Hydroxychloroquine/chloroquine for the treatment of hospitalized patients with COVID-19: An individual participant data meta-analysis

BACKGROUND: Results from observational studies and randomized clinical trials (RCTs) have led to the consensus that hydroxychloroquine (HCQ) and chloroquine (CQ) are not effective for COVID-19 prevention or treatment. Pooling individual participant data, including unanalyzed data from trials terminated early, enables more detailed investigation of the efficacy and safety of HCQ/CQ among subgroups of hospitalized patients. METHODS: We searched ClinicalTrials.gov in May and June 2020 for US-based RCTs evaluating HCQ/CQ in hospitalized COVID-19 patients in which the outcomes defined in this study were recorded or could be extrapolated. The primary outcome was a 7-point ordinal scale measured between day 28 and 35 post enrollment; comparisons used proportional odds ratios. Harmonized de-identified data were collected via a common template spreadsheet sent to each principal investigator. The data were analyzed by fitting a prespecified Bayesian ordinal regression model and standardizing the resulting predictions. RESULTS: Eight of 19 trials met eligibility criteria and agreed to participate. Patient-level data were available from 770 participants (412 HCQ/CQ vs 358 control). Baseline characteristics were similar between groups. We did not find evidence of a difference in COVID-19 ordinal scores between days 28 and 35 post-enrollment in the pooled patient population (odds ratio, 0.97; 95% credible interval, 0.76-1.24; higher favors HCQ/CQ), and found no convincing evidence of meaningful treatment effect heterogeneity among prespecified subgroups. Adverse event and serious adverse event rates were numerically higher with HCQ/CQ vs control (0.39 vs 0.29 and 0.13 vs 0.09 per patient, respectively). CONCLUSIONS: The findings of this individual participant data meta-analysis reinforce those of individual RCTs that HCQ/CQ is not efficacious for treatment of COVID-19 in hospitalized patients

Performance of the lateral flow assay and the latex agglutination serum cryptococcal antigen test in cryptococcal disease in patients with and without HIV

Cryptococcal epidemiology is shifting toward HIV-negative populations who have diverse presentations. Cryptococcal antigen (CrAg) testing is also changing, with development of the lateral flow assay (LFA) having reported increased sensitivity and specificity, but with minimal knowledge in the HIV-negative population. In this study, we evaluate the real-life performance of CrAg testing in patients with cryptococcal disease. We conducted a retrospective review of patients with cryptococcosis from 2002 to 2019 at Barnes-Jewish Hospital. Latex agglutination (LA) was used exclusively until April 2016, at which point LFA was used exclusively. Demographics, presentations, and testing outcomes were evaluated. Serum CrAg testing was completed in 227 patients with cryptococcosis. Of 141 HIV-negative patients, 107 had LA testing and 34 had LFA testing. In patients with disseminated disease, serum CrAg sensitivity by LA was 78.1% compared to 82.6% for LFA. In patients with localized pulmonary disease, serum CrAg sensitivity was 23.5% compared to 90.9% for LFA. Of 86 people living with HIV (PLWH), 76 had LA testing, and 10 had LFA testing. Serum CrAg sensitivity for LA was 94.7% compared to 100% for LFA in patients with disseminated disease. We noted a significant improvement in sensitivity from LA testing to LFA testing, predominantly in those with localized pulmonary disease. However, both LFA and LA appear to be less sensitive in HIV-negative patients than previously described in PLWH

Brain age estimation at tract group level and its association with daily life measures, cardiac risk factors and genetic variants

