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Individuals with serious mental illness have a high prevalence of tobacco use disorder and related early mortality but underutilize smoking cessation medication. The authors determined whether clinician-delivered education to primary care providers regarding safety, efficacy, and importance of cessation medication (provider education [PE]) alone or combined with community health worker (CHW) support would increase tobacco abstinence in this population, compared with usual care.All adult current tobacco smokers receiving psychiatric rehabilitation for serious mental illness through two community agencies in Greater Boston were eligible, regardless of readiness to quit smoking. Primary care clinics were cluster randomized to PE or usual care, with a nested, participant-level randomization to CHW or no CHW in PE-assigned clinics. The primary outcome was blindly assessed, biochemically verified tobacco abstinence at year 2.Overall, 1,010 eligible participants were enrolled. PE was delivered to providers in 53 of 55 assigned clinics; 220 of 336 CHW-assigned participants consented to CHW support. Year 2 abstinence rates were significantly higher among participants assigned to PE+CHW versus usual care (12% vs. 5%; adjusted odds ratio [AOR]=2.40, 95% confidence interval [CI]=1.20-4.79) or PE alone (12% vs. 7%; AOR=1.84, 95% CI=1.04-3.24). No effect of PE alone on abstinence was detected. Compared with participants assigned to usual care, those assigned to PE+CHW had greater odds of varenicline use (OR=2.77, 95% CI=1.61-4.75), which was associated with higher year 2 abstinence (OR=1.97, 95% CI=1.16-3.33).Combined PE and CHW tobacco cessation support increased tobacco abstinence rates among adults with serious mental illness.

Respiratory failure is a lethal complication of COVID-19 that has remained resistant to drug therapy. Vasoactive intestinal peptide (VIP) is shown in nonclinical studies to upregulate surfactant production, inhibit cytokine synthesis, prevent cytopathy, and block replication of the severe acute respiratory syndrome coronavirus 2 virus in pulmonary cells. The study aims to determine whether Aviptadil (synthetic VIP) can improve survival and recovery in patients with COVID-19 respiratory failure compared with placebo and demonstrate biological effects in such patients.A multicenter, placebo-controlled trial.Ten U.S. hospitals: six tertiary-care hospitals and four community hospitals.A total of 196 patients with COVID-19 respiratory failure.Participants were randomized 2:1 to receive 3 days of IV Aviptadil or placebo.The primary end point (alive and free from respiratory failure at day 60) did not reach statistical significance (odds ratio [OR], 1.6; 95% CI, 0.86-3.11) for patients treated with Aviptadil when controlling for baseline ventilation status as prespecified in the protocol. There was, however, a statistically significant two-fold odds of improved survival (OR, 2.0; 95% CI, 1.1-3.9) at 60 days ( p = 0.035). There was significant improvement in respiratory distress ratio and reduced interleukin 6 cytokine release ( p = 0.02) by day 3.Subgroup analysis identified a statistically significant likelihood of achieving primary end point among those treated with high-flow nasal oxygen at baseline ( p = 0.039). Subjects on mechanical ventilation also experienced a 10-fold increased odds of survival with drug versus placebo ( p = 0.031).The primary end point did not reach statistical significance, indicating that there was no difference between Aviptadil versus placebo. However, Aviptadil improves the likelihood of survival from respiratory failure at day 60 in critical COVID-19 across all sites of care. Given the absence of drug-related serious adverse events and acceptable safety profile, we believe the benefit versus risk for the use of Aviptadil is favorable for patient treatment.

Longitudinal clinical trials are often designed to compare treatments on the basis of multiple outcomes. For example in the case of cardiac trials, the outcomes of interest include mortality as well as cardiac events and hospitalization. For a COVID-19 trial, the outcomes of interest include mortality, time on ventilator, and time in hospital. Earlier work by these authors proposed a non-parametric test based on a composite of multiple endpoints referred to as the Finkelstein-Schoenfeld (FS) test (Finkelstein and Schoenfeld. Stat Med. 1999;18(11):1341-1354.). More recently, an estimate of the treatment comparison based on multiple endpoints (related to the FS test) was proposed (Pocock et al. Eur Heart J. 2011;33(2):176-182.). This estimate, which summarized the ratio of the number of patients who fared better vs worse on the experimental arm was coined the win ratio. The aim of this article is to provide guidance in the design of a trial that will use the FS test or the win ratio. The issues that will be considered are the sample size, sequential monitoring, and adaptive designs.

Supplementary Data from Loss of PBRM1 Alters Promoter Histone Modifications and Activates ALDH1A1 to Drive Renal Cell Carcinoma

Supplementary Figure from Loss of PBRM1 Alters Promoter Histone Modifications and Activates ALDH1A1 to Drive Renal Cell Carcinoma

BACKGROUND: Studies of neurologic outcomes have found conflicting results regarding differences between patients with substance-related cardiac arrests (SRCA) and non-SRCA. We investigate the effects of SRCA on severe cerebral edema development, a neuroimaging intermediate endpoint for neurologic injury. METHODS: 327 out-of-hospital comatose cardiac arrest patients were retrospectively analyzed. Demographics and baseline clinical characteristics were examined. SRCA categorization was based on admission toxicology screens. Severe cerebral edema classification was based on radiology reports. Poor clinical outcomes were defined as discharge Cerebral Performance Category scores>3. RESULTS: SRCA patients (N=86) were younger (P

