Writing Committee for the REMAP-CAP Investigators IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThe ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONSThe immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURESThe primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11...

Coronavirus disease 2019 (COVID-19) created unprecedented changes in our society. Millions of people have been called to shelter in place (avoid nonessential travel outside of the home) and social distance (keeping space between yourself and others outside your home) to reduce the transmission of the novel coronavirus, which causes COVID-19. However, these and other public health measures require a level of privilege: a home to live in, access to hygiene supplies, and control over your movements. They require the ability to stay home from work, avoid public transportation when travel is necessary, and stock up on items to reduce trips to the store. Homeless and unstably housed people, including children, are not able to access these privileges, likely placing them at higher risk of exposure to the novel coronavirus. In many ways, the ability to practice social distancing has become a social determinant of health during this crisis.Homelessness is not just living in a shelter or on the street; people experiencing homelessness, especially children and families, are often couch surfing, "doubling up" with friends or relatives, or living in motels, hotels, or campgrounds. 1,2 Fifty-nine percent of people experiencing homelessness are children aged ,18 years who are either unaccompanied by an adult or are homeless as part of a family unit. 2 Within a 12-month period, 4.3% of 13-to 17-year-olds and 9.7% of 18-to 25-year-olds report homelessness unaccompanied by an adult. 3 Additionally, ∼58 000 families, including .100 000 children, experience homelessness on any given night. 2 That is roughly the equivalent of 1400 school buses full of children, enough to stretch 12 miles end to end.The relationship between housing and child health, including COVID-19, is bidirectional (Fig 1), and homelessness results in increased morbidity and mortality. 1,4 Children who are homeless are more likely to experience developmental delays, asthma exacerbations and admissions, obesity, dental and vision problems, and mental health problems, and they are more likely to be a victim of both accidental and nonaccidental injury. 1,4 They are at higher risk of many infections, including otitis media, gastroenteritis, and viral upper respiratory infections.

of participants who are members of racial and ethnic minority groups in clinical trials enhances inclusivity in the scientific process and generalizability of results.OBJECTIVE To assess participant race and ethnicity in pediatric clinical trials published from 2011 to 2020. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study examined articles reporting pediatric clinical trials conducted in the US published in 5 leading general pediatric and 5 leading general medical journals from January 1, 2011, to December 31, 2020. MAIN OUTCOMES AND MEASURESReporting of participant race and ethnicity and comparison of enrolled participants vs US census populations of pediatric racial and ethnic groups in published clinical trials. RESULTSThe study included 612 articles reporting pediatric clinical trials during the study period, with 565 618 total participants (median per trial, 200 participants [IQR, 90-571 participants]). Of the 612 articles, 486 (79.4%) reported participant race and 338 (55.2%) reported participant ethnicity. From 2011 to 2020, relative rates of reporting of participant race increased by 7.9% per year (95% CI, 0.2%-16.3% per year) and reporting of ethnicity increased by 11.4% per year (95% CI, 4.8%-18.4% per year). Among articles reporting race and ethnicity, the method of assignment was not reported in 261 of 511 articles (51.1%) and 207 of 359 articles (57.7%), respectively. Black/African American children were enrolled proportionally more than the US population of Black/African American children (odds ratio [OR], 1.88; 95% CI, 1.87-1.89). Hispanic/Latino children were enrolled commensurately with the US population of Hispanic/Latino children (OR, 1.02; 95% CI, 1.01-1.03). American Indian/Alaska Native (OR, 0.82; 95% CI, 0.79-0.85), Asian (OR, 0.56; 95% CI, 0.55-0.57), and Native Hawaiian/Pacific Islander (OR, 0.66; 95% CI, 0.61-0.72) children were enrolled significantly less compared with the respective US populations of these groups. White children were enrolled less than expected (OR, 0.84; 95% CI, 0.84-0.85) but represented 188 156 (46.0%) of participants in trials reporting race or ethnicity. CONCLUSIONS AND RELEVANCEThis cross-sectional study revealed that the proportion of published pediatric clinical trials that reported participant race and ethnicity increased from 2011 to 2020, but participant race and ethnicity were still underreported. Disparities existed in pediatric clinical trial enrollment of American Indian/Alaska Native, Asian, and Native Hawaiian/Pacific Islander children. The greater representation of Black/African American children compared with the US population suggests inclusive research practices that could be extended to other historically disenfranchised racial and ethnic groups.

Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates MAPK signaling pathways and regulates cellular responses such as proliferation, migration and apoptosis. Here we report high levels of total and phospho-MLK3 in ovarian cancer cell lines in comparison to immortalized nontumorigenic ovarian epithelial cell lines. Using small interfering RNA (siRNA)-mediated gene silencing, we determined that MLK3 is required for the invasion of SKOV3 and HEY1B ovarian cancer cells. Furthermore, mlk3 silencing substantially reduced matrix metalloproteinase (MMP) -1, -2, -9 and -12 gene expression and MMP-2 and -9 activities in SKOV3 and HEY1B ovarian cancer cells. MMP-1, -2, -9 and-12 expression, and MLK3-induced activation of MMP-2 and MMP-9 requires both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase activities. In addition, inhibition of activator protein-1 (AP-1) reduced MMP-1, MMP-9 and MMP-12 gene expression. Collectively, these findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells.

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The Neurofibromatosis-2 (NF2) tumor suppressor merlin negatively regulates cell proliferation in numerous cell types. We have previously shown that the NF2 protein (merlin/schwannomin) associates with mixed lineage kinase 3 (MLK3), a mitogen-activated protein kinase (MAPK) kinase kinase that is required for the proliferation of normal and neoplastic cells. In the current study, we show that merlin inhibits MLK3 activity as well as the activation of its downstream effectors, B-Raf, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). The ability of merlin to regulate MLK3 activity requires a direct association between MLK3 and residues in the C-terminal region of merlin. Merlin integrates Rho GTPase family signaling with MAPK activity by inhibiting the binding between MLK3 and its upstream activator, Cdc42. Furthermore, we demonstrate that MLK3 is required for merlin suppression of cell proliferation and invasion. Collectively, these results establish merlin as a potent inhibitor of MLK3, ERK and JNK activation in cancer, and provide a mechanistic link between deregulated MAPK and Rho GTPase signaling in NF2 growth control.

Psychotic spectrum disorders are serious illnesses with symptoms that significantly impact functioning and quality of life. An accumulating body of literature has demonstrated that specialized treatments that are offered early after symptom onset are disproportionately more effective in managing symptoms and improving outcomes than when these same treatments are provided later in the course of illness. Specialized, multicomponent treatment packages are of particular importance, which are comprised of services offered as soon as possible after the onset of psychosis with the goal of addressing multiple care needs within a single care setting. As specialized programs continue to develop worldwide, it is crucial to consider how to increase access to such specialized services. In the current review, we utilize an ecological model of understanding barriers to care, with emphasis on understanding how individuals with first-episode psychosis interact with and are influenced by a variety of systemic factors that impact help-seeking behaviors and engagement with treatment. Future work in this area will be important in understanding how to most effectively design and implement specialized care for individuals early in the course of a psychotic disorder.

Introduction and hypothesis Obstetrical external anal sphincter (EAS) injury and subsequent dysfunction are leading risk factors for female fecal incontinence (FI). Limited knowledge of the EAS structure–function relationship hinders treatment optimization. We directly measured functionally relevant intrinsic parameters of human EAS and tested whether vaginal delivery alters the EAS structure–function relationship. Methods Major predictors of in vivo EAS function were compared between specimens procured from vaginally nulliparous (VN, n = 5) and vaginally parous (VP, n = 7) cadaveric donors: operational sarcomere length (Ls), which dictates force–length relationship; physiological cross-sectional area (PCSA), which determines isometric force-generating capacity; fiber length (Lfn), responsible for muscle excursion and contractile velocity; and muscle stiffness. Data were analyzed using unpaired and paired t tests, α < 0.05. Results are presented as mean ± SEM. Results The VN and VP (median parity 3) groups were similar in age and BMI. No gross anatomical defects were identified. EAS Ls (2.36 ± 0.05 μm) was shorter than the optimal Lso (2.7 μm), at which contractile force is maximal, P = 0.0001. Stiffness was lower at L s than L s o (5.4 ± 14 kPa/μm vs 35.3 ± 12 kPa/μm, P < 0.0001). This structural design allows active and passive tension to increase with EAS stretching. EAS relatively long Lfn (106 ± 24.8 mm) permits rapid contraction without decreased force, whereas intermediate PCSA (1.3 ± 0.3 cm2) is conducive to maintaining resting tone. All parameters were similar between groups. Conclusions This first direct examination of human EAS underscores how EAS intrinsic design matches its intended function. Knowledge of the EAS structure–function relationship is important for understanding the pathogenesis of FI and the optimization of treatments for EAS dysfunction.