Abstract Brain age can be estimated using different Magnetic Resonance Imaging (MRI) modalities including diffusion MRI. Recent studies demonstrated that white matter (WM) tracts that share the same function might experience similar alterations. Therefore, in this work, we sought to investigate such issue focusing on five WM bundles holding that feature that is Association, Brainstem, Commissural, Limbic and Projection fibers, respectively. For each tract group, we estimated brain age for 15,335 healthy participants from United Kingdom Biobank relying on diffusion MRI data derived endophenotypes, Bayesian ridge regression modeling and 10 fold-cross validation. Furthermore, we estimated brain age for an Ensemble model that gathers all the considered WM bundles. Association analysis was subsequently performed between the estimated brain age delta as resulting from the six models, that is for each tract group as well as for the Ensemble model, and 38 daily life style measures, 14 cardiac risk factors and cardiovascular magnetic resonance imaging features and genetic variants. The Ensemble model that used all tracts from all fiber groups (FG) performed better than other models to estimate brain age. Limbic tracts based model reached the highest accuracy with a Mean Absolute Error (MAE) of 5.08, followed by the Commissural ( $$\hbox {MAE}=5.23$$ MAE = 5.23 ), Association ( $$\hbox {MAE}=5.24$$ MAE = 5.24 ), and Projection ( $$\hbox {MAE}=5.28$$ MAE = 5.28 ) ones. The Brainstem tracts based model was the less accurate achieving a MAE of 5.86. Accordingly, our study suggests that the Limbic tracts experience less brain aging or allows for more accurate estimates compared to other tract groups. Moreover, the results suggest that Limbic tract leads to the largest number of significant associations with daily lifestyle factors than the other tract groups. Lastly, two SNPs were significantly (p value $$< 5\hbox {E}{-}8$$ < 5 E - 8 ) associated with brain age delta in the Projection fibers. Those SNPs are mapped to HIST1H1A and SLC17A3 genes

Creation and internal validation of a clinical predictive model for fluconazole resistance in patients with Candida bloodstream infection

BACKGROUND: Fluconazole is recommended as first-line therapy for candidemia when risk of fluconazole resistance (fluc-R) is low. Lack of methods to estimate resistance risk results in extended use of echinocandins and prolonged hospitalization. This study aimed to develop a clinical predictive model to identify patients at low risk for fluc-R where initial or early step-down fluconazole would be appropriate. METHODS: Retrospective analysis of hospitalized adult patients with positive blood culture for RESULTS: We identified 539 adults with candidemia and 72 CONCLUSIONS: This model is a potential tool for identifying patients at low risk for fluc-R candidemia to receive first-line or early step-down fluconazole

Brain age estimation at tract group level and its association with daily life measures, cardiac risk factors and genetic variants

Brain age can be estimated using different Magnetic Resonance Imaging (MRI) modalities including diffusion MRI. Recent studies demonstrated that white matter (WM) tracts that share the same function might experience similar alterations. Therefore, in this work, we sought to investigate such issue focusing on five WM bundles holding that feature that is Association, Brainstem, Commissural, Limbic and Projection fibers, respectively. For each tract group, we estimated brain age for 15,335 healthy participants from United Kingdom Biobank relying on diffusion MRI data derived endophenotypes, Bayesian ridge regression modeling and 10 fold-cross validation. Furthermore, we estimated brain age for an Ensemble model that gathers all the considered WM bundles. Association analysis was subsequently performed between the estimated brain age delta as resulting from the six models, that is for each tract group as well as for the Ensemble model, and 38 daily life style measures, 14 cardiac risk factors and cardiovascular magnetic resonance imaging features and genetic variants. The Ensemble model that used all tracts from all fiber groups (FG) performed better than other models to estimate brain age. Limbic tracts based model reached the highest accuracy with a Mean Absolute Error (MAE) of 5.08, followed by the Commissural ([Formula: see text]), Association ([Formula: see text]), and Projection ([Formula: see text]) ones. The Brainstem tracts based model was the less accurate achieving a MAE of 5.86. Accordingly, our study suggests that the Limbic tracts experience less brain aging or allows for more accurate estimates compared to other tract groups. Moreover, the results suggest that Limbic tract leads to the largest number of significant associations with daily lifestyle factors than the other tract groups. Lastly, two SNPs were significantly (p value [Formula: see text]) associated with brain age delta in the Projection fibers. Those SNPs are mapped to HIST1H1A and SLC17A3 genes

