SARS-CoV-2 infects cells lining the blood-retinal barrier and induces a hyperinflammatory immune response in the retina via systemic exposure.

SARS-CoV-2 has been shown to cause wide-ranging ocular abnormalities and vision impairment in COVID-19 patients. However, there is limited understanding of SARS-CoV-2 in ocular transmission, tropism, and associated pathologies. The presence of viral RNA in corneal/conjunctival tissue and tears, along with the evidence of viral entry receptors on the ocular surface, has led to speculation that the eye may serve as a potential route of SARS-CoV-2 transmission. Here, we investigated the interaction of SARS-CoV-2 with cells lining the blood-retinal barrier (BRB) and the role of the eye in its transmission and tropism. The results from our study suggest that SARS-CoV-2 ocular exposure does not cause lung infection and moribund illness in K18-hACE2 mice despite the extended presence of viral remnants in various ocular tissues. In contrast, intranasal exposure not only resulted in SARS-CoV-2 spike (S) protein presence in different ocular tissues but also induces a hyperinflammatory immune response in the retina. Additionally, the long-term exposure to viral S-protein caused microaneurysm, retinal pigmented epithelium (RPE) mottling, retinal atrophy, and vein occlusion in mouse eyes. Notably, cells lining the BRB, the outer barrier, RPE, and the inner barrier, retinal vascular endothelium, were highly permissive to SARS-CoV-2 replication. Unexpectedly, primary human corneal epithelial cells were comparatively resistant to SARS-CoV-2 infection. The cells lining the BRB showed induced expression of viral entry receptors and increased susceptibility towards SARS-CoV-2-induced cell death. Furthermore, hyperglycemic conditions enhanced the viral entry receptor expression, infectivity, and susceptibility of SARS-CoV-2-induced cell death in the BRB cells, confirming the reported heightened pathological manifestations in comorbid populations. Collectively, our study provides the first evidence of SARS-CoV-2 ocular tropism via cells lining the BRB and that the virus can infect the retina via systemic permeation and induce retinal inflammation.

2024 AHA/ACC/ACS/ASNC/HRS/SCA/SCCT/SCMR/SVM Guideline for Perioperative Cardiovascular Management for Noncardiac Surgery: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 AHA/ACC/ACS/ASNC/HRS/SCA/SCCT/SCMR/SVM Guideline for Perioperative Cardiovascular Management for Noncardiac Surgery" provides recommendations to guide clinicians in the perioperative cardiovascular evaluation and management of adult patients undergoing noncardiac surgery. METHODS: A comprehensive literature search was conducted from August 2022 to March 2023 to identify clinical studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: Recommendations from the "2014 ACC/AHA Guideline on Perioperative Cardiovascular Evaluation and Management of Patients Undergoing Noncardiac Surgery" have been updated with new evidence consolidated to guide clinicians; clinicians should be advised this guideline supersedes the previously published 2014 guideline. In addition, evidence-based management strategies, including pharmacological therapies, perioperative monitoring, and devices, for cardiovascular disease and associated medical conditions, have been developed.

Viral infections and pathogenesis of glaucoma: a comprehensive review.

Glaucoma is a leading cause of irreversible blindness worldwide, caused by the gradual degeneration of retinal ganglion cells and their axons. While glaucoma is primarily considered a genetic and age-related disease, some inflammatory conditions, such as uveitis and viral-induced anterior segment inflammation, cause secondary or uveitic glaucoma. Viruses are predominant ocular pathogens and can impose both acute and chronic pathological insults to the human eye. Many viruses, including herpes simplex virus, varicella-zoster virus, cytomegalovirus, rubella virus, dengue virus, chikungunya virus, Ebola virus, and, more recently, Zika virus (ZIKV) and severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), have been associated with sequela of either primary or secondary glaucoma. Epidemiological and clinical studies suggest the association between these viruses and subsequent glaucoma development. Despite this, the ocular manifestation and sequela of viral infections are not well understood. In fact, the association of viruses with glaucoma is considered relatively uncommon in part due to underreporting and/or lack of long-term follow-up studies. In recent years, literature on the pathological spectrum of emerging viral infections, such as ZIKV and SARS-CoV-2, has strengthened this proposition and renewed research activity in this area. Clinical studies from endemic regions as well as laboratory and preclinical investigations demonstrate a strong link between an infectious trigger and development of glaucomatous pathology. In this article, we review the current understanding of the field with a particular focus on viruses and their association with the pathogenesis of glaucoma.

Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease.

BACKGROUND: The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy. METHODS: Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis. RESULTS: A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]). CONCLUSIONS: In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

The multifaceted functions of long non-coding RNA HOTAIR in neuropathologies and its potential as a prognostic marker and therapeutic biotarget.

Long non-coding RNAs (lncRNAs) are progressively being perceived as prominent molecular agents controlling multiple aspects of neuronal (patho)physiology. Amongst these is the HOX transcript antisense intergenic RNA, often abbreviated as HOTAIR. HOTAIR epigenetically regulates its target genes via its interaction with two different chromatin-modifying agents; histone methyltransferase polycomb-repressive complex 2 and histone demethylase lysine-specific demethylase 1. Parenthetically, HOTAIR elicits trans-acting sponging function against multiple micro-RNA species. Oncological research studies have confirmed the pathogenic functions of HOTAIR in multiple cancer types, such as gliomas and proposed it as a pro-oncological lncRNA. In fact, its expression has been suggested to be a predictor of the severity/grade of gliomas, and as a prognostic biomarker. Moreover, a propound influence of HOTAIR in other aspects of brain heath and disease states is just beginning to be unravelled. The objective of this review is to recapitulate all the relevant data pertaining to the regulatory roles of HOTAIR in neuronal (patho)physiology. To this end, we discuss the pathogenic mechanisms of HOTAIR in multiple neuronal diseases, such as neurodegeneration, traumatic brain injury and neuropsychiatric disorders. Finally, we also summarize the results from the studies incriminating HOTAIR in the pathogeneses of gliomas and other brain cancers. Implications of HOTAIR serving as a suitable therapeutic target in neuropathologies are also discussed.

Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder.

PURPOSE: Biallelic INPP4A variants have recently been associated with severe neurodevelopmental disease in single case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations. METHODS: Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies. RESULTS: We characterize a clinically variable disorder with cardinal features including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in Inpp4a-/- mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition. CONCLUSION: Our studies comprehensively characterise INPP4A-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.

Roles of HOTAIR Long Non-coding RNA in Gliomas and Other CNS Disorders.

HOX transcript antisense intergenic RNA (HOTAIR) is a long non-coding RNA (lncRNA) which is increasingly being perceived as a tremendous molecular mediator of brain pathophysiology at multiple levels. Epigenetic regulation of target gene expression carried out by HOTAIR is thorough modulation of chromatin modifiers; histone methyltransferase polycomb repressive complex 2 (PRC2) and histone demethylase lysine-specific demethylase 1 (LSD1). Incidentally, HOTAIR was the first lncRNA shown to elicit sponging of specific microRNA (miRNA or miR) species in a trans-acting manner. It has been extensively studied in various cancers, including gliomas and is regarded as a prominent pro-tumorigenic and pro-oncogenic lncRNA. Indeed, the expression of HOTAIR may serve as glioma grade predictor and prognostic biomarker. The objective of this timely review is not only to outline the multifaceted pathogenic roles of HOTAIR in the development and pathophysiology of gliomas and brain cancers, but also to delineate the research findings implicating it as a critical regulator of overall brain pathophysiology. While the major focus is on neuro-oncology, wherein HOTAIR represents a particularly potent underlying pathogenic player and a suitable therapeutic target, mechanisms underlying the regulatory actions of HOTAIR in neurodegeneration, traumatic, hypoxic and ischemic brain injuries, and neuropsychiatric disorders are also presented.

Effect of exercise on fatigue and depression in breastcancer women undergoing chemotherapy: a systematic review and meta-analysis.

This meta-analysis examined the effectiveness of exercise interventions in reducing fatigue and depression among women undergoing chemotherapy for breast cancer. The study followed PRISMA guidelines and analysed seven randomized controlled trials between 2016 and 2022. The results showed that exercise can substantially reduce fatigue levels (MD: -0.40, CI: -0.66, -0.14, P: 0.003), a common side effect of chemotherapy. Although depression did not significantly change (MD: -0.39, CI: -0.98, 0.20, P: 0.19), this study highlights the positive impact of exercise on mental health outcomes. The control group also experienced decreased quality of life (MD: 0.18, CI: 0.01-0.35, P: 0.03), emphasizing the importance of incorporating exercise interventions to improve overall well-being during breast cancer treatment. In addition to primary outcomes, the study revealed that exercise positively affected secondary aspects such as cognitive fatigue, social function, physical function, constipation, and dyspnoea.

