Convolutional Neural Network-Based Automatic Analysis of Chest Radiographs for the Detection of COVID-19 Pneumonia: A Prioritizing Tool in the Emergency Department, Phase I Study and Preliminary “Real Life” Results

The aim of our study is the development of an automatic tool for the prioritization of COVID-19 diagnostic workflow in the emergency department by analyzing chest X-rays (CXRs). The Convolutional Neural Network (CNN)-based method we propose has been tested retrospectively on a single-center set of 542 CXRs evaluated by experienced radiologists. The SARS-CoV-2 positive dataset (n = 234) consists of CXRs collected between March and April 2020, with the COVID-19 infection being confirmed by an RT-PCR test within 24 h. The SARS-CoV-2 negative dataset (n = 308) includes CXRs from 2019, therefore prior to the pandemic. For each image, the CNN computes COVID-19 risk indicators, identifying COVID-19 cases and prioritizing the urgent ones. After installing the software into the hospital RIS, a preliminary comparison between local daily COVID-19 cases and predicted risk indicators for 2918 CXRs in the same period was performed. Significant improvements were obtained for both prioritization and identification using the proposed method. Mean Average Precision (MAP) increased (p < 1.21 × 10(−21) from 43.79% with random sorting to 71.75% with our method. CNN sensitivity was 78.23%, higher than radiologists’ 61.1%; specificity was 64.20%. In the real-life setting, this method had a correlation of 0.873. The proposed CNN-based system effectively prioritizes CXRs according to COVID-19 risk in an experimental setting; preliminary real-life results revealed high concordance with local pandemic incidence

Cost of Illness Due to Typhoid Fever in Pemba, Zanzibar, East Africa

The aim of this study was to estimate the economic burden of typhoid fever in Pemba, Zanzibar, East Africa. This study was an incidence-based cost-of-illness analysis from a societal perspective. It covered new episodes of blood culture-confirmed typhoid fever in patients presenting at the outpatient or inpatient departments of three district hospitals between May 2010 and December 2010. Cost of illness was the sum of direct costs and costs for productivity loss. Direct costs covered treatment, travel, and meals. Productivity costs were loss of income by patients and caregivers. The analysis included 17 episodes. The mean age of the patients, was 23 years (range=5-65, median=22). Thirty-five percent were inpatients, with a mean of 4.75 days of hospital stay (range=3-7, median=4.50). The mean cost for treatment alone during hospital care was US$21.97 at 2010 prices (US$ 1=1,430.50 Tanzanian Shilling\u2500TSH). The average societal cost was US$154.47 per typhoid episode. The major expenditure was productivity cost due to lost wages of US$ 128.02 (83%). Our results contribute to the further economic evaluation of typhoid fever vaccination in Zanzibar and other sub-Saharan African countries

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Changes in the miRNA-mRNA Regulatory Network Precede Motor Symptoms in a Mouse Model of Multiple System Atrophy: Clinical Implications.

Multiple system atrophy (MSA) is a fatal rapidly progressive α-synucleinopathy, characterized by α-synuclein accumulation in oligodendrocytes. It is accepted that the pathological α-synuclein accumulation in the brain of MSA patients plays a leading role in the disease process, but little is known about the events in the early stages of the disease. In this study we aimed to define potential roles of the miRNA-mRNA regulatory network in the early pre-motor stages of the disease, i.e., downstream of α-synuclein accumulation in oligodendroglia, as assessed in a transgenic mouse model of MSA. We investigated the expression patterns of miRNAs and their mRNA targets in substantia nigra (SN) and striatum, two brain regions that undergo neurodegeneration at a later stage in the MSA model, by microarray and RNA-seq analysis, respectively. Analysis was performed at a time point when α-synuclein accumulation was already present in oligodendrocytes at neuropathological examination, but no neuronal loss nor deficits of motor function had yet occurred. Our data provide a first evidence for the leading role of gene dysregulation associated with deficits in immune and inflammatory responses in the very early, non-symptomatic disease stages of MSA. While dysfunctional homeostasis and oxidative stress were prominent in SN in the early stages of MSA, in striatum differential gene expression in the non-symptomatic phase was linked to oligodendroglial dysfunction, disturbed protein handling, lipid metabolism, transmembrane transport and altered cell death control, respectively. A large number of putative miRNA-mRNAs interaction partners were identified in relation to the control of these processes in the MSA model. Our results support the role of early changes in the miRNA-mRNA regulatory network in the pathogenesis of MSA preceding the clinical onset of the disease. The findings thus contribute to understanding the disease process and are likely to pave the way towards identifying disease biomarkers for early diagnosis of MSA

Motor analysis of MSA versus age-matched control mice.

<p>Motor analysis of MSA versus age-matched control mice.</p

Neuropathological and behavioral characterization of a mouse model of a pre-motor stage of MSA.

<p>(A) Human α-synuclein overexpression in MSA transgenic mice resulted in α-synuclein accumulation in oligodendrocytes (arrows) detectable both in substantia nigra and striatum. (B) No dopaminergic neuronal loss was identified in the pre-motor stage in substantia nigra of MSA mice (n = 6) as compared to controls (n = 4) by stereological determination of the number of tyrosine hydroxylase (TH)-immunoreactrive (IR) neurons. (C) No GABAergic medium spiny neurons loss was identified in the pre-motor stage in striatum of MSA mice (n = 6) as compared to controls (n = 4) by stereological determination of the number of DARPP-32-IR neurons. (D) Iba-1-IR was used to determine the number and activation status of microglia (type A, B, C, and D [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150705#pone.0150705.ref029" target="_blank">29</a>]) in MSA (n = 3) and control mice (n = 3). No significant differences were detected between the groups with predominant representation of type A resting microglia in both substantia nigra and striatum. (E) GFAP-immunohistochemistry was used to determine the level of astroglial activation in MSA (n = 5) and control mice (n = 3) in substantia nigra and striatum. No significant differences were identified between the groups. Statistical analysis of the neuropathological data to compare control and transgenic MSA mice was done by t-test analysis with GraphPad Prism 5.03 software. Statistical significance was set at p<0.05. Data are presented as mean ± SEM. (F) TUNEL staining detected no cell death in SN and striatum of PM3 MSA mice. As a positive control we applied aged PM12 MSA mice (an age when detectable neuronal loss is recorded) that demonstrated positive TUNEL staining.</p

Deregulated miRNA-mRNA regulatory network to “Immune system process” in MSA mice in disease pre-motor stage.

<p>Differentially expressed miRNAs with predicted negatively correlated differentially expressed mRNA targets are visualized by employing Cytoscape (version 3.2.1). Round nodes show mRNA and triangle nodes miRNA. Node size is proportional to its degree. Fold change (log₂ transformed) for each node is ranging from red (negative) to green (positive). Interaction arrow thickness is proportional to the number of algorithms predicting the miRNA-mRNA target 3’ UTR interaction, ranging from one to four. Differential expression of genes, in striatum and SN, such as <i>Anln</i>, <i>Car2</i>, <i>Cd59a</i>, <i>Hba-a1</i> and <i>Rps17</i>, is visualized by color corresponding to the mean fold change (exact values can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150705#pone.0150705.s007" target="_blank">S2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0150705#pone.0150705.s008" target="_blank">S3</a> Tables).</p