Specialized Tfh cell subsets driving type-1 and type-2 humoral responses in lymphoid tissue.

Effective antibody responses are essential to generate protective humoral immunity. Different inflammatory signals polarize T cells towards appropriate effector phenotypes during an infection or immunization. Th1 and Th2 cells have been associated with the polarization of humoral responses. However, T follicular helper cells (Tfh) have a unique ability to access the B cell follicle and support the germinal center (GC) responses by providing B cell help. We investigated the specialization of Tfh cells induced under type-1 and type-2 conditions. We first studied homogenous Tfh cell populations generated by adoptively transferred TCR-transgenic T cells in mice immunized with type-1 and type-2 adjuvants. Using a machine learning approach, we established a gene expression signature that discriminates Tfh cells polarized towards type-1 and type-2 response, defined as Tfh1 and Tfh2 cells. The distinct signatures of Tfh1 and Tfh2 cells were validated against datasets of Tfh cells induced following lymphocytic choriomeningitis virus (LCMV) or helminth infection. We generated single-cell and spatial transcriptomics datasets to dissect the heterogeneity of Tfh cells and their localization under the two immunizing conditions. Besides a distinct specialization of GC Tfh cells under the two immunizations and in different regions of the lymph nodes, we found a population of Gzmk+ Tfh cells specific for type-1 conditions. In human individuals, we could equally identify CMV-specific Tfh cells that expressed Gzmk. Our results show that Tfh cells acquire a specialized function under distinct types of immune responses and with particular properties within the B cell follicle and the GC.

Losartan potassium liquid formulation for paediatric hospital use: development and stability evaluation.

OBJECTIVES: This study aimed to develop a liquid oral formulation containing losartan potassium, an angiotensin II receptor antagonist drug used for its antihypertensive activity, and to perform a preliminary stability assessment under different temperatures and packages to ensure paediatric therapeutic adherence and facilitate the hospital routine. METHODS: A syrup containing losartan potassium (1.0 and 2.5 mg/mL) (excipients: potassium sorbate, sucrose (85%), water, citric acid and raspberry flavouring) was prepared. The packaging was carried out in amber polyethylene terephthalate (PET) and amber glass bottles (in triplicate) under the following conditions: (a) room temperature (15-30°C); (b) refrigeration (2-8°C); and (c) oven temperature (40°C) for 28 days. An analytical method by high performance liquid chromatography using a reverse-phase column was also developed and validated for quantitative determination of the drug in the formulations. RESULTS: The analytical method showed satisfactory linearity, detection and quantification limits, precision, accuracy and robustness. Samples at room temperature maintained content values between 90% and 110% for 7 days, while those stored under refrigeration maintained a homogeneous appearance and content between 90% and 110% for a period of 21 days. Values of pH stayed in a narrow range. Viscosity results were between 40.1 and 49.2 centipoise (cp) for glass bottles and 42.4 and 54.7 cp for PET bottles. CONCLUSIONS: A simple and economical losartan potassium liquid formulation was produced and was shown to be stable under refrigeration for 21 days in both PET and glass packages.

Capturing COPD heterogeneity: anomaly detection and parametric response mapping comparison for phenotyping on chest computed tomography.

