The Health Informatics Trial Enhancement Project (HITE): Using routinely collected primary care data to identify potential participants for a depression trial

<p>Abstract</p> <p>Background</p> <p>Recruitment to clinical trials can be challenging. We identified anonymous potential participants to an existing pragmatic randomised controlled depression trial to assess the feasibility of using routinely collected data to identify potential trial participants. We discuss the strengths and limitations of this approach, assess its potential value, report challenges and ethical issues encountered.</p> <p>Methods</p> <p>Swansea University's Health Information Research Unit's Secure Anonymised Information Linkage (SAIL) database of routinely collected health records was interrogated, using Structured Query Language (SQL). Read codes were used to create an algorithm of inclusion/exclusion criteria with which to identify suitable anonymous participants. Two independent clinicians rated the eligibility of the potential participants' identified. Inter-rater reliability was assessed using the kappa statistic and inter-class correlation.</p> <p>Results</p> <p>The study population (N = 37263) comprised all adults registered at five general practices in Swansea UK. Using the algorithm 867 anonymous potential participants were identified. The sensitivity and specificity results > 0.9 suggested a high degree of accuracy from the algorithm. The inter-rater reliability results indicated strong agreement between the confirming raters. The Intra Class Correlation Coefficient (Cronbach's Alpha) > 0.9, suggested excellent agreement and Kappa coefficient > 0.8; almost perfect agreement.</p> <p>Conclusions</p> <p>This proof of concept study showed that routinely collected primary care data can be used to identify potential participants for a pragmatic randomised controlled trial of folate augmentation of antidepressant therapy for the treatment of depression. Further work will be needed to assess generalisability to other conditions and settings and the inclusion of this approach to support Electronic Enhanced Recruitment (EER).</p

The genomic basis of parasitism in the Strongyloides clade of nematodes.

Soil-transmitted nematodes, including the Strongyloides genus, cause one of the most prevalent neglected tropical diseases. Here we compare the genomes of four Strongyloides species, including the human pathogen Strongyloides stercoralis, and their close relatives that are facultatively parasitic (Parastrongyloides trichosuri) and free-living (Rhabditophanes sp. KR3021). A significant paralogous expansion of key gene families--families encoding astacin-like and SCP/TAPS proteins--is associated with the evolution of parasitism in this clade. Exploiting the unique Strongyloides life cycle, we compare the transcriptomes of the parasitic and free-living stages and find that these same gene families are upregulated in the parasitic stages, underscoring their role in nematode parasitism

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Let It Go: Cognitive Strategy Use Selectively Changes Temporal Context Effects in Risky Monetary Decision-Making

Some of the most influential modern theories of risky monetary decision-making assume that choices result from stable, trait-like preferences, invariant to contextual influences such as recent events. Recent research has challenged this assumption, demonstrating that decisions under risk, even when values and their probabilities are explicit and known, are contextually sensitive, affected by recent events on multiple timescales, including immediate (previous monetary outcomes), neighborhood (recently encountered values), and global (cumulative earnings relative to dynamic expectations) events. Such temporal context-dependencies are perplexing, because relying on recent events at any timescale is inconsistent with the assumed goal of risky monetary decision-making: to maximize payoff. Identifying this suboptimal behavioral pattern raises the possibility it can be mitigated using behavioral change strategies. We tested whether the effects of temporal context in risk-taking can be attenuated with an intentional cognitive strategy. 124 participants completed two rounds of a context-sensitive gambling task with trial-by-trial feedback, the Emotion Regulation Questionnaire, and working memory capacity tasks. Participants were randomly assigned to complete each gambling round with a strategy either emphasizing a natural, uncontrolled decision-making approach or directly instructing participants to ignore context. Instructions to ignore context influenced temporal context effects on the immediate timescale but did not change those on the neighborhood or global timescales. The strategy was not uniformly effective for all individuals. The cognitive strategy eliminated (and even reversed) contextual effects on the immediate timescale for individuals with moderate and high habitual use of reappraisal. However, the cognitive strategy paradoxically strengthened contextual effects on the immediate timescale for individuals with low habitual use of reappraisal. The selective effects of strategic control on the influence of context indicates promising future directions for attempts to optimize human decision-making, but also suggests that the ability to do so has bounds

Multiple timescales of temporal context in risky choice: Behavioral identification and relationships to physiological arousal.

Context-dependence is fundamental to risky monetary decision-making. A growing body of evidence suggests that temporal context, or recent events, alters risk-taking at a minimum of three timescales: immediate (e.g. trial-by-trial), neighborhood (e.g. a group of consecutive trials), and global (e.g. task-level). To examine context effects, we created a novel monetary choice set with intentional temporal structure in which option values shifted between multiple levels of value magnitude ("contexts") several times over the course of the task. This structure allowed us to examine whether effects of each timescale were simultaneously present in risky choice behavior and the potential mechanistic role of arousal, an established correlate of risk-taking, in context-dependency. We found that risk-taking was sensitive to immediate, neighborhood, and global timescales: risk-taking decreased following large (vs. small) outcome amounts, increased following large positive (but not negative) shifts in context, and increased when cumulative earnings exceeded expectations. We quantified arousal with skin conductance responses, which were related to the global timescale, increasing with cumulative earnings, suggesting that physiological arousal captures a task-level assessment of performance. Our results both replicate and extend prior research by demonstrating that risky decision-making is consistently dynamic at multiple timescales and that the role of arousal in risk-taking extends to some, but not all timescales of context-dependence

Cognitive strategy use selectively changes temporal context effects in risky monetary decision-making

Some of the most influential modern theories of risky monetary decision-making assume that choices result from stable, trait-like preferences, invariant to contextual influences such as recent events. Recent research has challenged this assumption, demonstrating that even when values and probabilities are explicit and known, decisions under risk are contextually sensitive, affected by recent events on multiple timescales, including immediate (previous monetary outcomes), neighborhood (recently encountered values), and global (cumulative earnings relative to dynamic expectations) events. Such temporal context-dependencies are perplexing, because relying on recent events at any timescale is inconsistent with the assumed goal of risky monetary decision-making: to maximize payoff. Identifying this suboptimal behavioral pattern raises the possibility it can be mitigated using behavioral change strategies. We tested whether the effects of temporal context in risk-taking can be attenuated with an intentional cognitive strategy. 124 participants completed two rounds of a contextually structured gambling task with trial-by-trial feedback, the Emotion Regulation Questionnaire, and working memory capacity tasks. Participants were randomly assigned to complete each gambling round with a strategy either emphasizing a natural, uncontrolled decision-making approach or directly instructing participants to ignore context. Instructions to ignore context influenced temporal context effects on the immediate timescale but did not change those on the neighborhood or global timescales. The strategy was not uniformly effective for all individuals. The cognitive strategy eliminated (and even reversed) contextual effects on the immediate timescale for individuals with moderate and high habitual use of reappraisal. However, the cognitive strategy paradoxically strengthened contextual effects on the immediate timescale for individuals with low habitual use of reappraisal. The selective effects of strategic control on contextual influence indicates both intriguing possibilities and limits on the ability to optimize human decision-making, and suggests that people do not simply maximize local utility, but rather that even simple risky decision-making may be fundamentally goal-dependent