Use of tocilizumab and sarilumab alone or in combination with corticosteroids for covid-19: systematic review and network meta-analysis

Objective: To compare the effects of interleukin 6 receptor blockers, tocilizumab and sarilumab, with or without corticosteroids, on mortality in patients with covid-19. Design: Systematic review and network meta-analysis. Data sources: World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses (up to 9 June 2021). Review methods: Trials in which people with suspected, probable, or confirmed covid-19 were randomised to interleukin 6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. The analysis used a bayesian framework and assessed the certainty of evidence using the GRADE approach. Results from the fixed effect meta-analysis were used for the primary analysis. Results: Of 45 eligible trials (20 650 patients) identified, 36 (19 350 patients) could be included in the network meta-analysis. Of 36 trials, 27 were at high risk of bias, primarily due to lack of blinding. Tocilizumab, in combination with corticosteroids, suggested a reduction in the risk of death compared with corticosteroids alone (odds ratio 0.79, 95% credible interval 0.70 to 0.88; 35 fewer deaths per 1000 people, 95% credible interval 52 fewer to 18 fewer per 1000; moderate certainty of evidence), as did sarilumab in combination with corticosteroids, compared with corticosteroids alone (0.73, 0.58 to 0.92; 43 fewer per 1000, 73 fewer to 12 fewer; low certainty). Tocilizumab and sarilumab, each in combination with corticosteroids, appeared to have similar effects on mortality when compared with each other (1.07, 0.86 to 1.34; eight more per 1000, 20 fewer to 35 more; low certainty). The effects of tocilizumab (1.12, 0.91 to 1.38; 20 more per 1000, 16 fewer to 59 more; low certainty) and sarilumab (1.07, 0.81 to 1.40; 11 more per 1000, 38 fewer to 55 more; low certainty), when used alone, suggested an increase in the risk of death. Conclusion: These findings suggest that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumab, in combination with corticosteroids, might also reduce mortality. Tocilizumab and sarilumab, in combination with corticosteroids, could have similar effectiveness. Tocilizumab and sarilumab, when used alone, might not be beneficial.This project is supported by two Canadian Institutes of Health Research grants (VR4-172738; MM1-174897). The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication.publishedVersio

Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies

Background Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. Methods We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Findings Between Oct 1, 2017, and Aug 9, 2018, we analysed 7·8 million single nucleotide polymorphisms in 37 688 cases, 18 618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1·4 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16–36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0·0035 for intracranial volume, p=0·024 for putamen volume), smoking status (p=0·024), and educational attainment (p=0·038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8·00 × 10−7). Interpretation These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. Funding The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources)

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/

A living WHO guideline on drugs for covid-19

CITATION: Agarwal, A. et al. 2022. A living WHO guideline on drugs for covid-19. British Medical Journal, 370. doi:10.1136/bmj.m3379The original publication is available at https://jcp.bmj.com/This living guideline by Arnav Agarwal and colleagues (BMJ 2020;370:m3379, doi:10.1136/bmj.m3379) was last updated on 22 April 2022, but the infographic contained two dosing errors: the dose of ritonavir with renal failure should have read 100 mg, not 50 mg; and the suggested regimen for remdesivir should have been 3 days, not 5-10 days. The infographic has now been corrected.Publishers versio

Identification of candidate Parkinson disease genes by integrating genome-wide association study, expression, and epigenetic data sets

Importance Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies

Chronicle (Paterson, NJ) Vol. 32, No. 19, May 8, 1960

Local information pertaining to Paterson, N.J. and surrounding Passaic County. Issues may include events, government, business, political cartoons, engagement and marriage announcements, and birth announcements. This publication was also known as the Paterson Chronicle (1952) and the Paterson Sunday Chronicle (1951-1952)

Sex-specific vagal and spinal modulation of swallow and its coordination with breathing.

