy and safety of bamlanivimab may differ depending on whether an endogenous nAb response has been mounted. The limited sample size of the study does not allow firm conclusions based on these findings, and further independent trials are required that assess other types of passive immune therapies in the same patient setting., Primary Funding Source: U.S. government Operation Warp Speed and National Institute of Allergy and Infectious Diseases.