The +276 G/T Single Nucleotide Polymorphism of the Adiponectin Gene Is Associated With Coronary Artery Disease in Type 2 Diabetic Patients

OBJECTIVE —Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45T>G and +276G>T) have been associated with low circulating adiponectin levels, insulin resistance, and type 2 diabetes. We investigated whether these genetic markers are determinants of coronary artery disease (CAD) in type 2 diabetic patients. RESEARCH DESIGN AND METHODS —A total of 376 consecutive type 2 diabetic patients were studied: 142 case subjects with coronary stenosis >50% or previous myocardial infarction and 234 control subjects with no symptoms, no electrocardiogram (ECG) signs of myocardial ischemia, and a normal ECG stress test ( n = 189) and/or ( n = 45) with coronary stenosis ≤50%. RESULTS —No association with CAD was observed for the +45 SNP ( P = 0.48). By contrast, a significant association was observed for the +276 SNP, with T/T homozygotes having a lower risk of CAD than carriers of other genotypes (adjusted odds ratio [OR] 0.13 [95% CI 0.037–0.46], P = 0.002). A similarly protective effect of the +276 T/T genotype was observed in 110 case and 45 control subjects for whom the CAD status had been determined by angiography (0.04 [0.006–0.30], P = 0.002).  Serum adiponectin, although clearly related to several features of the proatherogenic/insulin-resistant phenotype, was not different between control subjects and CAD patients (26 ± 17 vs. 25 ± 13 μg/ml). CONCLUSIONS —In conclusion, the +276 G>T polymorphism is a determinant of CAD risk in type 2 diabetic patients. This marker may assist in the identification of diabetic individuals at especially high risk of CAD, so that preventive programs can be targeted at these subjects

Prevalence, Cardiac Phenotype, and Outcomes of Transthyretin Variants in the UK Biobank Population

Importance: The population prevalence of cardiac transthyretin amyloidosis (ATTR) caused by pathogenic variation in the TTR gene (vATTR) is unknown. // Objective: To estimate the population prevalence of disease-causing TTR variants and evaluate associated phenotypes and outcomes. // Design, Setting, and Participants: This population-based cohort study analyzed UK Biobank (UKB) participants with whole-exome sequencing, electrocardiogram, and cardiovascular magnetic resonance data. Participants were enrolled from 2006 to 2010, with a median follow-up of 12 (IQR, 11-13) years (cutoff date for the analysis, March 12, 2024). Sixty-two candidate TTR variants were extracted based on rarity (minor allele frequency ≤0.0001) and/or previously described associations with amyloidosis if more frequent. // Exposure: Carrier status for TTR variants. // Main Outcomes and Measures: Associations of TTR carrier status with vATTR prevalence and cardiovascular imaging and electrocardiogram traits were explored using descriptive statistics. Associations between TTR carrier status and atrial fibrillation, conduction disease, heart failure, and all-cause mortality were evaluated using adjusted Cox proportional hazards models. Genotypic and diagnostic concordance was examined using International Statistical Classification of Diseases, Tenth Revision codes from the hospital record. // Results: The overall cohort included 469 789 UKB participants (mean [SD] age, 56.5 [8.1] years; 54.2% female and 45.8% male). A likely pathogenic/pathogenic (LP/P) TTR variant was detected in 473 (0.1%) participants, with Val142Ile being the most prevalent (367 [77.6%]); 91 individuals (0.02%) were carriers of a variant of unknown significance . The overall prevalence of LP/P variants was 0.02% (105 of 444 243) in participants with European ancestry and 4.3% (321 of 7533) in participants with African ancestry. The LP/P variants were associated with higher left ventricular mass indexed to body surface area (β = 4.66; 95% CI, 1.87-7.44), and Val142Ile was associated with a longer PR interval (β = 18.34; 95% CI, 5.41-31.27). The LP/P carrier status was associated with a higher risk of heart failure (hazard ratio [HR], 2.68; 95% CI, 1.75-4.12) and conduction disease (HR, 1.88; 95% CI, 1.25-2.83). Higher all-cause mortality risk was observed for non-Val142Ile LP/P variants (HR, 1.98; 95% CI, 1.06-3.67). Thirteen participants (2.8%) with LP/P variants had diagnostic codes compatible with cardiac or neurologic amyloidosis. Variants of unknown significance were not associated with outcomes. // Conclusions and Relevance: This study found that approximately 1 in 1000 UKB participants were LP/P TTR variant carriers, exceeding previously reported prevalence. The findings emphasize the need for clinical vigilance in identifying individuals at risk of developing vATTR and associated poor outcomes