Ineffective ventilation in a very low birth weight infant with H-type Tracheoesophageal Fistula with bilateral chemical pneumonitis. A lesson learned.

Tracheoesophageal fistula (TEF) with or without associated esophageal atresia (EA) in the neonate is challenging to diagnose and manage its complications like aspiration, respiratory distress, and other associated anomalies. To stabilize, ventilate and prepare for surgical correction, understanding the H-nature of disease and anticipation of problems and their management will improve survival. We present a newborn with tracheoesophageal fistula without atresia from resource-limited settings and lessons we learned from the case.

"I Just Wanted Nothing More Than to Get in a Real Shower": Patient Experience of the Inpatient Wait for a Heart Transplant.

BACKGROUND: Patients waiting for heart transplant may be hospitalized for weeks to months before undergoing transplantation. This high-stress period is further complicated by restrictions of daily privileges including diet, rooming, access to the outdoors, and hygiene (eg, limited in ability to shower). However, there is a paucity of research on the experience of this waiting period. We sought to describe the inpatient experience among patients awaiting heart transplantation and to better understand the needs of inpatients waiting for heart transplant. METHODS AND RESULTS: We conducted in-depth, semistructured phone interviews with a purposeful sample of patients who received a heart transplant in the past 10 years and waited in the hospital for at least 2 weeks before surgery. Using the prior literature, the lived experience of the lead author, and input from qualitative experts, we developed an interview guide. Interviews were recorded, transcribed, and analyzed in an iterative process until theoretical saturation was achieved. A 3-person coding team identified, discussed, and reconciled emergent themes. We conducted interviews with 15 patients. Overarching themes included food, hygiene, relationship with health care professionals, living environment, and stressors. Patients reported that strong bonds were formed between the patients and the staff, and the overwhelming majority only had positive comments about these relationships. However, many expressed negative comments about the experience of the food and limitations in personal hygiene. Other stressors included the unknown length of the waiting period, lack of communication about position on the transplant list, worry about family, and concerns that their life must be saved by the death of another. Many participants described that they would benefit from more interaction with recent heart transplant recipients. CONCLUSIONS: Hospitals and care units have the opportunity to make small changes that could greatly benefit the experience of waiting for a heart transplant, as well as the experience of hospitalization more generally.

Association Between End-Stage Liver Disease and Incident Heart Failure in an Integrated Health System.

BACKGROUND: End-stage liver disease (ESLD) and heart failure (HF) often coexist and are associated with significant morbidity and mortality. However, the true incidence of HF among patients with ESLD remains understudied. OBJECTIVE: This study aims to evaluate the association between ESLD and incident HF in a real-world clinical cohort. DESIGN AND PARTICIPANTS: A retrospective electronic health records database analysis of individuals with ESLD and frequency-matched controls without ESLD in a large integrated health system. MAIN MEASURES: The primary outcome was incident HF, which was defined by the International Classification of Disease codes and manually adjudicated by physician reviewers. The Kaplan-Meier method was used to estimate the cumulative incidence of HF. Multivariate proportional hazards models adjusted for shared metabolic factors (diabetes, hypertension, chronic kidney disease, coronary heart disease, body mass index) were used to compare the risk of HF in patients with and without ESLD. KEY RESULTS: Of 5004 patients (2502 with ESLD and 2502 without ESLD), the median (Q1-Q3) age was 57.0 (55.0-65.0) years, 59% were male, and 18% had diabetes. Over a median (Q1-Q3) follow-up of 2.3 (0.6-6.0) years, 121 incident HF cases occurred. Risk for incident HF was significantly higher for patients with ESLD compared with the non-ESLD group (adjusted HR: 4.67; 95% CI: 2.82-7.75; p < 0.001), with the majority of the ESLD group (70.7%) having HF with preserved ejection fraction (ejection fraction ≥ 50%). CONCLUSION: ESLD was significantly associated with a higher risk of incident HF, independent of shared metabolic risk factors, with the predominant phenotype being HF with preserved ejection fraction.

Molecular mechanisms of neuroprotective offerings by rosmarinic acid against neurodegenerative and other CNS pathologies.