Objective Early administration of tranexamic acid (TXA) has been shown to save lives in trauma patients, and some U.S. emergency medical systems (EMS) have begun providing this therapy prehospital. Treatment protocols vary from state to state: Some offer TXA broadly to major trauma patients, others reserve it for patients meeting vital sign criteria, and still others defer TXA entirely pending a hospital evaluation. The purpose of this study is to compare the avoidable mortality achievable under each of these strategies, and to report on the various approaches used by EMS. Methods We used the National Center for Health Statistics Underlying Cause of Death data to identify a TXA-naïve population of trauma patients who died from 2007 to 2012 due to hemorrhage. We estimated the proportion of deaths where the patient was hypotensive or tachycardic using the National Trauma Data Bank. We used avoidable mortality risk ratios from the landmark CRASH 2 study to calculate lives saved had TXA been given within one hour of injury based on a clinician’s gestalt the patient was at risk for significant hemorrhage; had it been reserved only for hypotensive or tachycardic patients; or had it been given between hours one to three of injury, considered here as a surrogate for deferring the question to the receiving hospital. Results Had TXA been given within 1 hour of injury, an average of 3409 deaths per year could have been averted nationally. Had TXA been given between one and three hours after injury, 2236 deaths per year could have been averted. Had TXA only been given to either tachycardic or hypotensive trauma patients, 1371 deaths per year could have been averted. Had TXA only been given to hypotensive trauma patients, 616 deaths per year could have been averted. Similar trends are seen at the individual state level. A review of EMS practices found 15 statewide protocols that allow EMS providers to administer TXA for trauma. Conclusion Providing early TXA to persons at risk of significant hemorrhage has the potential to prevent many deaths from trauma, yet most states do not offer it in statewide prehospital treatment protocols.

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The lumbar spine is most severely affected. Low bone formation is associated with relative insulin-like growth factor 1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with recombinant human (rh) IGF-1 used off-label followed by antiresorptive therapy with risedronate would increase BMD more than risedronate or placebo in women with anorexia nervosa. We conducted a 12-month, randomized, placebo-controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD). Participants were randomized to three groups: 6 months of rhIGF-1 followed by 6 months of risedronate ("rhIGF-1/Risedronate") (n = 33), 12 months of risedronate ("Risedronate") (n = 33), or double placebo ("Placebo") (n = 16). Outcome measures were lumbar spine (1° endpoint: postero-anterior [PA] spine), hip, and radius aBMD by dual-energy X-ray absorptiometry (DXA), and vertebral, tibial, and radial volumetric BMD (vBMD) and estimated strength by high-resolution peripheral quantitative computed tomography (HR-pCT) (for extremity measurements) and multi-detector computed tomography (for vertebral measurements). At baseline, mean age, body mass index (BMI), aBMD, and vBMD were similar among groups. At 12 months, mean PA lumbar spine aBMD was higher in the rhIGF-1/Risedronate (p = 0.03) group and trended toward being higher in the Risedronate group than Placebo. Mean lateral lumbar spine aBMD was higher, in the rhIGF-1/Risedronate than the Risedronate or Placebo groups (p

Background Research on predictors of treatment outcome in body dysmorphic disorder, a common and severe disorder, is very limited, and no prior studies have examined moderators of outcome. Because treatment is often but not always efficacious, it is important to identify who is more likely to benefit. We examined predictors and moderators of improvement with therapist-delivered cognitive-behavioral therapy versus supportive psychotherapy in the only study of these treatments for body dysmorphic disorder. This report presents secondary analyses from a study whose primary findings have previously been published (Wilhelm et al., 2019). Methods Participants (N=120) with DSM-IV body dysmorphic disorder were randomized to therapist-delivered weekly cognitive-behavioral therapy or supportive therapy for 24 weeks. Using reliable and valid measures, we tested baseline body dysmorphic disorder severity, insight/delusionality, and depression severity as predictors and moderators of overall and treatment modality-specific symptom change. We explored additional variables as predictors and moderators of outcome. Results Greater treatment credibility (p=0.02) and presence of obsessive-compulsive personality disorder (p=0.03) predicted greater improvement. Serotonin-reuptake inhibitor treatment at baseline (unchanged during the study) (p=0.01) predicted less improvement. No other variables predicted or moderated outcome (all p>0.05). Limitations The study was not powered a priori to detect predictor or moderation effects, which limited our ability to detect them unless they were strong. Conclusions Because greater treatment credibility predicted better outcomes, fostering credibility during therapy may maximize gains. Improvement was not impeded by more severe body dysmorphic disorder, depressive symptoms, or poorer insight. No variables moderated treatment-specific improvement.