Background: Chronic obstructive pulmonary disease (COPD) poses a substantial global health burden, demanding advanced diagnostic tools for early detection and accurate phenotyping. In this line, this study seeks to enhance COPD characterization on chest computed tomography (CT) by comparing the spatial and quantitative relationships between traditional parametric response mapping (PRM) and a novel self-supervised anomaly detection approach, and to unveil potential additional insights into the dynamic transitional stages of COPD. Methods: Non-contrast inspiratory and expiratory CT of 1,310 never-smoker and GOLD 0 individuals and COPD patients (GOLD 1-4) from the COPDGene dataset were retrospectively evaluated. A novel self-supervised anomaly detection approach was applied to quantify lung abnormalities associated with COPD, as regional deviations. These regional anomaly scores were qualitatively and quantitatively compared, per GOLD class, to PRM volumes (emphysema: PRMEmph, functional small-airway disease: PRMfSAD) and to a Principal Component Analysis (PCA) and Clustering, applied on the self-supervised latent space. Its relationships to pulmonary function tests (PFTs) were also evaluated. Results: Initial t-Distributed Stochastic Neighbor Embedding (t-SNE) visualization of the self-supervised latent space highlighted distinct spatial patterns, revealing clear separations between regions with and without emphysema and air trapping. Four stable clusters were identified among this latent space by the PCA and Cluster Analysis. As the GOLD stage increased, PRMEmph, PRMfSAD, anomaly score, and Cluster 3 volumes exhibited escalating trends, contrasting with a decline in Cluster 2. The patient-wise anomaly scores significantly differed across GOLD stages (p < 0.01), except for never-smokers and GOLD 0 patients. In contrast, PRMEmph, PRMfSAD, and cluster classes showed fewer significant differences. Pearson correlation coefficients revealed moderate anomaly score correlations to PFTs (0.41-0.68), except for the functional residual capacity and smoking duration. The anomaly score was correlated with PRMEmph (r = 0.66, p < 0.01) and PRMfSAD (r = 0.61, p < 0.01). Anomaly scores significantly improved fitting of PRM-adjusted multivariate models for predicting clinical parameters (p < 0.001). Bland-Altman plots revealed that volume agreement between PRM-derived volumes and clusters was not constant across the range of measurements. Conclusion: Our study highlights the synergistic utility of the anomaly detection approach and traditional PRM in capturing the nuanced heterogeneity of COPD. The observed disparities in spatial patterns, cluster dynamics, and correlations with PFTs underscore the distinct - yet complementary - strengths of these methods. Integrating anomaly detection and PRM offers a promising avenue for understanding of COPD pathophysiology, potentially informing more tailored diagnostic and intervention approaches to improve patient outcomes.

Genetic characteristics involved in COVID-19 severity. The CARGENCORS case-control study and meta-analysis.

Pre-existing coronary artery disease (CAD), and thrombotic, inflammatory, or virus infectivity response phenomena have been associated with COVID-19 disease severity. However, the association of candidate single nucleotide variants (SNVs) related to mechanisms of COVID-19 complications has been seldom analysed. Our aim was to test and validate the effect of candidate SNVs on COVID-19 severity. CARGENCORS (CARdiovascular GENetic risk score for Risk Stratification of patients positive for SARS-CoV-2 [COVID-19] virus) is an age- and sex-matched case-control study with 818 COVID-19 cases hospitalized with hypoxemia, and 1636 controls with COVID-19 treated at home. The association between severity and SNVs related to CAD (n = 32), inflammation (n = 19), thrombosis (n = 14), virus infectivity (n = 11), and two published to be related to COVID-19 severity was tested with adjusted logistic regression models. Two external independent cohorts were used for meta-analysis (SCOURGE and UK Biobank). After adjustment for potential confounders, 14 new SNVs were associated with COVID-19 severity in the CARGENCORS Study. These SNVs were related to CAD (n = 10), thrombosis (n = 2), and inflammation (n = 2). We also confirmed eight SNVs previously related to severe COVID-19 and virus infectivity. The meta-analysis showed five SNVs associated with severe COVID-19 in adjusted analyses (rs11385942, rs1561198, rs6632704, rs6629110, and rs12329760). We identified 14 novel SNVs and confirmed eight previously related to COVID-19 severity in the CARGENCORS data. In the meta-analysis, five SNVs were significantly associated to COVID-19 severity, one of them previously related to CAD.

Greater perceived stress management skills and heightened brain metabolic activity in cortical and subcortical stress processing regions in metastatic breast cancer patients.

PURPOSE: Emotional distress and adversity can contribute to negative health outcomes in women with breast cancer. Individual differences in perceived stress management skills such as cognitive reframing and relaxation for coping with adversity have been shown to predict less distress and better psychological and physiological adaptation. Prior work shows that more distressed breast cancer patients reveal less metabolic activity in brain regions such as the insula, thalamus, ventromedial and lateral prefrontal cortices. This led us to pose the hypothesis that breast cancer patients with greater stress management skills (e.g., ability to reframe stressors and use relaxation) may conversely show greater activation in these brain regions and thereby identify brain activity that may be modifiable through stress management interventions. The main objective of this study was to examine the association of perceived stress management skill efficacy with the metabolism of 9 key stress-implicated brain regions in women diagnosed with metastatic breast cancer. METHODS: Sixty women (mean age 59.86 ± 10.04) with a diagnosis of mBC underwent 18F-fluorodeoxyglucose positron emission tomography. Perceived stress management skill efficacy was assessed with the Measure of Current Status Scale. RESULTS: Greater perceived stress management skill efficacy related significantly to higher metabolic activity in the insula, thalamus, ventromedial and lateral prefrontal cortices, and basal ganglia; this network of regions overlaps with those previously shown to be under-activated with greater level of distress in this same sample of metastatic breast cancer patients. CONCLUSION: This is the first study to demonstrate in metastatic cancer patients that greater perceptions of stress management skill efficacy are associated with metabolic activity in key brain regions and paves the way for future studies tracking neural mechanisms sensitive to change following stress management interventions for this population.

