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IMPORTANCE: There is clinical equipoise for COVID-19 convalescent plasma (CCP) use in patients hospitalized with COVID-19. OBJECTIVE: To determine the safety and efficacy of CCP compared with placebo in hospitalized patients with COVID-19 receiving noninvasive supplemental oxygen. DESIGN, SETTING, AND PARTICIPANTS: CONTAIN COVID-19, a randomized, double-blind, placebo-controlled trial of CCP in hospitalized adults with COVID-19, was conducted at 21 US hospitals from April 17, 2020, to March 15, 2021. The trial enrolled 941 participants who were hospitalized for 3 or less days or presented 7 or less days after symptom onset and required noninvasive oxygen supplementation. INTERVENTIONS: A unit of approximately 250 mL of CCP or equivalent volume of placebo (normal saline). MAIN OUTCOMES AND MEASURES: The primary outcome was participant scores on the 11-point World Health Organization (WHO) Ordinal Scale for Clinical Improvement on day 14 after randomization; the secondary outcome was WHO scores determined on day 28. Subgroups were analyzed with respect to age, baseline WHO score, concomitant medications, symptom duration, CCP SARS-CoV-2 titer, baseline SARS-CoV-2 serostatus, and enrollment quarter. Outcomes were analyzed using a bayesian proportional cumulative odds model. Efficacy of CCP was defined as a cumulative adjusted odds ratio (cOR) less than 1 and a clinically meaningful effect as cOR less than 0.8. RESULTS: Of 941 participants randomized (473 to placebo and 468 to CCP), 556 were men (59.1%); median age was 63 years (IQR, 52-73); 373 (39.6%) were Hispanic and 132 (14.0%) were non-Hispanic Black. The cOR for the primary outcome adjusted for site, baseline risk, WHO score, age, sex, and symptom duration was 0.94 (95% credible interval [CrI], 0.75-1.18) with posterior probability (P[cOR<1] = 72%); the cOR for the secondary adjusted outcome was 0.92 (95% CrI, 0.74-1.16; P[cOR<1] = 76%). Exploratory subgroup analyses suggested heterogeneity of treatment effect: at day 28, cORs were 0.72 (95% CrI, 0.46-1.13; P[cOR<1] = 93%) for participants enrolled in April-June 2020 and 0.65 (95% CrI, 0.41 to 1.02; P[cOR<1] = 97%) for those not receiving remdesivir and not receiving corticosteroids at randomization. Median CCP SARS-CoV-2 neutralizing titer used in April to June 2020 was 1:175 (IQR, 76-379). Any adverse events (excluding transfusion reactions) were reported for 39 (8.2%) placebo recipients and 44 (9.4%) CCP recipients (P = .57). Transfusion reactions occurred in 2 (0.4) placebo recipients and 8 (1.7) CCP recipients (P = .06). CONCLUSIONS AND RELEVANCE: In this trial, CCP did not meet the prespecified primary and secondary outcomes for CCP efficacy. However, high-titer CCP may have benefited participants early in the pandemic when remdesivir and corticosteroids were not in use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04364737

To date, there are no biomarkers for major depressive disorder (MDD) treatment response in clinical use. Such biomarkers could allow for individualized treatment selection, reducing time spent on ineffective treatments and the burden of MDD. In search of such a biomarker, multisite pretreatment and early-treatment (1 week into treatment) structural magnetic resonance (MR) images were acquired from 184 patients with MDD randomized to an 8-week trial of the selective serotonin reuptake inhibitor (SSRI) sertraline or placebo. This study represents a large, multisite, placebo-controlled effort to examine the association between pretreatment differences or early-treatment changes in cortical thickness and treatment-specific outcomes. For standardization, a novel, robust site harmonization procedure was applied to structural measures in a priori regions (rostral and caudal anterior cingulate, lateral orbitofrontal, rostral middle frontal, and hippocampus), chosen based on previously published reports. Pretreatment cortical thickness or volume did not significantly associate with SSRI response. Thickening of the rostral anterior cingulate cortex in the first week of treatment was associated with better 8-week responses to SSRI (p= 0.010). These findings indicate that frontal lobe structural alterations in the first week of treatment may be associated with long-term treatment efficacy. While these associational findings may help to elucidate the specific neural targets of SSRIs, the predictive accuracy of pretreatment or early-treatment structural alterations in classifying treatment remitters from nonremitters was limited to 63.9%. Therefore, in this large sample of adults with MDD, structural MR imaging measures were not found to be clinically translatable biomarkers of treatment response to SSRI or placebo.

