34 research outputs found
The Impact of Interventions to Prevent Neonatal Healthcare-associated Infections in Low- and Middle-income Countries: A Systematic Review.
BACKGROUND: Clinically suspected and laboratory-confirmed bloodstream infections are frequent causes of morbidity and mortality during neonatal care. The most effective infection prevention and control interventions for neonates in low- and middle-income countries (LMIC) are unknown. AIM: To identify effective interventions in the prevention of hospital-acquired bloodstream infections in LMIC neonatal units. METHODS: Medline, PUBMED, the Cochrane Database of Systematic Reviews, EMBASE and PsychInfo (January 2003 to October 2020) were searched to identify studies reporting single or bundled interventions for prevention of bloodstream infections in LMIC neonatal units. RESULTS: Our initial search identified 5206 articles; following application of filters, 27 publications met the inclusion and Integrated Quality Criteria for the Review of Multiple Study Designs assessment criteria and were summarized in the final analysis. No studies were carried out in low-income countries, only 1 in Sub-Saharan Africa and just 2 in multiple countries. Of the 18 single-intervention studies, most targeted skin (n = 4) and gastrointestinal mucosal integrity (n = 5). Whereas emollient therapy and lactoferrin achieved significant reductions in proven neonatal infection, glutamine and mixed probiotics showed no benefit. Chlorhexidine gluconate for cord care and kangaroo mother care reduced infection in individual single-center studies. Of the 9 studies evaluating bundles, most focused on prevention of device-associated infections and achieved significant reductions in catheter- and ventilator-associated infections. CONCLUSIONS: There is a limited evidence base for the effectiveness of infection prevention and control interventions in LMIC neonatal units; bundled interventions targeting device-associated infections were most effective. More multisite studies with robust study designs are needed to inform infection prevention and control intervention strategies in low-resource neonatal units
Social Science and Neuroscience beyond Interdisciplinarity: Experimental Entanglements
This article is an account of the dynamics of interaction across the social sciences and neurosciences. Against an arid rhetoric of ‘interdisciplinarity’, it calls for a more expansive imaginary of what experiment – as practice and ethos – might offer in this space. Arguing that opportunities for collaboration between social scientists and neuroscientists need to be taken seriously, the article situates itself against existing conceptualizations of these dynamics, grouping them under three rubrics: ‘critique’, ‘ebullience’ and ‘interaction’. Despite their differences, each insists on a distinction between sociocultural and neurobiological knowledge, or does not show how a more entangled field might be realized. The article links this absence to the ‘regime of the inter-’, an ethic of interdisciplinarity that guides interaction between disciplines on the understanding of their pre-existing separateness. The argument of the paper is thus twofold: (1) that, contra the ‘regime of the inter-’, it is no longer practicable to maintain a hygienic separation between sociocultural webs and neurobiological architecture; (2) that the cognitive neuroscientific experiment, as a space of epistemological and ontological excess, offers an opportunity to researchers, from all disciplines, to explore and register this realization
Height, selected genetic markers and prostate cancer risk:Results from the PRACTICAL consortium
Background: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a
possible role for its association with the risk of aggressive prostate cancer.
Methods: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a
subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects
and their possible interactions.
Results: The results suggest that height is associated with high-grade prostate cancer risk. Men with height 4180cm are at a 22%
increased risk as compared to men with height o173cm (OR 1.22, 95% CI 1.01–1.48). Genetic variants in the growth pathway gene
showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased
risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as
compared to lowest score group.
Conclusions: There was no evidence of gene-environment interaction between height and the selected candidate SNPs. Our
findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is
seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.</p
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Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707
Colliding Worlds: Asteroid research and the legitimization of war in space
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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
Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.
The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)
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
Mother-to-child transmission of HIV in a community-based antiretroviral clinic in South Africa.
OBJECTIVE: To examine the uptake of ART among pregnant women referred to an ART service and the associated rates and risk factors for vertical HIV transmission. METHOD: Retrospective analysis of an observational cohort at a community ART clinic in Cape Town. RESULTS: Between 2002 and 2008, 367 treatment-naive pregnant women accessed the clinic. The median age was 27.5 years, and median gestation at presentation was 28 weeks. The median baseline CD4 count and viral load were 134 cells/µl and 28 282 copies/ml. Two hundred and sixty-five women (72%) commenced ART before giving birth, 73 women (20%) were referred for prevention of mother-to-child transmission therapy (PMTCT), and 29 (8%) received no intervention. Among ART-eligible women, 13% were lost to follow-up. Of those starting ART, median duration of therapy prior to birth was 7.6 weeks (interquartile range (IQR) 4 - 11.9).The HIV transmission rate was 5.1% (95% confidence interval (CI) 2.8 - 9.0%). Factors associated with transmission were advanced maternal WHO disease stage (odds ratio (OR) 9.57, p=0.02), and follow-up viral load above 50 copies/ml (OR 3.64, p=0.03). Each additional week on ART reduced transmission by 20% (p=0.05). There was no HIV transmission among women who received more than 8 weeks' therapy. CONCLUSIONS: The rate of HIV transmission in this study was higher than reported in high-income countries. Prevention of vertical transmission with ART was hindered by women presenting late in pregnancy and with advanced stage of HIV disease. Interventions that facilitate earlier ART commencement and improve programmatic retention of pregnant women are required