A genome-wide association study meta-analysis in a European sample of stage III/IV grade C periodontitis patients ≤35 years of age identifies new risk loci.

AIM: Few genome-wide association studies (GWAS) have been conducted for severe forms of periodontitis (stage III/IV grade C), and the number of known risk genes is scarce. To identify further genetic risk variants to improve the understanding of the disease aetiology, a GWAS meta-analysis in cases with a diagnosis at ≤35 years of age was performed. MATERIALS AND METHODS: Genotypes from German, Dutch and Spanish GWAS studies of III/IV-C periodontitis diagnosed at age ≤35 years were imputed using TopMed. After quality control, a meta-analysis was conducted on 8,666,460 variants in 1306 cases and 7817 controls with METAL. Variants were prioritized using FUMA for gene-based tests, functional annotation and a transcriptome-wide association study integrating eQTL data. RESULTS: The study identified a novel genome-wide significant association in the FCER1G gene (p = 1.0 × 10-9 ), which was previously suggestively associated with III/IV-C periodontitis. Six additional genes showed suggestive association with p < 10-5 , including the known risk gene SIGLEC5. HMCN2 showed the second strongest association in this study (p = 6.1 × 10-8 ). CONCLUSIONS: This study expands the set of known genetic loci for severe periodontitis with an age of onset ≤35 years. The putative functions ascribed to the associated genes highlight the significance of oral barrier tissue stability, wound healing and tissue regeneration in the aetiology of these periodontitis forms and suggest the importance of tissue regeneration in maintaining oral health.

Prediction of disease severity in COPD: a deep learning approach for anomaly-based quantitative assessment of chest CT.

OBJECTIVES: To quantify regional manifestations related to COPD as anomalies from a modeled distribution of normal-appearing lung on chest CT using a deep learning (DL) approach, and to assess its potential to predict disease severity. MATERIALS AND METHODS: Paired inspiratory/expiratory CT and clinical data from COPDGene and COSYCONET cohort studies were included. COPDGene data served as training/validation/test data sets (N = 3144/786/1310) and COSYCONET as external test set (N = 446). To differentiate low-risk (healthy/minimal disease, [GOLD 0]) from COPD patients (GOLD 1-4), the self-supervised DL model learned semantic information from 50 × 50 × 50 voxel samples from segmented intact lungs. An anomaly detection approach was trained to quantify lung abnormalities related to COPD, as regional deviations. Four supervised DL models were run for comparison. The clinical and radiological predictive power of the proposed anomaly score was assessed using linear mixed effects models (LMM). RESULTS: The proposed approach achieved an area under the curve of 84.3 ± 0.3 (p < 0.001) for COPDGene and 76.3 ± 0.6 (p < 0.001) for COSYCONET, outperforming supervised models even when including only inspiratory CT. Anomaly scores significantly improved fitting of LMM for predicting lung function, health status, and quantitative CT features (emphysema/air trapping; p < 0.001). Higher anomaly scores were significantly associated with exacerbations for both cohorts (p < 0.001) and greater dyspnea scores for COPDGene (p < 0.001). CONCLUSION: Quantifying heterogeneous COPD manifestations as anomaly offers advantages over supervised methods and was found to be predictive for lung function impairment and morphology deterioration. CLINICAL RELEVANCE STATEMENT: Using deep learning, lung manifestations of COPD can be identified as deviations from normal-appearing chest CT and attributed an anomaly score which is consistent with decreased pulmonary function, emphysema, and air trapping. KEY POINTS: • A self-supervised DL anomaly detection method discriminated low-risk individuals and COPD subjects, outperforming classic DL methods on two datasets (COPDGene AUC = 84.3%, COSYCONET AUC = 76.3%). • Our contrastive task exhibits robust performance even without the inclusion of expiratory images, while voxel-based methods demonstrate significant performance enhancement when incorporating expiratory images, in the COPDGene dataset. • Anomaly scores improved the fitting of linear mixed effects models in predicting clinical parameters and imaging alterations (p < 0.001) and were directly associated with clinical outcomes (p < 0.001).