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Antidepressant medications are commonly used to treat depression, but only about 30% of patients reach remission with any single first-step antidepressant. If the first-step treatment fails, response and remission rates at subsequent steps are even more limited. The literature on biomarkers for treatment response is largely based on secondary analyses of studies designed to answer primary questions of efficacy, rather than on a planned systematic evaluation of biomarkers for treatment decision. The lack of evidence-based knowledge to guide treatment decisions for patients with depression has lead to the recognition that specially designed studies with the primary objective being to discover biosignatures for optimizing treatment decisions are necessary. Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) is one such discovery study. Stage 1 of EMBARC is a randomized placebo controlled clinical trial of 8 week duration. A wide array of patient characteristics is collected at baseline, including assessments of brain structure, function and connectivity along with electrophysiological, biological, behavioral and clinical features. This paper reports on the data analytic strategy for discovering biosignatures for treatment response based on Stage 1 of EMBARC.

IMPORTANCE: Low-income minority children living in urban neighborhoods are at high risk for mental health problems and underachievement. ParentCorps, a family-centered, school-based intervention in prekindergarten, improves parenting and school readiness (ie, self-regulation and preacademic skills) in 2 randomized clinical trials. The longer-term effect on child mental health and academic performance is not known. OBJECTIVE: To examine whether ParentCorps delivered as an enhancement to prekindergarten programs in high-poverty urban schools leads to fewer mental health problems and increased academic performance in the early elementary school years. DESIGN, SETTING, AND PARTICIPANTS: This is a 3-year follow-up study of a cluster randomized clinical trial of ParentCorps in public schools with prekindergarten programs in New York City. Ten elementary schools serving a primarily low-income, black student population were randomized in 2005, and 4 consecutive cohorts of prekindergarten students were enrolled from September 12, 2005, through December 31, 2008. We report follow-up for the 3 cohorts enrolled after the initial year of implementation. Data analysis was performed from September 1, 2014, to December 31, 2015. INTERVENTIONS: ParentCorps included professional development for prekindergarten and kindergarten teachers and a program for parents and prekindergarten students (13 two-hour group sessions delivered after school by teachers and mental health professionals). MAIN OUTCOMES AND MEASURES: Annual teacher ratings of mental health problems and academic performance and standardized tests of academic achievement in kindergarten and second grade by testers masked to the intervention or control group randomization. RESULTS: A total of 1050 children (4 years old; 518 boys [49.3%] and 532 girls [50.7%]) in 99 prekindergarten classrooms participated in the trial (88.1% of the prekindergarten population), with 792 students enrolled from 2006 to 2008. Most families in the follow-up study (421 [69.6%]) were low income; 680 (85.9%) identified as non-Latino black, 78 (9.8%) as Latino, and 34 (4.3%) as other. Relative to their peers in prekindergarten programs, children in ParentCorps-enhanced prekindergarten programs had lower levels of mental health problems (Cohen d = 0.44; 95% CI, 0.08-0.81) and higher teacher-rated academic performance (Cohen d = 0.21; 95% CI, 0.02-0.39) in second grade. CONCLUSIONS AND RELEVANCE: Intervention in prekindergarten led to better mental health and academic performance 3 years later. Family-centered early intervention has the potential to prevent problems and reduce disparities for low-income minority children. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01670227

