Endothelial-mediated coronary flow reserve in patients with mild thyroid hormone deficiency

ContextAlthough coronary flow reserve (CFR) is reduced in patients with subclinical hypothyroidism (SHypo), the endothelial response of coronary vasomotion has never been explored in this clinical setting.ObjectiveTo investigate the endothelial response of coronary flow in young and middle-aged patients with SHypo, without associated cardiovascular risk factors compared with healthy control subjects.Patients and methodsThe study population consisted of 20 women (mean age 38.4+12.1 years) with newly diagnosed, untreated and persistent SHypo due to Hashimoto's thyroiditis. A total of 15 volunteers served as controls. Age, gender, body surface area, glucose, insulin levels, heart rate, systolic, diastolic, and mean blood pressure were similar in patients and controls. Body mass index was significantly higher in SHypo patients. Total cholesterol and low-density lipoprotein cholesterol, despite not significant, tended to be higher, and high-density lipoprotein cholesterol to be lower in SHypo. Coronary blood flow velocities were recorded in patients at rest and after the cold pressor test (CPT), a stimulus that can be considered totally endothelium-dependent. CFR was calculated as the ratio of hyperemic-to-resting diastolic peak velocities.ResultsCoronary diastolic peak velocities at rest did not differ between the two groups but were significantly lower after CPT in patients with SHypo, thereby resulting in a lower CFR. The difference remained significant after adjusting resting and CPT velocities for the respective mean blood pressures. TSH was inversely correlated with CFR in the pooled population.ConclusionPatients with SHypo without associated cardiovascular risk factors have a coronary endothelial dysfunction that appears in response to a physiological stimulus (the CPT)

Hypertension, type 2 diabetes, obesity, and p53 mutations negatively correlate with metastatic colorectal cancer patients’ survival

IntroductionWe studied the predictive and prognostic influences of hypertension (HT), type 2 diabetes (T2D), weight, and p53 mutations in metastatic colorectal cancer (CRC) patients.Patients and methodsT2D was diagnosed according to the ADA criteria. HT was classified according to the ACC/AHA guidelines. BMI (body-mass index) was calculated and classified according to the WHO criteria. TruSigt™Oncology 500 kit was applied to construct the genomic libraries for Next Generation Sequencing (NGS) analysis. The Illumina NovaSeq 6000 technological platform and the Illumina TruSight Oncology 500 bioinformatics pipeline were applied to analyze results. Overall survival (OS) was calculated through Kaplan-Meier curves. Univariate and multivariate analyses were performed to assess the relationships between clinical and/or molecular covariates. Associations between HT, T2D, BMI, p53, and clinical variables were evaluated by the χ2 test. P < 0.05 were considered statistically significant.ResultsTwo-hundred-forty-four patients were enrolled. One-hundred-twenty (49.2%), 110 (45.1%), and 50 (20.5%) patients were affected by overweight, HT, and T2D, respectively. DC (disease control) was achieved more frequently in patients without T2D (83.1%) compared to the diabetic ones (16.9%) (P = 0.0246). DC, KRAS mutational status, T2D, BMI, and concomitant presence of T2D, BMI, and HT associated with survival (P < 0.05). At multivariate analysis, age (≥65 vs. <65 years), response to first-line chemotherapy (DC vs. no DC), and concomitant presence of T2D, BMI, and HT (HR: 4.56; 95% CI: 2.40–8.67; P = 0.0217) emerged as independent prognostic variables. P53 was mutated in 31/53 analyzed cases (60.4%). The most frequent gene variants were p.Arg175His and p.Cys135Tyr. High BMI (>25 kg/m2) associated with occurrence of p53 mutations (P < 0.0001). P53 mutated patients presented a worse prognosis compared to the wild-type ones (HR: 3.21; 95% CI: 1.43–7.23; P = 0.0047).ConclusionDiabetic, hypertensive and overweight metastatic CRC patients are a negative prognostic subgroup deserving specific therapeutic strategies. P53 mutations associate with prognosis and BMI unrevealing complex and unexplored connections between metabolism and cancer occurrence