Context Anorexia nervosa (AN) is prevalent in adolescent girls and is associated with bone impairment driven by hormonal alterations in nutritional deficiency. Objective To assess the impact of estrogen replacement with and without recombinant human insulin-like growth factor-1 (rhIGF-1) administration on bone outcomes. Design Double-blind, randomized, placebo-controlled 12-month longitudinal study. Participants Seventy-five adolescent and young adult women with AN age 14 to 22 years. Thirty-three participants completed the study. Intervention Transdermal 17-beta estradiol 0.1 mg/day with (i) 30 mcg/kg/dose of rhIGF-1 administered subcutaneously twice daily (AN-IGF-1+) or (ii) placebo (AN-IGF-1−). The dose of rhIGF-1 was adjusted to maintain levels in the upper half of the normal pubertal range. Main Outcome Measures Bone turnover markers and bone density, geometry, microarchitecture, and strength estimates. Results Over 12 months, lumbar areal bone mineral density increased in AN-IGF-1− compared to AN-IGF-1+ (P = 0.004). AN-IGF-1+ demonstrated no improvement in areal BMD in the setting of variable compliance to estrogen treatment. Groups did not differ for 12-month changes in bone geometry, microarchitecture, volumetric bone mineral density (vBMD), or strength (and results did not change after controlling for weight changes over 12 months). Both groups had increases in radial cortical area and vBMD, and tibia cortical vBMD over 12 months. Levels of a bone resorption marker decreased in AN-IGF-1− (P = 0.042), while parathyroid hormone increased in AN-IGF-1+ (P = 0.019). AN-IGF-1− experienced irregular menses more frequently than did AN-IGF-1+, but incidence of all other adverse events did not differ between groups. Conclusions We found no additive benefit of rhIGF-1 administration for 12 months over transdermal estrogen replacement alone in this cohort of young women with AN.

How to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

Despite the legalization and widespread use of cannabis products for a variety of medical concerns in the US, there is not yet a strong clinical literature to support such use. The risks and benefits of obtaining a medical marijuana card for common clinical outcomes are largely unknown.To evaluate the effect of obtaining a medical marijuana card on target clinical and cannabis use disorder (CUD) symptoms in adults with a chief concern of chronic pain, insomnia, or anxiety or depressive symptoms.This pragmatic, single-site, single-blind randomized clinical trial was conducted in the Greater Boston area from July 1, 2017, to July 31, 2020. Participants were adults aged 18 to 65 years with a chief concern of pain, insomnia, or anxiety or depressive symptoms. Participants were randomized 2:1 to either the immediate card acquisition group (n = 105) or the delayed card acquisition group (n = 81). Randomization was stratified by chief concern, age, and sex. The statistical analysis followed an evaluable population approach.The immediate card acquisition group was allowed to obtain a medical marijuana card immediately after randomization. The delayed card acquisition group was asked to wait 12 weeks before obtaining a medical marijuana card. All participants could choose cannabis products from a dispensary, the dose, and the frequency of use. Participants could continue their usual medical or psychiatric care.Primary outcomes were changes in CUD symptoms, anxiety and depressive symptoms, pain severity, and insomnia symptoms during the trial. A logistic regression model was used to estimate the odds ratio (OR) for CUD diagnosis, and linear models were used for continuous outcomes to estimate the mean difference (MD) in symptom scores.A total of 186 participants (mean [SD] age 37.2 [14.4] years; 122 women [65.6%]) were randomized and included in the analyses. Compared with the delayed card acquisition group, the immediate card acquisition group had more CUD symptoms (MD, 0.28; 95% CI, 0.15-0.40; P .001); fewer self-rated insomnia symptoms (MD, -2.90; 95% CI, -4.31 to -1.51; P .001); and reported no significant changes in pain severity or anxiety or depressive symptoms. Participants in the immediate card acquisition group also had a higher incidence of CUD during the intervention (17.1% [n = 18] in the immediate card acquisition group vs 8.6% [n = 7] in the delayed card acquisition group; adjusted odds ratio, 2.88; 95% CI, 1.17-7.07; P = .02), particularly those with a chief concern of anxiety or depressive symptoms.This randomized clinical trial found that immediate acquisition of a medical marijuana card led to a higher incidence and severity of CUD; resulted in no significant improvement in pain, anxiety, or depressive symptoms; and improved self-rating of insomnia symptoms. Further investigation of the benefits of medical marijuana card ownership for insomnia and the risk of CUD are needed, particularly for individuals with anxiety or depressive symptoms.ClinicalTrials.gov Identifier: NCT03224468.

As evidence emerged supporting noninvasive strategies for coronavirus disease 2019 (COVID-19)–related respiratory distress, we implemented a noninvasive COVID-19 respiratory protocol (NCRP) that encouraged high-flow nasal cannula (HFNC) and self-proning across our healthcare system. To assess safety, we conducted a retrospective chart review evaluating mortality and other patient safety outcomes after implementation of the NCRP protocol (April 3, 2020, to April 15, 2020) for adult patients hospitalized with COVID-19, compared with preimplementation outcomes (March 15, 2020, to April 2, 2020). During the study, there were 469 COVID-19 admissions. Fewer patients underwent intubation after implementation (10.7% [23 of 215]), compared with before implementation (25.2% [64 of 254]) (P < .01). Overall, 26.2% of patients died (24% before implementation vs 28.8% after implementation; P = .14). In patients without a do not resuscitate/do not intubate order prior to admission, mortality was 21.8% before implementation vs 21.9% after implementation. Overall, we found no significant increase in mortality following implementation of a noninvasive respiratory protocol that decreased intubations in patients with COVID-19.