The risk of Alzheimer’s disease can be predicted by volumetric analyses of MRI data in the medial temporal lobe. The present study compared a volumetric measurement of the hippocampus with a novel measure of hippocampal integrity (HI) derived from the ratio of parenchyma volume over total volume. Participants were cognitively intact and aged 60 years or older at baseline, and were tested twice, roughly 3 years apart. Participants had been recruited for a study on late-life major depression (LLMD) and were evenly split between depressed patients and controls. Linear regression models were applied to the data with a cognitive composite score as the outcome, and HI and volume, together or separately, as predictors. Subsequent cognitive performance was predicted well by models that included an interaction between HI and LLMD status, such that lower HI scores predicted more cognitive decline in depressed patients. More research is needed, but tentative results from this study appear to suggest that the newly introduced measure HI is an effective tool for the purpose of predicting future changes in general cognitive ability, and especially so in individuals with LLMD.

Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals.

Methods:The methods and results of the 4 U.S. treatment trials are described and their critiques evaluated.Results:2 of the 4 U.S. treatment trials demonstrated efficacy of IV ceftriaxone on primary and/or secondary outcome measures.Conclusions:Future treatment guidelines should clarify that efficacy of IV ceftriaxone for post-treatment Lyme fatigue was demonstrated in one RCT and supported by a second RCT, but that its use was not recommended primarily due to adverse events stemming from the IV route of treatment. While repeated IV antibiotic therapy can be effective, safer modes of delivery are needed.Four federally funded randomized placebo-controlled treatment trials of post-treatment Lyme syndrome in the United States have been conducted. Most international treatment guidelines summarize these trials as having shown no acute or sustained benefit to repeated antibiotic therapy. The goal of this paper is to determine whether this summary con-clusion is supported by the evidence.

Mentorship is an important component of graduate education. This study assessed the perceptions of general psychiatry chief residents regarding the adequacy of mentorship provided during training. The authors surveyed 229 chief residents participating in the APA National Chief Residents Leadership Program in 2004 and 2005. The survey assessed domains such as work hours, didactics, home and family life, and mentorship. Of the chief psychiatric residents surveyed, 49% reported that they did not have a clearly defined career development mentor, and 39% reported that they did not feel adequately mentored. Gender, race/ethnicity, marital status, moonlighting, medical school (American versus international), and type of residency program (academic versus community based) did not show significant association with either “having a clearly defined mentor” or “feeling adequately mentored,” based on chisquared tests for independence. Chief residents who had authored peer-reviewed publications were significantly more likely to report having a clearly defined mentor and to feel adequately mentored than those who did not author publications. Logistic regression analysis showed that having a clearly defined mentor was associated with twice the odds for feeling well prepared to practice psychiatry upon graduation compared with those who did not have a clearly defined mentor, even after controlling for gender, race, medical school, and residency program type. Half of the psychiatric chief residents surveyed reported the lack of a clearly defined career development mentor. In addition, a chief resident’s response of lacking a clear mentor was associated with the perception of being less prepared to practice psychiatry upon graduation. Psychiatric residency training programs may benefit from further clarification and implementation of effective mentorship programs.

This study assessed the efficacy, durability, and tolerability of fluoxetine for hypochondriasis, a disorder for which controlled pharmacological trials are scarce.