The main concerns of European anaesthesiology postgraduate trainees: A European survey

This is the first study intended to identify the European anaesthesiology trainees' main concerns, to initiate a process of improvement of the training in anaesthesiology by the European Society of Anaesthesiology (ESA). The authors developed an electronic survey which addressed seven different concerns: autonomy transition, technical skills, exchange programs, residency costs, residency workload, employment prospects and educational contents/preparation for the European Diploma in Anaesthesiology and Intensive Care (EDAIC). The survey was disseminated by email to all anaesthesiology trainees registered in ESA and all European National Societies were asked to distribute the survey to their graduating trainees. 665 trainees initiated the survey with a completion rate of 54.6%. The trainees' main concerns were in descending order: educational contents, residency costs, employment prospects, residency workload, exchange programs, technical skills and autonomy transition. This report analyzes the three main concerns in more detail. 68% of respondents were unaware of the existence of the ESA e-learning platform. Other means to improve the preparation for the EDAIC such as a multiple-choice questions book should be developed. The main reason for not becoming an ESA Trainee member was the associated cost and 68% of respondents gave up activities or opportunities during their residency due to economic constraints; 56% of respondents considered emigrating for economic reasons and 28% elected Northern/Central Europe. The results of the present survey may provide additional background information for the development of specific improvements in strategies for training in anaesthesiology. (c) 2018 Elsevier Ltd. All rights reserved

Circulating mitochondrial DNA is an early indicator of severe illness and mortality from COVID-19

BackgroundMitochondrial DNA (MT-DNA) are intrinsically inflammatory nucleic acids released by damaged solid organs. Whether circulating cell-free MT-DNA quantitation could be used to predict the risk of poor COVID-19 outcomes remains undetermined.MethodsWe measured circulating MT-DNA levels in prospectively collected, cell-free plasma samples from 97 subjects with COVID-19 at hospital presentation. Our primary outcome was mortality. Intensive care unit (ICU) admission, intubation, vasopressor, and renal replacement therapy requirements were secondary outcomes. Multivariate regression analysis determined whether MT-DNA levels were independent of other reported COVID-19 risk factors. Receiver operating characteristic and area under the curve assessments were used to compare MT-DNA levels with established and emerging inflammatory markers of COVID-19.ResultsCirculating MT-DNA levels were highly elevated in patients who eventually died or required ICU admission, intubation, vasopressor use, or renal replacement therapy. Multivariate regression revealed that high circulating MT-DNA was an independent risk factor for these outcomes after adjusting for age, sex, and comorbidities. We also found that circulating MT-DNA levels had a similar or superior area under the curve when compared against clinically established measures of inflammation and emerging markers currently of interest as investigational targets for COVID-19 therapy.ConclusionThese results show that high circulating MT-DNA levels are a potential early indicator for poor COVID-19 outcomes.FundingWashington University Institute of Clinical Translational Sciences COVID-19 Research Program and Washington University Institute of Clinical Translational Sciences (ICTS) NIH grant UL1TR002345