A Genome-Wide Association Study of Small Cell Lung Cancer

Introduction: Small cell lung cancer (SCLC) comprises 10–15% of all lung cancer cases and is the most aggressive histological type. Survival is poor and the molecular landscape of this disease is extraordinarily complex. The objective of this paper was to perform a Genome-Wide Association Study (GWAS) of this disease using a case–control study specifically designed for small cell lung cancer (SCLC). Methods: Incident cases were consecutively recruited from 8 hospitals from different regions of Spain. Controls were recruited from the same hospitals using a frequency sampling based on age and sex distribution of cases. Biological samples were obtained along with detailed information on cases and controls lifestyle, including tobacco and radon exposure. Results: We included 271 SCLC cases and 557 controls. We found evidence (p-values<10−5) of an association in the complete dataset for several loci, while MAP4 showed a significant association in the gene-based analysis. Pathway analysis suggested that ATR, ATRIP, MCM4, MCM5, ORC4, RPA3 and CDC25A genes have a role on the onset of SCLC. Conclusion: This study provides biological evidence for pathways related to SCLC, offering novel loci for further research. (AU)

Sensing their plasma membrane curvature allows migrating cells to circumvent obstacles.

To navigate through diverse tissues, migrating cells must balance persistent self-propelled motion with adaptive behaviors to circumvent obstacles. We identify a curvature-sensing mechanism underlying obstacle evasion in immune-like cells. Specifically, we propose that actin polymerization at the advancing edge of migrating cells is inhibited by the curvature-sensitive BAR domain protein Snx33 in regions with inward plasma membrane curvature. The genetic perturbation of this machinery reduces the cells' capacity to evade obstructions combined with faster and more persistent cell migration in obstacle-free environments. Our results show how cells can read out their surface topography and utilize actin and plasma membrane biophysics to interpret their environment, allowing them to adaptively decide if they should move ahead or turn away. On the basis of our findings, we propose that the natural diversity of BAR domain proteins may allow cells to tune their curvature sensing machinery to match the shape characteristics in their environment.

A Genome-Wide Association Study of Small Cell Lung Cancer.

INTRODUCTION: Small cell lung cancer (SCLC) comprises 10-15% of all lung cancer cases and is the most aggressive histological type. Survival is poor and the molecular landscape of this disease is extraordinarily complex. The objective of this paper was to perform a Genome-Wide Association Study (GWAS) of this disease using a case-control study specifically designed for small cell lung cancer (SCLC). METHODS: Incident cases were consecutively recruited from 8 hospitals from different regions of Spain. Controls were recruited from the same hospitals using a frequency sampling based on age and sex distribution of cases. Biological samples were obtained along with detailed information on cases and controls lifestyle, including tobacco and radon exposure. RESULTS: We included 271 SCLC cases and 557 controls. We found evidence (p-values<10-5) of an association in the complete dataset for several loci, while MAP4 showed a significant association in the gene-based analysis. Pathway analysis suggested that ATR, ATRIP, MCM4, MCM5, ORC4, RPA3 and CDC25A genes have a role on the onset of SCLC. CONCLUSION: This study provides biological evidence for pathways related to SCLC, offering novel loci for further research.

Criterion and construct validity of the Beck Depression Inventory (BDI-II) to measure depression in patients with cancer: The contribution of somatic items

Background/Objective: Screening for depression in patients with cancer can be difficult due to overlap between symptoms of depression and cancer. We assessed validity of the Beck Depression Inventory (BDI-II) in this population. Method: Data was obtained in an outpatient neuropsychiatry unit treating patients with and without cancer. Psychometric properties of the BDI-II Portuguese version were assessed separately in 202 patients with cancer, and 376 outpatients with mental health complaints but without cancer. Results: Confirmatory factor analysis suggested a three-factor structure model (cognitive, affective and somatic) provided best fit to data in both samples. Criterion validity was good for detecting depression in oncological patients, with an area under the ROC curve (AUC) of 0.85 (95% confidence interval [CI], 0.76–0.91). A cut-off score of 14 had sensitivity of 87% and specificity of 73%. Excluding somatic items did not significantly change the ROC curve for BDI-II (difference AUCs = 0.002, p=0.9). A good criterion validity for BDI-II was also obtained in the non-oncological population (AUC = 0.87; 95% CI 0.81–0.91), with a cut-off of 18 (sensitivity=84%; specificity=73%). Conclusions: The BDI-II demonstrated good psychometric properties in patients with cancer, comparable to a population without cancer. Exclusion of somatic items did not affect screening accuracy. (AU)