Objective: Although binge eating disorder is a common and distressing concomitant of obesity, it has not yet been established whether affected individuals presenting to behavioral weight control programs should receive specialized treatments to supplement standard treatment. This study was designed to examine the added benefit of two adjunctive interventions, individual cognitive behavioral therapy (CBT) and fluoxetine, offered in the context of group behavioral weight control treatment. Research Methods and Procedures: One hundred sixteen overweight/obese women and men with binge eating disorder were all assigned to receive a 16‐session group behavioral weight control treatment over 20 weeks. Simultaneously, subjects were randomly assigned to receive CBT + fluoxetine, CBT + placebo, fluoxetine, or placebo in a two‐by‐two factorial design. Outcome measures, assessed at the end of the 16‐session acute treatment phase, included binge frequency, weight, and measures of eating‐related and general psychopathology. Results: Overall, subjects showed substantial improvement in binge eating and both general and eating‐related psychopathology, but little weight loss. Subjects who received individual CBT improved more in binge frequency than did those not receiving CBT (p< 0.001), and binge abstinence was significantly more common in subjects receiving CBT vs. those who did not (62% vs. 33%, p< 0.001). Fluoxetine treatment was associated with greater reduction in depressive symptoms (p< 0.05). The 54 subjects who achieved binge abstinence improved more on all measures than the 62 subjects who did not. In particular, these subjects lost, on average, 6.2 kg compared with a gain of 0.7 kg among non‐abstainers. Discussion: Adjunctive individual CBT results in significant additional binge reduction in obese binge eaters receiving standard behavioral weight control treatment.

Objectives/Hypothesis:The traditional blind passage of a transesophageal echocardiography probe transorally through the hypopharynx is considered safe. Yet, severe hypopharyngeal complications during transesophageal echocardiography at several institutions led the authors to investigate whether traditional probe passage results in a greater incidence of hypopharyngeal injuries when compared with probe passage under direct visualization.

Some studies indicate that the blind in clinical trials of the efficacy of antidepressant drugs is less than perfect. It has been suggested that, as a consequence of this incomplete blind, biased raters inflate efficacy and that, in fact, these drugs are relatively ineffective. However, in the literature, we could find no prior attempt to quantify rater bias and, thus, measure its contribution to claims of antidepressant efficacy. We used the distribution of SCL-90 (Symptom Check List) depression scale scores to derive a patient-based effect size, and contrasted this with the clinician-based effect size. We propose the difference between these two effect sizes (patient self-rating and clinician-derived) to be an indirect measure of bias. If patients had a prodrug bias, this method would be invalid. However the response rate from studies with active placebo suggest a patient prodrug bias is unlikely. The effect sizes derived from patient self-ratings are smaller than those derived from clinician ratings. This allows for the possibility that some clinician ratings were biased. However, quantifying the effect of bias suggests that it was insufficient to invalidate the original study conclusions based on clinician ratings, because the proportion of responders, based on patient self-ratings, differed significantly between the two drugs and placebo. Their 95% confidence intervals (CI) did not overlap. This analysis allows that some clinician ratings may be biased. However, the extent of bias appears insufficient to alter conclusions based on clinician ratings regarding efficacy of antidepressant drugs in this trial. Application of our approach in other trials is necessary to establish generalizability.

Substance use (i.e., use of recreational drugs and alcohol) has been associated with HIV-related sexual risk behavior in several studies involving gay men. One explanatory hypothesis proposes that substance use and sexual risk behavior are both a function of underlying personality traits. This paper examines sensation seeking and alcohol and drug use during sex as predictors of unprotected anal and oral sex and of a sexual risk index. The sample includes 117 predominantly gay-identified men (73 HIV+ and 44 HIV−) who participated in a 5-year natural history study of HIV disease in New York City. Repeated measures regression analyses tested predictor variables individually and in models including all predictor variables simultaneously. Alcohol use, drug use, and sensation seeking were each significantly associated with all sexual risk behavior variables when entered individually. When predictor variables were entered simultaneously in analyses involving unprotected receptive and insertive anal sex, sensation seeking remained a significant predictor, with substance use typically falling to marginal significance. However, significant associations between substance use and the other sexual risk behavior variables (oral sex and a risk index) are maintained even when controlling for sensation seeking. The results suggest that sensation seeking may partially account for the association between substance use and sexual risk behavior, but substantial independent associations also exist.