An orally administered, fixed‐dose coformulation of sodium phenylbutyrate‐taurursodiol (PB‐TURSO) significantly slowed functional decline in a randomized, placebo‐controlled, phase 2 trial in ALS (CENTAUR). Herein we report results of a long‐term survival analysis of participants in CENTAUR. In CENTAUR, adults with ALS were randomized 2:1 to PB‐TURSO or placebo. Participants completing the 6‐month (24‐week) randomized phase were eligible to receive PB‐TURSO in the open‐label extension. An all‐cause mortality analysis (35‐month maximum follow‐up post‐randomization) incorporated all randomized participants. Participants and site investigators were blinded to treatment assignments through the duration of follow‐up of this analysis. Vital status was obtained for 135 of 137 participants originally randomized in CENTAUR. Median overall survival was 25.0 months among participants originally randomized to PB‐TURSO and 18.5 months among those originally randomized to placebo (hazard ratio, 0.56; 95% confidence interval, 0.34‐0.92; P = .023). Initiation of PB‐TURSO treatment at baseline resulted in a 6.5‐month longer median survival as compared with placebo. Combined with results from CENTAUR, these results suggest that PB‐TURSO has both functional and survival benefits in ALS.

Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation.The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21-70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity.The participants' mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo.Adjunctive transdermal testosterone, although well tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.

The ORCHID (Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease) trial is a multicenter, blinded, randomized trial of hydroxychloroquine versus placebo for the treatment of adults hospitalized with coronavirus disease (COVID-19). This document provides the rationale and background for the trial and highlights key design features. We discuss five novel challenges to the design and conduct of a large, multicenter, randomized trial during a pandemic, including 1) widespread, off-label use of the study drug before the availability of safety and efficacy data; 2) the need to adapt traditional procedures for documentation of informed consent during an infectious pandemic; 3) developing a flexible and robust Bayesian analysis incorporating significant uncertainty about the disease, outcomes, and treatment; 4) obtaining indistinguishable drug and placebo without delaying enrollment; and 5) rapidly obtaining administrative and regulatory approvals. Our goals in describing how the ORCHID trial progressed from study conception to enrollment of the first patient in 15 days are to inform the development of other high-quality, multicenter trials targeting COVID-19. We describe lessons learned to improve the efficiency of future clinical trials, particularly in the setting of pandemics. The ORCHID trial will provide high-quality, clinically relevant data on the safety and efficacy of hydroxychloroquine for the treatment of COVID-19 among hospitalized adults.Clinical trial registered with www.clinicaltrials.gov (NCT04332991).

There is a need for safe and effective platform vaccines to protect against coronavirus disease 2019 (COVID-19) and other infectious diseases. In this randomized, double-blinded, placebo-controlled phase 2/3 trial, we evaluate the safety and efficacy of a multi-dose Bacillus Calmette-Guérin (BCG) vaccine for the prevention of COVID-19 and other infectious disease in a COVID-19-unvaccinated, at-risk-community-based cohort. The at-risk population is made of up of adults with type 1 diabetes. We enrolled 144 subjects and randomized 96 to BCG and 48 to placebo. There were no dropouts over the 15-month trial. A cumulative incidence of 12.5% of placebo-treated and 1% of BCG-treated participants meets criteria for confirmed COVID-19, yielding an efficacy of 92%. The BCG group also displayed fewer infectious disease symptoms and lesser severity and fewer infectious disease events per patient, including COVID-19. There were no BCG-related systemic adverse events. BCG's broad-based infection protection suggests that it may provide platform protection against new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants and other pathogens.

Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the tumor-suppressor protein PBRM1 (BAF180), as well as ARID2 (BAF200), that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, histone modification ChIP-seq, and ATAC-seq data to show that loss of PBRM1 results in de novo gains in H3K4me3 peaks throughout the epigenome, including activation of a retinoic acid biosynthesis and signaling gene signature. We show that one such target gene, ALDH1A1, which regulates a key step in retinoic acid biosynthesis, is consistently upregulated with PBRM1 loss in ccRCC cell lines and primary tumors, as well as non-malignant cells. We further find that ALDH1A1 increases the tumorigenic potential of ccRCC cells. Using biochemical methods, we show that ARID2 remains bound to other PBAF subunits after loss of PBRM1 and is essential for increased ALDH1A1 after loss of PBRM1, whereas other core SWI/SNF components are dispensable, including the ATPase subunit BRG1. In total, this study uses global epigenomic approaches to uncover novel mechanisms of PBRM1 tumor suppression in ccRCC. Implications: This study implicates the SWI/SNF subunit and tumor-suppressor PBRM1 in the regulation of promoter histone modifications and retinoic acid biosynthesis and signaling pathways in ccRCC and functionally validates one such target gene, the aldehyde dehydrogenase ALDH1A1.

Introduction: Previous studies have shown that women have poorer neurological outcomes than men following out-of-hospital cardiac arrest (OHCA). However, those studies focused on survival, a measure that may be confounded by withdrawal of life-sustaining therapy (WLST) decisions. We sought to assess sex differences in severe cerebral edema development following cardiac arrest. Methods: Data from adult OHCA patients presenting between 2007-2019 were retrospectively analyzed. Patients with multiple concomitant acute neurologic dysfunctions were excluded. Severe cerebral edema was classified as herniation or more than minimal ventricular effacement in MRI or CT radiology reports. Arrest types were categorized as shockable (VT/VF) or non-shockable (PEA, asystole). Poor outcomes were defined as Cerebral Performance Category > 3 at discharge. Multivariable backward stepwise logistic regression was performed. Results: 359 patients met our inclusion criteria. Demographics, imaging and clinical outcomes are summarized in Table 1. Women were more likely than men to have a non-shockable initial rhythm (P=0.003) and develop severe cerebral edema (P=0.005). Backwards stepwise logistic regression of an initial model including age, sex, rhythm, witnessed arrest and TTM-treatment, produced a final model that showed younger age (P Conclusion: For OHCA patients who are initially comatose, women are more likely than men to have non-shockable rhythms and severe cerebral brain edema. These differences may be responsible for the poorer discharge outcomes that have been observed by other studies.

Clinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system.

ObjectiveLinking emergency medical services (EMS) electronic patient care reports (ePCRs) to emergency department (ED) records can provide clinicians access to vital information that can alter management. It can also create rich databases for research and quality improvement. Unfortunately, previous attempts at ePCR and ED record linkage have had limited success. In this study, we use supervised machine learning to derive and validate an automated record linkage algorithm between EMS ePCRs and ED records.Materials and MethodsAll consecutive ePCRs from a single EMS provider between June 2013 and June 2015 were included. A primary reviewer matched ePCRs to a list of ED patients to create a gold standard. Age, gender, last name, first name, social security number, and date of birth were extracted. Data were randomly split into 80% training and 20% test datasets. We derived missing indicators, identical indicators, edit distances, and percent differences. A multivariate logistic regression model was trained using 5-fold cross-validation, using label k-fold, L2 regularization, and class reweighting.ResultsA total of 14 032 ePCRs were included in the study. Interrater reliability between the primary and secondary reviewer had a kappa of 0.9. The algorithm had a sensitivity of 99.4%, a positive predictive value of 99.9%, and an area under the receiver-operating characteristic curve of 0.99 in both the training and test datasets. Date-of-birth match had the highest odds ratio of 16.9, followed by last name match (10.6). Social security number match had an odds ratio of 3.8.ConclusionsWe were able to successfully derive and validate a record linkage algorithm from a single EMS ePCR provider to our hospital EMR.

Ventilator-free days (VFDs) are a commonly reported composite outcome measure in acute respiratory distress syndrome trials. VFDs combine survival and duration of ventilation in a manner that summarizes the “net effect” of an intervention on these two outcomes. However, this combining of outcome measures makes VFDs difficult to understand and analyze, which contributes to imprecise interpretations. We discuss the strengths and limitations of VFDs and other “failure-free day” composites, and we provide a framework for when and how to use these outcome measures. We also provide a comprehensive discussion of the different analytic methods for analyzing and interpreting VFDs, including Student’s t tests and rank-sum tests, as well as competing risk regressions treating extubation as the primary outcome and death as the competing risk. Using simulations, we illustrate how the statistical test with optimal power depends on the relative contributions of mortality and ventilator duration on the composite effect size. Finally, we recommend a simple analysis and reporting framework using the competing risk approach, which provides clear information on the effect size of an intervention, a statistical test and measure of confidence with the ability to adjust for baseline factors and allow interim monitoring for trials. We emphasize that any approach to analyzing a composite outcome, including other “failure-free day” constructs, should also be accompanied by an examination of the components.

Context Anorexia nervosa (AN) is a psychiatric illness with considerable morbidity and no approved medical therapies. We have shown that relative androgen deficiency in AN is associated with greater depression and anxiety symptom severity. Objective To determine whether low-dose testosterone therapy is an effective endocrine-targeted therapy for AN. Design Double-blind, randomized, placebo-controlled trial. Setting Clinical research center. Participants Ninety women, 18 to 45 years, with AN and free testosterone levels below the median for healthy women. Intervention Transdermal testosterone, 300 μg daily, or placebo patch for 24 weeks. Main Outcome Measures Primary end point: body mass index (BMI). Secondary end points: depression symptom severity [Hamilton Depression Rating Scale (HAM-D)], anxiety symptom severity [Hamilton Anxiety Rating Scale (HAM-A)], and eating disorder psychopathology and behaviors. Results Mean BMI increased by 0.0 ± 1.0 kg/m2 in the testosterone group and 0.5 ± 1.1 kg/m2 in the placebo group (P = 0.03) over 24 weeks. At 4 weeks, there was a trend toward a greater decrease in HAM-D score (P = 0.09) in the testosterone vs placebo group. At 24 weeks, mean HAM-D and HAM-A scores decreased similarly in both groups [HAM-D: −2.9 ± 4.9 (testosterone) vs −3.0 ± 5.0 (placebo), P = 0.72; HAM-A: −4.5 ± 5.3 (testosterone) vs −4.3 ± 4.4 (placebo), P = 0.25]. There were no significant differences in eating disorder scores between groups. Testosterone therapy was safe and well tolerated with no increase in androgenic side effects compared with placebo. Conclusion Low-dose testosterone therapy for 24 weeks was associated with less weight gain—and did not lead to sustained improvements in depression, anxiety, or disordered eating symptoms—compared with placebo in women with AN.