Pediatric Overweight, Fatness and Risk for Dyslipidemia Are Related to Diet: A Cross-Sectional Study in 9-year-old Children.

Pediatric overweight, dyslipidemia and insulin resistance can result from unhealthy lifestyle habits and increase morbidity and mortality in adulthood. Herein, we evaluated the relationship between diet and physical activity patterns with the metabolic health of 9-year-old school children. Measurements included anthropometry, adiposity, lipid, and glycemic profiles. Questionnaires evaluated diet and physical activity. Exploratory factor analysis (EFA) screened for diet patterns, and multilevel models evaluated diet and physical activity patterns against overweight, dyslipidemia, and insulin resistance markers across schools and children. EFA highlighted two diet patterns, Western and Traditional. Food rich in fat, salt, and sugar and fewer vegetables and fruits defined the Western pattern. The Traditional pattern, linked to healthier eating habits, had analogies to the Mediterranean diet. Overall, 39% of the children were overweight (including the obese), while 62% presented cardiovascular risk factors on their lipid profiles. Normal-weight children presented 60% high cholesterol incidence. Global insulin resistance incidence was 4.1%, but almost doubled among the overweight/obese. The Westernized diet consistently linked to worse cardiovascular risk markers, even independently of physical practice. Intensive or competitive physical activity was associated with decreased triglycerides (p = 0.003), regardless of diet. Future prospective studies are warranted to validate these results externally.

Criterion and construct validity of the Beck Depression Inventory (BDI-II) to measure depression in patients with cancer: The contribution of somatic items.

Background/Objective: Screening for depression in patients with cancer can be difficult due to overlap between symptoms of depression and cancer. We assessed validity of the Beck Depression Inventory (BDI-II) in this population. Method: Data was obtained in an outpatient neuropsychiatry unit treating patients with and without cancer. Psychometric properties of the BDI-II Portuguese version were assessed separately in 202 patients with cancer, and 376 outpatients with mental health complaints but without cancer. Results: Confirmatory factor analysis suggested a three-factor structure model (cognitive, affective and somatic) provided best fit to data in both samples. Criterion validity was good for detecting depression in oncological patients, with an area under the ROC curve (AUC) of 0.85 (95% confidence interval [CI], 0.76-0.91). A cut-off score of 14 had sensitivity of 87% and specificity of 73%. Excluding somatic items did not significantly change the ROC curve for BDI-II (difference AUCs = 0.002, p=0.9). A good criterion validity for BDI-II was also obtained in the non-oncological population (AUC = 0.87; 95% CI 0.81-0.91), with a cut-off of 18 (sensitivity=84%; specificity=73%). Conclusions: The BDI-II demonstrated good psychometric properties in patients with cancer, comparable to a population without cancer. Exclusion of somatic items did not affect screening accuracy.

Development, Quality by Design-Based Optimization, and Stability Assessment of Oral Liquid Formulations Containing Baclofen for Hospital Use.

The absence of oral liquid pharmaceutical forms appropriate for use in pediatric and adult patients with difficulty swallowing is a public health problem, especially in the hospital context. Baclofen is a muscle relaxant of choice for treating spasticity, generally marketed only in tablet form, highlighting the need for liquid formulations to facilitate dose adjustment, administration, and swallowing. The present study aimed to develop oral liquid formulations containing baclofen, optimize them through the quality by design approach, and evaluate their physicochemical and microbiological stability. Preformulation and preliminary stability studies were carried out for the development of formulations. Experimental screening and optimization designs resulted in eleven experiments for each step that were evaluated for 28 days. A stability-indicating method by high-performance liquid chromatography presented linearity, low limits of detection and quantification, precision, accuracy, and robustness. The experimental design led to two optimized formulations containing baclofen, glycerin, potassium sorbate, citric acid, ultrapure water, flavor, and sucrose syrup or sodium carboxymethylcellulose solution as a vehicle, the last one with sucralose as a sweetener. The formulations were placed in amber glass flasks and subjected to a physicochemical and microbiological stability study. Both formulations showed physicochemical and microbiological stability when stored at room temperature and refrigerated for 84 days. The results of this study may serve as a reference in the preparation of liquid oral formulations containing baclofen in the hospital routine and collaborate with the safety and adherence to the treatment of adult and pediatric patients.