BACKGROUND: We attempt to identify the time when patients whose conditions are unimproved while receiving antidepressants are unlikely to respond and should have their treatment changed. METHODS: A total of 593 patients were studied. The course of treatment for patients was examined to determine the weeks at which patients who received drug therapy had a better chance of being rated as responders at the study end (week 6) vs patients who received placebo. RESULTS: At the end of week 3, 19 (32%) of the 59 patients who received drug therapy and 6 (10%) of the 57 patients who received placebo and who never minimally improved were rated as responders at week 6. For those who showed no improvement by week 4, the effects of drug therapy and the placebo were equal. Patients who received drug therapy and whose conditions were unimproved but who had been minimally improved at some point had a superior prognosis with drug therapy vs placebo until week 4. Of those unimproved at week 4 but minimally improved at some point previously, 20 (39%) of the 51 patients who received drug therapy vs 3 (8%) of the 36 patients who received pIacebo were rated as responders at week 6. Of the 75 patients who minimally improved while receiving drug therapy at the end of week 5, 33 (44%) had a chance of being rated a responder at the end of week 6 vs 9 (26%) of the 35 patients receiving placebo. CONCLUSIONS: Patients tolerant of an adequate dose, whose conditions have never been at least minimally improved by the end of week 4, should have their treatment regimen altered. These patients represented a minority of drug-treated patients in the sample studied (ie, 39/392 [10%]). Patients whose conditions minimally improve at some prior week but not after week 5 should have their treatment changed. Patients whose conditions minimally improve in week 5 should continue treatment until week 6.

We give a unified treatment of statistical methods for assessing collapsibility in regression problems, including some possible extensions to the class of generalized linear models. Terminology is borrowed from the contingency table area where various methods for assessing collapsibility have been proposed. Our procedures, however, can be motivated by considering extensions, and alternative derivations, of common procedures for omitted-variable bias in linear regression. Exact tests and interval estimates with optimal properties are available for linear regression with normal errors, and asymptotic procedures follow for models with estimated weights. The methods given here can be used to compareβ1and β2in the common setting where the response function is first modeled asXβ1(reduced model) and then asXβ2+Zγ(full model), withZa vector of covariates omitted from the reduced model. These procedures can be used in experimental settings (X= randomly asigned treatments,Z= covariates) or in nonexperimental settings where two models viewed as alternative behavioral or structural explanations are compared (one model withXonly, another model withXandZ).

Statistical methods are developed for comparing regression coefficients between models in the setting where one of the models is nested in the other. Comparisons of this kind are of interest whenever two explanations of a given phenomenon are specified as linear models. In this case, researchers should ask whether the coefficients associated with a given set of predictors change in a significant way when other predictors or covariates are added as controls. Simple calculations based on quantities provided by routines for regression analysis can be used to obtain the standard errors and other statistics that are required. Results are also given for the class of generalized linear models (e.g., logistic regression, log-linear models, etc.). We recommend fundamental change in strategies for model comparison in social research as well as modifications in the presentation of results from regression or regression-type models.

Non-specific responses to treatment (commonly known as placebo response) are pervasive when treating mental illness. Subjects treated with an active drug may respond in part due to non-specific aspects of the treatment, i.e, those not related to the chemical effect of the drug. To determine the extent a subject responds due to the chemical effect of a drug, one must disentangle the specific drug effect from the non-specific placebo effect. This paper presents a unique statistical model that allows for the separate prediction of a specific effect and non-specific effects in drug treated subjects. Data from a clinical trial comparing fluoxetine to a placebo for treating depression is used to illustrate this methodology.

Non-specific responses to treatment (commonly known as placebo response) are pervasive when treating mental illness. Subjects treated with an active drug may respond in part due to non-specific aspects of the treatment, i.e, those not related to the chemical effect of the drug. To determine the extent a subject responds due to the chemical effect of a drug, one must disentangle the specific drug effect from the non-specific placebo effect. This paper presents a unique statistical model that allows for the separate prediction of a specific effect and non-specific effects in drug treated subjects. Data from a clinical trial comparing fluoxetine to a placebo for treating depression is used to illustrate this methodology.