Rosmarinic acid (RA) is a natural phenolic compound present in culinary herbs of the Boraginaceae, Lamiaceae/Labiatae, and Nepetoideae families. While the medicinal applications of these plants have been known for ages, RA has only been relatively recently established as an effective ameliorative agent against various disorders including cardiac diseases, cancer, and neuropathologies. In particular, several studies have confirmed the neuroprotective potential of RA in multiple cellular and animal models, as well as in clinical studies. The neuroprotective effects mediated by RA stem from its multimodal actions on a plethora of cellular and molecular pathways; including oxidative, bioenergetic, neuroinflammatory, and synaptic signaling. In recent years, RA has garnered tremendous interest as an ideal therapeutic candidate for treating neurodegenerative diseases. This review first briefly discusses the pharmacokinetics of RA and then proceeds to detail the neuroprotective mechanisms of RA at the molecular levels. Finally, the authors focus on the ameliorative potential of RA against several central nervous system (CNS) disorders, ranging from neuropsychological stress and epilepsy to neurodegenerative diseases such as Alzheimer's disease, Huntington's disease, Parkinson's disease, Lewy body dementia, and amyotrophic lateral sclerosis.

The Emerging Role of Artificial Intelligence in Valvular Heart Disease.

Valvular heart disease (VHD) is a morbid condition in which timely identification and evidence-based treatments can lead to improved outcomes. Artificial intelligence broadly refers to the ability for computers to perform tasks and problem solve like the human mind. Studies applying AI to VHD have used a variety of structured (eg, sociodemographic, clinical) and unstructured (eg, electrocardiogram, phonocardiogram, and echocardiograms) and machine learning modeling approaches. Additional researches in diverse populations, including prospective clinical trials, are needed to evaluate the effectiveness and value of AI-enabled medical technologies in clinical care for patients with VHD.

A Cohort Analysis of Statin Treatment Patterns Among Small-Sized Primary Care Practices.

BACKGROUND: Small-sized primary care practices, defined as practices with fewer than 10 clinicians, delivered the majority of outpatient visits in the USA. Statin therapy in high-risk individuals reduces atherosclerotic cardiovascular disease (ASCVD) events, but prescribing patterns in small primary care practices are not well known. This study describes statin treatment patterns in small-sized primary care practices and examines patient- and practice-level factors associated with lack of statin treatment. METHODS: We conducted a retrospective cohort analysis of statin-eligible patients from practices that participated in Healthy Hearts in the Heartland (H3), a quality improvement initiative aimed at improving cardiovascular care measures in small primary care practices. All statin-eligible adults who received care in one of 53 H3 practices from 2013 to 2016. Statin-eligible adults include those aged at least 21 with (1) clinical ASCVD, (2) low-density lipoprotein cholesterol (LDL-C) ≥ 190 mg/dL, or (3) diabetes aged 40-75 and with LDL-C 70-189 mg/dL. Eligible patients with no record of moderate- to high-intensity statin prescription are defined by ACC/AHA guidelines. RESULTS: Among the 13,330 statin-eligible adults, the mean age was 58 years and 52% were women. Overall, there was no record of moderate- to high-intensity statin prescription among 5,780 (43%) patients. Younger age, female sex, and lower LDL-C were independently associated with a lack of appropriate intensity statin therapy. Higher proportions of patients insured by Medicaid and having only family medicine trained physicians (versus having at least one internal medicine trained physician) at the practice were also associated with lower appropriate intensity statin use. Lack of appropriate intensity statin therapy was higher in independent practices than in Federally Qualified Health Centers (FQHCs) (50% vs. 40%, p value < 0.01). CONCLUSIONS: There is an opportunity for improved ASCVD risk reduction in small primary care practices. Statin treatment patterns and factors influencing lack of treatment vary by practice setting, highlighting the importance of tailored approaches to each setting.

Direct Comparison of Diagnostic Accuracy of Fast Kilovoltage Switching Dual-Energy Computed Tomography and Magnetic Resonance Imaging for Detection of Enhancement in Renal Masses.