AI-Supported Comprehensive Detection and Quantification of Biomarkers of Subclinical Widespread Diseases at Chest CT for Preventive Medicine.

Automated image analysis plays an increasing role in radiology in detecting and quantifying image features outside of the perception of human eyes. Common AI-based approaches address a single medical problem, although patients often present with multiple interacting, frequently subclinical medical conditions. A holistic imaging diagnostics tool based on artificial intelligence (AI) has the potential of providing an overview of multi-system comorbidities within a single workflow. An interdisciplinary, multicentric team of medical experts and computer scientists designed a pipeline, comprising AI-based tools for the automated detection, quantification and characterization of the most common pulmonary, metabolic, cardiovascular and musculoskeletal comorbidities in chest computed tomography (CT). To provide a comprehensive evaluation of each patient, a multidimensional workflow was established with algorithms operating synchronously on a decentralized Joined Imaging Platform (JIP). The results of each patient are transferred to a dedicated database and summarized as a structured report with reference to available reference values and annotated sample images of detected pathologies. Hence, this tool allows for the comprehensive, large-scale analysis of imaging-biomarkers of comorbidities in chest CT, first in science and then in clinical routine. Moreover, this tool accommodates the quantitative analysis and classification of each pathology, providing integral diagnostic and prognostic value, and subsequently leading to improved preventive patient care and further possibilities for future studies.

Symptom provocation for treatment of obsessive-compulsive disorder using transcranial magnetic stimulation: A step-by-step guide for professional training.

Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique that was cleared by the Food and Drug Administration (FDA) for the treatment of Obsessive-Compulsive Disorder (OCD) in 2018. The approved protocol includes individualized symptom provocation before each stimulation session, to elicit a moderate level of obsessional distress. Although symptom provocation can be a delicate, demanding, and uncomfortable procedure, structured training methods for those who are going to apply it are not available. Here, we describe a model for training in symptom provocation for TMS technicians, developed at the Champalimaud Clinical Centre in Lisbon, Portugal. Our programme includes two-sessions dedicated to clinical communication and symptom provocation techniques from a theoretical and practical perspective. Additionally, supervision meetings are conducted during treatment of patients, allowing regular case discussion and redefinition of symptom provocation hierarchy, as needed. In addition to having a strong practical component, our training program is short and pragmatic, allowing for easy implementation and fluid transition to clinical practice. By sharing our experience, we hope to contribute to systematize training procedures required for symptom provocation in the context of TMS, and to qualitatively describe a methodology that can be used for implementation of TMS programmes for the treatment of OCD.

Novel genes and sex differences in COVID-19 severity.

Here, we describe the results of a genome-wide study conducted in 11 939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P < 5 × 10-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P = 1.3 × 10-22 and P = 8.1 × 10-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P = 4.4 × 10-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P = 2.7 × 10-8) and ARHGAP33 (P = 1.3 × 10-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P = 4.1 × 10-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or ≥60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.

Cross-Cultural Adaptation and Psychometric Evaluation of the Perceived Ability to Cope With Trauma Scale in Portuguese Patients With Breast Cancer.