Background Correlates of cannabis use and dependence among young adults have been widely studied. However, it is not known which factors are most strongly associated with severity of cannabis use dependence (CUD) severity. Identification of the salient correlates of CUD severity will be of increasing clinical significance as use becomes more socially normative. Methods This study used a data-driven, hypothesis-free approach to examine the most robust correlates of CUD severity among a sample of 76 young adults (ages 18 to 25 years) who used cannabis at least weekly. Seventy-one candidate variables were examined for association with CUD severity. These included demographic variables, self-reported and psychodiagnostic assessments of mood and anxiety, self-reported measures of personality, cannabis and other substance use characteristics, and objective and subjective measures of cognition. Results Of the 71 candidate variables considered, 27 were associated with CUD severity on a univariate level at a p-value ≤.20. Correlates of CUD severity in the multivariable model using stepwise selection were: more frequent cannabis use in the past 90 days, greater expectancies that cannabis causes cognitive and behavioral impairment, greater self-reported metacognitive deficits, greater anxiety, and lower reaction time variability on a test of sustained attention. Internal validation tests support high prediction accuracy of all variables in the multivariable model, except for lower reaction time variability. Conclusions Cannabis use frequency, beliefs about use, perceived cognitive abilities, and anxiety are robustly associated with CUD severity in young adult, regular cannabis users, and may be important in guiding prevention and treatment efforts.

IntroductionChronic, non-cancer pain impacts approximately 50 million adults in the USA (20%), approximately 25% of whom receive chronic prescription opioids for pain despite limited empirical efficacy data and strong dose-related risk for opioid use disorder and opioid overdose. Also despite lack of efficacy data, there are many reports of people using cannabis products to manage chronic pain and replace or reduce chronic opioids. Here we describe the protocol for a randomised trial of the effect of cannabis, when added to a behavioural pain management and prescription opioid taper support programme, on opioid utilisation, pain intensity and pain interference.MethodsThis is a pragmatic, single-blind, randomised, wait-list controlled trial that aims to enrol 250 adults taking prescription opioids at stable doses of ≥25 morphine milligram equivalents per day for chronic non-cancer pain who express interest in using cannabis to reduce their pain, their opioid dose or both. All participants will be offered a weekly, 24-session Prescription Opioid Taper Support group behavioural pain management intervention. Participants will be randomly assigned in 1:1 ratio to use cannabis products, primarily from commercial cannabis dispensaries or to abstain from cannabis use for 6 months. Coprimary outcomes are change in prescription monitoring programme-verified opioid dose and change in Pain, Enjoyment, General Activity scale scores. Secondary outcomes include quality of life, depression, anxiety, self-reported opioid dose and opioid and cannabis use disorder symptoms. All other outcomes will be exploratory. We will record adverse events.Ethics and disseminationThis study has ethical approval by the Massachusetts General Brigham Institutional Review Board (#2021P000871). Results will be published in peer-reviewed journals and presented at national conferences.Trial registration numberNCT04827992.

Copyright © 2020 International Association for the Study of Pain., Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

Importance Data on the efficacy of hydroxychloroquine for the treatment of coronavirus disease 2019 (COVID-19) are needed. Objective To determine whether hydroxychloroquine is an efficacious treatment for adults hospitalized with COVID-19. Design, Setting, and Participants This was a multicenter, blinded, placebo-controlled randomized trial conducted at 34 hospitals in the US. Adults hospitalized with respiratory symptoms from severe acute respiratory syndrome coronavirus 2 infection were enrolled between April 2 and June 19, 2020, with the last outcome assessment on July 17, 2020. The planned sample size was 510 patients, with interim analyses planned after every 102 patients were enrolled. The trial was stopped at the fourth interim analysis for futility with a sample size of 479 patients. Interventions Patients were randomly assigned to hydroxychloroquine (400 mg twice daily for 2 doses, then 200 mg twice daily for 8 doses) (n = 242) or placebo (n = 237). Main Outcomes and Measures The primary outcome was clinical status 14 days after randomization as assessed with a 7-category ordinal scale ranging from 1 (death) to 7 (discharged from the hospital and able to perform normal activities). The primary outcome was analyzed with a multivariable proportional odds model, with an adjusted odds ratio (aOR) greater than 1.0 indicating more favorable outcomes with hydroxychloroquine than placebo. The trial included 12 secondary outcomes, including 28-day mortality. Results Among 479 patients who were randomized (median age, 57 years; 44.3% female; 37.2% Hispanic/Latinx; 23.4% Black; 20.1% in the intensive care unit; 46.8% receiving supplemental oxygen without positive pressure; 11.5% receiving noninvasive ventilation or nasal high-flow oxygen; and 6.7% receiving invasive mechanical ventilation or extracorporeal membrane oxygenation), 433 (90.4%) completed the primary outcome assessment at 14 days and the remainder had clinical status imputed. The median duration of symptoms prior to randomization was 5 days (interquartile range [IQR], 3 to 7 days). Clinical status on the ordinal outcome scale at 14 days did not significantly differ between the hydroxychloroquine and placebo groups (median [IQR] score, 6 [4-7] vs 6 [4-7]; aOR, 1.02 [95% CI, 0.73 to 1.42]). None of the 12 secondary outcomes were significantly different between groups. At 28 days after randomization, 25 of 241 patients (10.4%) in the hydroxychloroquine group and 25 of 236 (10.6%) in the placebo group had died (absolute difference, −0.2% [95% CI, −5.7% to 5.3%]; aOR, 1.07 [95% CI, 0.54 to 2.09]). Conclusions and Relevance Among adults hospitalized with respiratory illness from COVID-19, treatment with hydroxychloroquine, compared with placebo, did not significantly improve clinical status at day 14. These findings do not support the use of hydroxychloroquine for treatment of COVID-19 among hospitalized adults. Trial Registration ClinicalTrials.gov:NCT04332991

BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate–taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate–taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was −1.24 points per month with the active drug and −1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate–taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate–taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR Clinicaltrials.gov number, NCT03127514.)

