This comprehensive picture of transcriptome-wide regulation in the brain's reward circuitry by cocaine SA and prolonged WD provides new insight into the molecular basis of cocaine addiction, which will guide future studies of the key molecular pathways involved.

Recent advances in large-scale gene expression profiling necessitate concurrent development of biostatistical approaches to reveal meaningful biological relationships. Most analyses rely on significance thresholds for identifying differentially expressed genes. We use an approach to compare gene expression datasets using ‘threshold-free’ comparisons. Significance cut-offs to identify genes shared between datasets may be too stringent and may miss concordant patterns of gene expression with potential biological relevance. A threshold-free approach gaining popularity in several research areas, including neuroscience, is Rank–Rank Hypergeometric Overlap (RRHO). Genes are ranked by their p-value and effect size direction, and ranked lists are compared to identify significantly overlapping genes across a continuous significance gradient rather than at a single arbitrary cut-off. We have updated the previous RRHO analysis by accurately detecting overlap of genes changed in the same and opposite directions between two datasets. Here, we use simulated and real data to show the drawbacks of the previous algorithm as well as the utility of our new algorithm. For example, we show the power of detecting discordant transcriptional patterns in the postmortem brain of subjects with psychiatric disorders. The new R package, RRHO2, offers a new, more intuitive visualization of concordant and discordant gene overlap.

The brain transcriptional profile of MDD differs greatly by sex, with multiple transcriptional changes in opposite directions between men and women with MDD.

Schizophrenia is associated with disrupted cognitive control and sleep-wake cycles. Here we identify diurnal rhythms in gene expression in the human dorsolateral prefrontal cortex (dlPFC), in schizophrenia and control subjects. We find significant diurnal (24 h) rhythms in control subjects, however, most of these transcripts are not rhythmic in subjects with schizophrenia. Instead, subjects with schizophrenia have a different set of rhythmic transcripts. The top pathways identified in transcripts rhythmic only in subjects with schizophrenia are associated with mitochondrial function. Importantly, these rhythms drive differential expression patterns of these and several other genes that have long been implicated in schizophrenia (including BDNF and GABAergic-related transcripts). Indeed, differential expression of these transcripts is only seen in subjects that died during the night, with no change in subjects that died during the day. These data provide insights into a potential mechanism that underlies changes in gene expression in the dlPFC with schizophrenia.

Background We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19. Methods In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov , NCT04501978 . Findings Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50–72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74–1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67–1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74–1·58]; BRII-196 plus BRII-198 1·00 [0·68–1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91–...