BACKGROUND: The impact of a cancer diagnosis may be traumatic, depending on the psychological resources used by patients. Appropriate coping strategies are related to better adaptation to the disease, with coping flexibility, corresponding to the ability to replace ineffective coping strategies, demonstrated to be highly related with self-efficacy to handle trauma. The Perceived Ability to Cope with Trauma (PACT) scale is a self-rated questionnaire that assesses the perceived ability to cope with potentially traumatic events, providing a measure of coping flexibility. The current study aimed at examining the psychometric properties of the PACT Scale in Portuguese patients with breast cancer. METHODS: The study included 172 patients recently diagnosed with early breast cancer. Participants completed a Portuguese version of the PACT scale, and instruments of self-efficacy for coping with cancer (Cancer Behavior Inventory-Brief Version-CBI-B), of quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30-QLQ-C30), and of psychological distress (Hospital Anxiety and Depression Scale-HADS) that were used as convergent and divergent measures, thus assessing construct validity. A confirmatory factor analysis (CFA) was performed to test the factor structure of the Portuguese version of PACT scale and reliabilities were examined. RESULTS: Results from the CFA confirmed the two-factor structure, consistent with the original Forward and Trauma focus subscales. The two subscales demonstrated high internal consistencies. Convergent and divergent validities were confirmed: the PACT scale was related to high self-efficacy to cope with cancer (CBI-B), to high perceived quality of life (QLQ-C30), and to low psychological distress (HADS). DISCUSSION: Overall, the current results support and replicate the psychometric properties of the PACT scale. The scale was found to be a valid and reliable self-reported measure to assess Portuguese breast cancer patients regarding beliefs about their capabilities in managing the potentially traumatic sequelae of cancer. The PACT is a simple and brief measure of coping flexibility to trauma, with potential relevance for application in clinical and research settings.

Cross-cultural adaptation and psychometric evaluation of the Portuguese version of the family resilience questionnaire - short form (FaRE-SF-P) in women with breast cancer.

Background: A diagnosis of cancer, and the resulting treatment process, can be perceived as a life-threatening event, affecting not only patients but also their social network and, more specifically, their relatives. While the ability to cope and adjust to difficult health situations may be challenging, family resilience may optimize a positive adaptation to adversity and contribute to enhance the patient's quality of life. The Family Resilience Questionnaire (FaRE) is a self-report measure of family resilience that assesses this construct systematically. We aimed to validate the Portuguese version of a short form of the FaRE (FaRE-SF-P) in a sample of women with breast cancer. Methods: 147 women recently diagnosed with early breast cancer were recruited at the Champalimaud Clinical Centre in Lisbon. Participants completed psychometric assessment including the Portuguese version of the FaRE-SF-P, composed by two subscales of the original version - the FaRE Perceived Family Coping (FaRE-PFC) and the FaRE Communication and Cohesion (FaRE-CC). Confirmatory factor analysis (CFA) was performed to assess the factor structure of the FaRE-SF-P. Construct validity was assessed using the Hospital Anxiety and Depression Scale (HADS) for divergent validity, and the Modified Medical Outcomes Study Social Support Survey (mMOS-SS) as well as the social functioning subscale from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) for convergent validity. Results: The CFA results confirmed a correlated two-factor structure model consistent with the Perceived Family Coping and the Communication and Cohesion subscales. Internal consistency reliability indicated good values both for Perceived Family Coping and Communication and Cohesion subscales. The results for construct validity showed acceptable convergent and divergent validity. Discussion: The FaRE-SF-P showed good psychometric properties demonstrating to be a valid and reliable family resilience measure to use in Portuguese women diagnosed with breast cancer. Since FaRE-SF-P is a short instrument it may be a useful screening tool in an oncological clinical practice routine.

Piauí Central Laboratory of Public Health: frequency of mycobacterial species and epidemiological aspects, 2014-2015 / Laboratorio Central de Salud Pública de Piauí: frecuencia de especies micobacterianas y aspectos epidemiológicos, 2014-2015 / Laboratório Central de Saúde Pública do Piauí: frequência de espécies de micobactérias e aspectos epidemiológicos, 2014-2015

Background and Objectives: Knowledge about species diversity of non-tuberculous mycobacteria (NTM) and the frequency of tuberculosis (TB) is an important issue in rural-urban regions such as Piauí (northeast of Brazil), of low incidence rate of TB , can help to improve diagnosis and prevention strategies. The aim of this study is to examine some epidemiological aspects and the frequency of Mycobacterium tuberculosis (Mtb) and NTM isolated at the central public health reference laboratory, Dr. Costa Alvarenga, Piauí (LACEN-PI). Methods: Data records of all mycobacterosis and tuberculosis cases from January 2014 to March 2015 were analyzed. Results : Of the 20% (142/706) positive growths, 70% (99) were Mtb and 10% NTM. The remainde was of inadequate clinical samples, not allowing the identification of even the suspected NTM. The most frequent clinical form was pulmonary with TB patients younger than those infected with NTM (p = 0.001), the majority living in Teresina (52%). NTMs identified were M. abscessus (36%), M. avium, M. intracellulare, Mycobacterium sp. (14% each) and M. asiaticum, M. szulgai, M. kansasii 7% (each). Mtb drug resistance (7.8%) and TB co-infection with the human immunodeficiency virus (HIV-TB) found to be high (49%, 19/39). Conclusion: The frequencies of Mtb infection, drug resistance and HIV-TB co-infection are still underestimated and failures in the identification of NTM may decrease the actual frequency of these infections. Therefore, there is a need for improvements in TB control and in the diagnosis of NTMs in Piauí.(AU)