PURPOSE: The aim of the study was to compare diagnostic accuracy of dual-energy computed tomography (DECT) and magnetic resonance imaging (MRI) to detect enhancement in renal masses. METHODS: Adults renal masses of 10 mm or greater with both fast kilovoltage potential switching DECT and contrast-enhanced MRI performed within 12 months were retrospectively included. Two blinded radiologists independently evaluated for enhancement subjectively (5-point Likert scales) and quantitatively (signal intensity ratio ≥15% for MRI, iodine concentration ≥1.2 or ≥2.0 mg/mL for DECT). Per-lesion diagnostic accuracy, with histologic reference standard for solid masses, was expressed as the area under the receiver operator curve (AUC) for each index test. Differences were evaluated for statistical significance using the DeLong test. RESULTS: We included 24 patients with 41 masses: 17 solid renal masses and 24 Bosniak 1 or 2 cysts. There was no significant difference in diagnostic accuracy comparing subjective enhancement by MRI and using iodine overlay DECT for reader 1 (AUC 0.99 vs 0.99, P = 0.38) or reader 2 (AUC 1.00 vs 0.94, P = 0.12) Interobserver agreement was κ = 0.61 for DECT and κ = 0.71 for MRI. There was no significant difference either in accuracy between quantitative assessment using signal intensity ratio or iodine concentration for reader 1 (AUC 0.94 vs 0.94, P = 0.88) or reader 2 (AUC 0.97 vs 0.92, P = 0.16). False-negative results in both subjective and quantitative assessment were nearly exclusively seen in papillary renal cell carcinoma, occurring with both DECT and MRI. CONCLUSIONS: We detected no significant differences in accuracy for detecting enhancement in renal masses comparing MRI and DECT. Our results require further investigation in larger sample sizes, but suggest that DECT may be comparable to MRI for detection of enhancement in renal masses.

Thoracic imaging tests for the diagnosis of COVID-19.