Objective: Nonresponse to selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor treatment is common in patients with major depressive disorder (MDD), particularly in women, occurring in about 70% of patients despite adequate dosing. Well-tolerated augmentation strategies are needed, particularly ones that do not cause or exacerbate symptoms such as fatigue and sexual dysfunction. Low-dose testosterone has been shown to improve depression symptom severity, fatigue and sexual function in small studies of women not formally diagnosed with MDD. We sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with treatment-resistant MDD. A functional MRI (fMRI) substudy examined effects of testosterone on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation. Methods: Randomized, double-blind, placebo-controlled, 8-week trial of adjunctive testosterone cream (AndroFeme® 1, Lawley Pharmaceuticals, Australia) in 101 women, ages 21–70, with treatment-resistant MDD. Testosterone was titrated to achieve blood levels near the upper normal reference limit. Primary outcome measure was depression severity by Montgomery-Asberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. fMRI substudy (n=20) primary outcome was change in ACC activity. Results: Mean age was 47±14 (SD) years and mean baseline MADRS score was 26.6±5.9. Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS depression scores decreased in both arms [testosterone: 26.8±6.3 to 15.3±9.6; placebo: 26.3±5.4 to 14.4±9.3 (baseline to 8 weeks, respectively)], with no difference between groups (p=0.91). Fatigue and sexual function improved without differences between groups. There were no group differences in side effects. fMRI results demonstrated a relationship between ACC activation and androgen levels pretreatment but no difference in ACC activation with treatment. Conclusions: This rigorously designed, double-blinded clinical trial did not find significant group differences between adjunctive low dose transdermal testosterone and placebo for antidepressant augmentation in women with treatment-resistant MDD and had a high placebo response rate. Low-dose testosterone was well tolerated but failed to differentially impact overall depressive symptom severity, fatigue, or sexual dysfunction. Testosterone did not result in greater activity in a brain region (ACC) implicated in MDD etiopathology compared to placebo. Thus, the addition of low-dose testosterone to ineffective antidepressant treatment should not be recommended for women with MDD. Further studies using strategies designed to reduce placebo effects may be warranted.

Clinical trials are often designed to compare treatments on the basis of multiple outcomes. For the analysis of the treatment comparison from such a trial, in 1999, the Finkelstein-Schoenfeld test was proposed, which was a generalization of the Gehan-Wilcoxon test based on pairwise comparison of patients on a primary outcome when possible but otherwise on a secondary outcome. In 2012, Pocock and colleagues suggested an estimate based on this concept, the Win Ratio, which summarized the ratio of the number of patients who fared better versus worse on the experimental arm. However, in 2016, Oakes noted that the Win Ratio could be a function of the distribution of follow-up times of the trial. The aim of this paper is to propose an approach to representing the Win Ratio graphically in such a way that the effect of time on the estimate would be apparent. In addition, the methods are used to display the contribution of each endpoint to the composite. We apply the methods to clinical trials in cancer, cardiology, and neurology. Software is available named winRatioAnalysis in CRAN.

Purpose/background The objective of this study was to determine whether a novel α7 nicotinic acetylcholine receptor partial agonist improves cognition during nicotine withdrawal and improves abstinence rates. To do so, the effect of the α7 nicotinic acetylcholine receptor partial agonist, encenicline, on cognition and abstinence was evaluated when given as monotherapy and when combined with transdermal nicotine patch (nicotine replacement therapy [NRT]). Methods Adult daily smokers, n = 160, who were motivated to quit smoking completed cognitive testing at satiated baseline and after overnight abstinence and then were randomized to receive a 12-week trial of encenicline 1 mg twice daily or identical placebo the day of the overnight abstinent cognitive testing. In the first 6 weeks of the 12-week encenicline administration, participants were also randomized to 6 weeks of NRT patch or placebo patch. Primary outcomes were cognition during abstinence and 7-day point-prevalence abstinence at week 12. Results No beneficial effects of encenicline were observed on cognition or abstinence when compared with placebo or when combined with NRT compared with placebo capsule + NRT. Of the 4 conditions, abstinence rates were lowest among those assigned to encenicline alone. Conclusions Beneficial effects of NRT were observed on cognitive and abstinence outcomes when combined with encenicline compared with encenicline plus placebo patch. Addition of NRT to encenicline improved odds of abstinence approximately 3-fold compared with encenicline plus placebo patch. We conclude that encenicline, 1 mg/d, did not improve abstinence-associated cognitive impairment or abstinence rates as monotherapy or adjunctive therapy to NRT patch.