Management of obstructive sleep apnea in Europe – A 10-year follow-up

Funding Information: Sleep medicine has been further established and recognized in the past 10 years. This is also shown by the fact that sleep-related diseases may receive a separate chapter in the new ICD-11 (International Classification of Diseases 11th Revision) [11]. However, the initial expansion in sleep laboratories and sleep centers seems to be over, at least in Europe, which stands in contradiction to the growing need. While sleep medical care still seems to be secured by the established structures, the gap between the increasing need and existing structures is still widening [ 12–14]. There is a lack of sleep medicine specialists, new outpatient structures, and new billing models with the sponsoring institutions. Approaches to solve these problems include the establishment and expansion of home sleep apnea testing (HSAT) [15] and telemedicine-based technologies in the diagnosis and treatment of OSA [16,17]. Telemedicine found its way into sleep medicine around 10 years ago [ 18–20]. One of the very first approaches as early as 1994 used a telephone circuit and a computer-controlled support system to improve OSA treatment by improving lifestyle through tele-guidance on nutrition and exercise [21]. Publisher Copyright: © 2022 The Authors Copyright © 2022 Elsevier B.V. All rights reserved.Objective: In 2010, a questionnaire-based study on obstructive sleep apnea (OSA) management in Europe identified differences regarding reimbursement, sleep specialist qualification, and titration procedures. Now, 10 years later, a follow-up study was conducted as part of the ESADA (European Sleep Apnea Database) network to explore the development of OSA management over time. Methods: The 2010 questionnaire including questions on sleep diagnostic, reimbursement, treatment, and certification was updated with questions on telemedicine and distributed to European Sleep Centers to reflect European OSA management practice. Results: 26 countries (36 sleep centers) participated, representing 20 ESADA and 6 non-ESADA countries. All 21 countries from the 2010 survey participated. In 2010, OSA diagnostic procedures were performed mainly by specialized physicians (86%), whereas now mainly by certified sleep specialists and specialized physicians (69%). Treatment and titration procedures are currently quite homogenous, with a strong trend towards more Autotitrating Positive Airway Pressure treatment (in hospital 73%, at home 62%). From 2010 to 2020, home sleep apnea testing use increased (76%–89%) and polysomnography as sole diagnostic procedure decreased (24%–12%). Availability of a sleep specialist qualification increased (52%–65%) as well as the number of certified polysomnography scorers (certified physicians: 36%–79%; certified technicians: 20%–62%). Telemedicine, not surveyed in 2010, is now in 2020 used in diagnostics (8%), treatment (50%), and follow-up (73%). Conclusion: In the past decade, formal qualification of sleep center personnel increased, OSA diagnostic and treatment procedures shifted towards a more automatic approach, and telemedicine became more prominent.Peer reviewe

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management. © 2021, The Author(s)

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Cognate MHC–TCR interaction leads to apoptosis of antigen-presenting cells

Abstract: Antigen presentation to T lymphocytes has been characterized extensively in terms of T lymphocyte activation and eventual cell death. In contrast, little is known about the consequences of antigen presentation for the antigen-presenting cell (APC). We have determined the outcome of major histocompatibility complex class II-restricted peptide presentation to a specific T cell. We demonstrate that specific T lymphocyte interaction with peptide-presenting APCs led to apoptosis in the APC population. In contrast, T lymphocyte interaction with nonpeptide-loaded APCs or APCs loaded with monosubstituted peptide failed to induce T lymphocyte secretion of interleukin-2 and APC apoptosis. Phosphatidylserine externalization and mitochondrial depolarization were used to evaluate APC apoptosis. Fas/Fas ligand interactions were not required, but cytoskeletal integrity and caspase activation were essential for APC apoptosis. Antigen presentation leading to T lymphocyte activation is therefore coordinated with apoptosis in the APC population and could provide a mechanism of immune response regulation by eliminating APCs, which have fulfilled their role as specific ligands for T lymphocyte activation. This pathway may have particular importance for APCs, which are not sensitive to death receptor-induced apoptosis. J. Leukoc. Biol. 75: 000–000; 2004. Key Words: MHC class II � T–B interaction � programmed cell deat