BACKGROUND: Our March 2021 edition of this review showed thoracic imaging computed tomography (CT) to be sensitive and moderately specific in diagnosing COVID-19 pneumonia. This new edition is an update of the review. OBJECTIVES: Our objectives were to evaluate the diagnostic accuracy of thoracic imaging in people with suspected COVID-19; assess the rate of positive imaging in people who had an initial reverse transcriptase polymerase chain reaction (RT-PCR) negative result and a positive RT-PCR result on follow-up; and evaluate the accuracy of thoracic imaging for screening COVID-19 in asymptomatic individuals. The secondary objective was to assess threshold effects of index test positivity on accuracy. SEARCH METHODS: We searched the COVID-19 Living Evidence Database from the University of Bern, the Cochrane COVID-19 Study Register, The Stephen B. Thacker CDC Library, and repositories of COVID-19 publications through to 17 February 2021. We did not apply any language restrictions. SELECTION CRITERIA: We included diagnostic accuracy studies of all designs, except for case-control, that recruited participants of any age group suspected to have COVID-19. Studies had to assess chest CT, chest X-ray, or ultrasound of the lungs for the diagnosis of COVID-19, use a reference standard that included RT-PCR, and report estimates of test accuracy or provide data from which we could compute estimates. We excluded studies that used imaging as part of the reference standard and studies that excluded participants with normal index test results. DATA COLLECTION AND ANALYSIS: The review authors independently and in duplicate screened articles, extracted data and assessed risk of bias and applicability concerns using QUADAS-2. We presented sensitivity and specificity per study on paired forest plots, and summarized pooled estimates in tables. We used a bivariate meta-analysis model where appropriate. MAIN RESULTS: We included 98 studies in this review. Of these, 94 were included for evaluating the diagnostic accuracy of thoracic imaging in the evaluation of people with suspected COVID-19. Eight studies were included for assessing the rate of positive imaging in individuals with initial RT-PCR negative results and positive RT-PCR results on follow-up, and 10 studies were included for evaluating the accuracy of thoracic imaging for imagining asymptomatic individuals. For all 98 included studies, risk of bias was high or unclear in 52 (53%) studies with respect to participant selection, in 64 (65%) studies with respect to reference standard, in 46 (47%) studies with respect to index test, and in 48 (49%) studies with respect to flow and timing. Concerns about the applicability of the evidence to: participants were high or unclear in eight (8%) studies; index test were high or unclear in seven (7%) studies; and reference standard were high or unclear in seven (7%) studies. Imaging in people with suspected COVID-19 We included 94 studies. Eighty-seven studies evaluated one imaging modality, and seven studies evaluated two imaging modalities. All studies used RT-PCR alone or in combination with other criteria (for example, clinical signs and symptoms, positive contacts) as the reference standard for the diagnosis of COVID-19. For chest CT (69 studies, 28285 participants, 14,342 (51%) cases), sensitivities ranged from 45% to 100%, and specificities from 10% to 99%. The pooled sensitivity of chest CT was 86.9% (95% confidence interval (CI) 83.6 to 89.6), and pooled specificity was 78.3% (95% CI 73.7 to 82.3). Definition for index test positivity was a source of heterogeneity for sensitivity, but not specificity. Reference standard was not a source of heterogeneity. For chest X-ray (17 studies, 8529 participants, 5303 (62%) cases), the sensitivity ranged from 44% to 94% and specificity from 24 to 93%. The pooled sensitivity of chest X-ray was 73.1% (95% CI 64. to -80.5), and pooled specificity was 73.3% (95% CI 61.9 to 82.2). Definition for index test positivity was not found to be a source of heterogeneity. Definition for index test positivity and reference standard were not found to be sources of heterogeneity. For ultrasound of the lungs (15 studies, 2410 participants, 1158 (48%) cases), the sensitivity ranged from 73% to 94% and the specificity ranged from 21% to 98%. The pooled sensitivity of ultrasound was 88.9% (95% CI 84.9 to 92.0), and the pooled specificity was 72.2% (95% CI 58.8 to 82.5). Definition for index test positivity and reference standard were not found to be sources of heterogeneity. Indirect comparisons of modalities evaluated across all 94 studies indicated that chest CT and ultrasound gave higher sensitivity estimates than X-ray (P = 0.0003 and P = 0.001, respectively). Chest CT and ultrasound gave similar sensitivities (P=0.42). All modalities had similar specificities (CT versus X-ray P = 0.36; CT versus ultrasound P = 0.32; X-ray versus ultrasound P = 0.89). Imaging in PCR-negative people who subsequently became positive For rate of positive imaging in individuals with initial RT-PCR negative results, we included 8 studies (7 CT, 1 ultrasound) with a total of 198 participants suspected of having COVID-19, all of whom had a final diagnosis of COVID-19. Most studies (7/8) evaluated CT. Of 177 participants with initially negative RT-PCR who had positive RT-PCR results on follow-up testing, 75.8% (95% CI 45.3 to 92.2) had positive CT findings. Imaging in asymptomatic PCR-positive people For imaging asymptomatic individuals, we included 10 studies (7 CT, 1 X-ray, 2 ultrasound) with a total of 3548 asymptomatic participants, of whom 364 (10%) had a final diagnosis of COVID-19. For chest CT (7 studies, 3134 participants, 315 (10%) cases), the pooled sensitivity was 55.7% (95% CI 35.4 to 74.3) and the pooled specificity was 91.1% (95% CI 82.6 to 95.7). AUTHORS' CONCLUSIONS: Chest CT and ultrasound of the lungs are sensitive and moderately specific in diagnosing COVID-19. Chest X-ray is moderately sensitive and moderately specific in diagnosing COVID-19. Thus, chest CT and ultrasound may have more utility for ruling out COVID-19 than for differentiating SARS-CoV-2 infection from other causes of respiratory illness. The uncertainty resulting from high or unclear risk of bias and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results.

Altered Brain Arginine Metabolism and Polyamine System in a P301S Tauopathy Mouse Model: A Time-Course Study.

Altered arginine metabolism (including the polyamine system) has recently been implicated in the pathogenesis of tauopathies, characterised by hyperphosphorylated and aggregated microtubule-associated protein tau (MAPT) accumulation in the brain. The present study, for the first time, systematically determined the time-course of arginine metabolism changes in the MAPT P301S (PS19) mouse brain at 2, 4, 6, 8 and 12 months of age. The polyamines putrescine, spermidine and spermine are critically involved in microtubule assembly and stabilization. This study, therefore, further investigated how polyamine biosynthetic and catabolic enzymes changed in PS19 mice. There were general age-dependent increases of L-arginine, L-ornithine, putrescine and spermidine in the PS19 brain (particularly in the hippocampus and parahippocampal region). While this profile change clearly indicates a shift of arginine metabolism to favor polyamine production (a polyamine stress response), spermine levels were decreased or unchanged due to the upregulation of polyamine retro-conversion pathways. Our results further implicate altered arginine metabolism (particularly the polyamine system) in the pathogenesis of tauopathies. Given the role of the polyamines in microtubule assembly and stabilization, future research is required to understand the functional significance of the polyamine stress response and explore the preventive and/or therapeutic opportunities for tauopathies by targeting the polyamine system.