Neuroinflammation is increasingly tied to disease progression in amyotrophic lateral sclerosis (ALS). Participants in the first-in-human trial of intra-spinal allogeneic stem cell therapy for ALS received immunosuppression, and one participant saw dramatic improvement across multiple outcome measures. The primary objective of this study (NCT01884571) was to assess the rate of clinical response to the same immunosuppressive regimen using basiliximab, tacrolimus, mycophenolate, and prednisone in people with ALS. A clinical response was defined as an improvement on the revised ALS Functional Rating Scale (ALSFRS-R) by six points over a 6-month period. Thirty-one participants were enrolled in this 15-month open label study and received an identical immunosuppression regimen. Clinical outcome measures and biospecimens were collected before, during, and after the treatment regimen. No patients met the pre-defined responder criteria. No difference in mean ALSFRS-R slope was seen in the treatment period compared to the pretreatment period (p = 0.200). The regimen was generally safe in an ALS population, although only 18 out of 31 patients completed the full 6 months of immunosuppression. Analyses of immune markers showed no change in peripheral regulatory T-cell populations during treatment compared to pretreatment (p = 0.200). Analysis of cerebrospinal fluid (CSF) cytokine levels showed an increase in IL-2 levels with immunosuppression (p = 0.004) followed by decrease during post-treatment follow-up (p = 0.031). Further studies are needed to understand how manipulation of the immune system may affect disease progression in ALS.

The goal of this research is to discover what groups of genes are associated with the disease process. We use binary and failure time outcomes to inform the clustering of longitudinally-collected microarray data. We propose a linear model with normally distributed cluster-specific random effects for the longitudinal gene expression trajectory. The random effects are linearly related to a latent continuous representation of the outcome, where the probability or hazard of the outcome depends on these latent variables. We apply our method to microarray data collected from trauma patients in the Inflammation and Host Response to Injury project.

Anorexia nervosa is complicated by low bone mineral density (BMD) and increased fracture risk associated with low bone formation and high bone resorption. The spine, particularly its trabecular component as measured by lateral spine dual-energy x-ray absorptiometry (DXA), is most severely affected. Low BMD and bone formation are associated with relative insulin-like growth hormone-1 (IGF-1) deficiency. Our objective was to determine whether bone anabolic therapy with off-label recombinant human (rh)IGF-1 followed by antiresorptive therapy with risedronate would increase BMD more than risedronate alone or placebo in women with anorexia nervosa. We conducted a 12-month, randomized, placebo-controlled study of 90 ambulatory women with anorexia nervosa and low areal BMD (aBMD) (Z- or T-score

Introduction: Urate has been identified as a predictor of ALS survival in some, but not all studies. Here we leverage the recent expansion of the PRO-ACT database to study the association between urate levels and ALS survival. Methods: Pooled data of 1,736 ALS participants from the PRO-ACT database were analyzed. Cox proportional hazards regression models were used to evaluate associations between urate levels at trial entry and survival. Results: After adjustment for potential confounders (i.e., creatinine and body mass index), there was an 11% reduction in risk of reaching a survival endpoint during the study with each 1 mg/dl increase in uric acid levels (adjusted HR: 0.89, 95% CI 0.82–0.97, p

Short-term follow-up in the Fluid and Catheter Treatment Trial (FACTT) suggested differential mortality by race with conservative fluid management, but no significant interaction.In a post hoc analysis of FACTT including 1-year follow-up, we sought to estimate long-term mortality by race and test for an interaction between fluids and race.We performed a post hoc analysis of FACTT and the Economic Analysis of Pulmonary Artery Catheters (EAPAC) study (which included 655 of the 1,000 FACTT patients with near-complete 1-year follow up). We fit a multistate Markov model to estimate 1-year mortality for all non-Hispanic black and white randomized FACTT subjects. The model estimated the distribution of time from randomization to hospital discharge or hospital death (available on all patients) and estimated the distribution of time from hospital discharge to death using data on patients after hospital discharge for patients in EAPAC. The 1-year mortality was found by combining these estimates.Non-Hispanic black (n = 217, 25%) or white identified subjects (n = 641, 75%) were included. There was a significant interaction between race and fluid treatment (P = 0.012). One-year mortality was lower for black subjects assigned to conservative fluids (38 vs. 54%; mean mortality difference, 16%; 95% confidence interval, 2-30%; P = 0.027 between conservative and liberal). Conversely, 1-year mortality for white subjects was 35% versus 30% for conservative versus liberal arms (mean mortality difference, -4.8%; 95% confidence interval, -13% to 3%; P = 0.23).In our cohort, conservative fluid management may have improved 1-year mortality for non-Hispanic black patients with ARDS. However, we found no long-term benefit of conservative fluid management in white subjects.

Objectives:In the contemporary ICU, mechanically ventilated patients may not have arterial blood gas measurements available at relevant timepoints. Severity criteria often depend on arterial blood gas results. Retrospective studies suggest that nonlinear imputation of PaO2/FIO2 from SpO2/FIO2 is acc

Introduction The structure of the interview day affects applicant interactions with faculty and residents, which can influence the applicant's rank list decision. We aim to determine if there was a difference in matched residents between those interviewing on a day on which didactics were held and had increased resident and faculty presence (Didactic Day) versus an interview day with less availability for applicant interactions with residents and faculty (Non-Didactic Day). Methods Retrospective study reviewing interview dates of matched residents from 2009-2015. Results 42 (61.8%) matched residents interviewed on a Didactic Day with increased faculty and resident presence versus 26 (38.2%) on a Non-Didactic interview day with less availability for applicant interactions (p=0.04). Conclusion There is an association between interviewing on a Didactic Day with increased faculty and resident presence and matching in our program.

Objective: To conduct a phase-II trial using a ranking and selection paradigm where multiple treatments are compared with limited sample size and the best is chosen for a subsequent efficacy trial ...