Swallow-breathing coordination is influenced by changes in lung volume, which is modulated by feedback from both vagal and spinal sensory afferents. The purpose of this study was to manipulate feedback from these afferents, with and without a simultaneous mechanical challenge (chest compression), in order to assess the influence of each sensory pathway on swallow in rats. We hypothesized that manipulation of afferent feedback would shift the occurrence of swallow toward the inspiratory phase of breathing. Afferent feedback was perturbed by lidocaine nebulization, extra-thoracic vagotomy, or lidocaine administration to the pleural space in sodium pentobarbital anesthetized rats (N = 43). These different afferent perturbations were performed both in control conditions (no chest compression), and with chest compression. Manipulating pulmonary stretch receptor-mediated volume feedback in male animals decreased swallow occurrence. Female rats appear to rely more on spinal afferent feedback, as swallow occurrence shifted to late expiration with chest compression and vagotomy or lidocaine injections. Results suggest that sex-specific mechanisms modulate swallow-breathing coordination, and that vagal feedback is inhibitory to swallow-related muscles, while spinal feedback from pleural afferents has excitatory effects. This study supports the theory that a balance of vagal and spinal afferent feedback is necessary to maintain an optimal swallow pattern and swallow-breathing coordination

Sex-specific vagal and spinal modulation of breathing with chest compression.

Lung volume is modulated by sensory afferent feedback via vagal and spinal pathways. The purpose of this study was to systematically alter afferent feedback with and without a mechanical challenge (chest compression). We hypothesized that manipulation of afferent feedback by nebulization of lidocaine, extra-thoracic vagotomy, or lidocaine administration to the pleural space would produce differential effects on the motor pattern of breathing during chest compression in sodium pentobarbital anesthetized rats (N = 43). Our results suggest that: 1) pulmonary stretch receptors are not the sole contributor to breathing feedback in adult male and female rats; 2) of our manipulations, chest compression had the largest effect on early expiratory diaphragm activity ("yield"); 3) reduction of spinally-mediated afferent feedback modulates breathing patterns most likely via inhibition; and 4) breathing parameters demonstrate large sex differences. Compared to males, female animals had lower respiratory rates (RR), which were further depressed by vagotomy, while chest compression increased RR in males, and decreased yield in females without changing RR. Collectively, our results suggest that balance between tonic vagal inhibition and spinal afferent feedback maintains breathing characteristics, and that it is important to specifically evaluate sex differences when studying control of breathing

Minimal important differences for improvement in shoulder condition patient-reported outcomes : a systematic review to inform a BMJ Rapid Recommendation

Objectives To identify credible anchor-based minimal important differences (MIDs) for patient-reported outcome measures (PROMs) relevant to a BMJ Rapid Recommendations addressing subacromial decompression surgery for shoulder pain. Design Systematic review. Outcome measures Estimates of anchor-based MIDs, and their credibility, for PROMs judged by the parallel BMJ Rapid Recommendations panel as important for informing their recommendation (pain, function and health-related quality of life (HRQoL)). Data sources MEDLINE, EMBASE and PsycINFO up to August 2018. Study selection and review methods We included original studies of any intervention for shoulder conditions reporting estimates of anchor-based MIDs for relevant PROMs. Two reviewers independently evaluated potentially eligible studies according to predefined selection criteria. Six reviewers, working in pairs, independently extracted data from eligible studies using a predesigned, standardised, pilot-tested extraction form and independently assessed the credibility of included studies using an MID credibility tool. Results We identified 22 studies involving 5562 patients that reported 74 empirically estimated anchor-based MIDs for 10 candidate instruments to assess shoulder pain, function and HRQoL. We identified MIDs of high credibility for pain and function outcomes and of low credibility for HRQoL. We offered median estimates for the systematic review team who applied these MIDs in Grading of Recommendations Assessment, Development and Evaluation (GRADE) evidence summaries and in their interpretations of results in the linked systematic review addressing the effectiveness of surgery for shoulder pain. Conclusions Our review provides anchor-based MID estimates, as well as a rating of their credibility, for PROMs for patients with shoulder conditions. The MID estimates inform the interpretation for a linked systematic review and guideline addressing subacromial decompression surgery for shoulder pain, and could also prove useful for authors addressing other interventions for shoulder problems.Peer reviewe