Justificativa e Objetivos: O conhecimento da diversidade de espécies de micobactérias não tuberculosas (MNT ) e a frequência da tuberculose (TB) é uma questão importante em regiões rurais-urbanas como o Piauí (nordeste do Brasil), com baixa incidência de TB, pode ajudar a melhorar o diagnóstico e estratégias de prevenção. O objetivo deste estudo é examinar alguns aspectos epidemiológicos e a frequência de Mycobacterium tuberculosis (Mtb) e MNT isolados, no Laboratório Central de Referência em Saúde Pública, Dr. Costa Alvarenga, Piauí (LACEN-PI). Métodos: Dados de todo s os casos de micobacterioses e tuberculose de janeiro de 2014 a março de 2015 foram analisados. Resultados: Dos 20% (142/706), de amostras com crescimento positivo 70% (99) foram Mtb e 10% MNT . O restante era de amostras clínicas inadequadas, não permitindo a identificação inclusive de MNT suspeitos. A forma clínica mais frequente foi pulmonar com pacientes TB mais jovens do que os infectados com MNT (p = 0,001), a maioria morando em Teresina (52%). As MNT s identificadas foram M. abscessus (36%), M. avium , M. intracellulare , M. sp. (14%, cada) e M. asiaticum, M. szulgai , M. kansasii 7% (cada). A droga resistência de Mtb (7,8%) e a co-infecção TB e vírus da imunodeficiência humana (HIV-TB) mostraram-se altas (49%, 19/39).Conclusão: As frequências de infecção por Mtb, de resistência a medicamentos e co-infecção HIV-TB ainda são subestimadas e as falhas na identificação de MNT podem diminuir a real frequência destas infecções . Portanto, há necessidade de melhorias no controle da TB e no diagnóstico de MNT s no Piauí.(AU)

Justificacion y objetivos: Conocer la diversidad de especies de micobacterias no tuberculosas (MNT) y la frecuencia de tuberculosis (TB) es tema importante en regiones rurales-urbanas como Piauí (noreste de Brasil) con baja tasa de incidencia de TB, y puede ayudar a mejorar el diagnóstico y las estrategias de prevenció. El objetivo de este estudio es examinar algunos aspectos epidemiológicos y la frecuencia de Mycobacterium tuberculosis (Mtb) y MNT aislado, en el laboratorio central de referencia de salud pública, Dr. Costa Alvarenga, Piauí (LACEN-PI). Métodos: Se analizaron los datos de todos los casos de micobacteriosis de enero de 2014 a marzo de 2015. Resultados: Del 20% (142/706), de las muestras con crecimiento positivo el 70% (99) fueron Mtb y el 10% MNT. El resto fue de muestras clínicas inadecuadas, no permitiendo la identificación de MNT incluso sospechosas. La forma clínica más frecuente fue la pulmonar y los pacientes con TB eran más jóvenes que los infectados con MNT (p = 0.001), la mayoría viviendo en Teresina (52%).Los MNT identificados fueron M.abscessus (36%), M.avium, M.intracellulare, Mycobacterium sp. (14% cada) y M.asiaticum, M.szulgai, M.kansasii 7% (cada ). La resistencia a los medicamentos de Mtb (7,8%) y la coinfección de TB y el virus de la inmunodeficiencia humana (VIH-TB) fueron altas (49%, 19/39 )Conclusión: Las frecuencias aún subestimadas de resistencia a los medicamentos, coinfección por VIH-TB y fallas de identificaciónidentificación de MNT pueden disminuir la frecuencia real de estas infecciones. Consecuentemente, es necesario mejorar el control y diagnóstico de TB y MNT en Piauí.(AU)