Comparison of 5 Rectal Preparation Strategies for Prostate MRI and Impact on Image Quality.

PURPOSE: To compare 5 different rectal preparation strategies for prostate MRI. METHODS: This 5-arm quality-assurance study evaluated 56 patients per arm (280 patients) including: no preparation, clear-fluids diet (CFD) beginning at 00:00 hours on the day of MRI, Fleet®-enema, enema + CFD, enema + CFD + IV-antispasmodic agent. The study was powered to 0.80 with alpha-error of 0.05. Three blinded radiologists independently evaluated T2-Weighted (T2W) and Diffusion Weighed Imaging (DWI) for: rectal diameter (maximal AP diameter), rectal content (stool, fluid, gas), rectal motion, T2W/DWI image quality, T2W image sharpness and DWI susceptibility artifact using 5-point Likert scales. Overall comparisons were performed using analysis of variance (ANOVA) and Kruskal-Wallis, with pair-wise comparisons using paired t-tests and Wilcoxon sign-rank tests. RESULTS: Rectal diameter and amount of gas were lower in enema compared to non-enema groups (p < 0.001), with smallest diameter and least gas in the enema + CFD + IV-antispasmodic group (p = 0.022-<0.001). T2W image quality and sharpness were highest in the enema + CFD groups (p < 0.001) with no difference comparing enema + CFD with/without IV-antispasmodic (p = 0.064, 0.084). Motion artifact was least in enema + CFD + IV-antispasmodic group compared to all other groups (p < 0.001), followed by the enema + CFD group (p = 0.008-<0.001). DWI image quality was highest (p < 0.001) and DWI susceptibility artifact lowest (p < 0.001) in the enema + CFD groups (p < 0.001) and did not differ comparing enema + CFD with/without anti-spasmodic (p = 0.058-0.202). CONCLUSIONS: Use of enema + clear-fluids diet before prostate MRI yields the highest T2W and DWI image quality with the least DWI artifact. IV-antispasmodic use reduces motion on T2W but does not improve image quality on T2W or DWI, or lessen DWI artifact compared to enema + clear-fluids diet.

Advances in Machine Learning Approaches to Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) represents a prototypical cardiovascular condition in which machine learning may improve targeted therapies and mechanistic understanding of pathogenesis. Machine learning, which involves algorithms that learn from data, has the potential to guide precision medicine approaches for complex clinical syndromes such as HFpEF. It is therefore important to understand the potential utility and common pitfalls of machine learning so that it can be applied and interpreted appropriately. Although machine learning holds considerable promise for HFpEF, it is subject to several potential pitfalls, which are important factors to consider when interpreting machine learning studies.

Teleological cooption of Mycobacterium tuberculosis PE/PPE proteins as porins: Role in molecular immigration and emigration.

Permeation through bacterial cells for exchange or uptake of biomolecules and ions invariably depend upon the existence of pore-forming proteins (porins) in their outer membrane. Mycobacterium tuberculosis (M. tb) harbours one of the most rigid cell envelopes across bacterial genera and is devoid of the classical porins for solute transport across the cell membrane. Though canonical porins are incompatible with the evolution of permeability barrier, porin like activity has been reported from membrane preparations of pathogenic mycobacteria. This suggests a sophisticated transport mechanism that has been elusive until now, along with the protein family responsible for it. Recent evidence suggests that these slow-growing mycobacteria have co-opted some of PE/PPE family proteins as molecular transport channels, in place of porins, to facilitate uptake of nutrients required to thrive in the restrictive host environment. These reports advocate that PE/PPE proteins, due to their structural ability, have a potential role in importing small molecules to the cell's interior. This mechanism unveils how a successful pathogen overcomes its restrictive membrane's transport limitations for selective uptake of nutrients. If extrapolated to have a role in drug transport, these channels could help understand the emergence of drug resistance. Further, as these proteins are associated with the export of virulence factors, they can be exploited as novel drug targets. There remains, however, an interesting question that as the PE/PPE proteins can allow the 'import' of molecules from outside the cell, is the reverse transport also possible across the M. tb membrane. In this review, we have discussed recent evidence supporting PE/PPE's role as a specific transport channel for selective uptake of small molecule nutrients and, as possible molecular export machinery of M. tb. This newly discovered role as transmembrane channels demands further research on this enigmatic family of proteins to comprehend the pathomechanism of this very smart pathogen.