Towards a New, Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants

Endofenotip; Prediccions de patogenicitat; Predictor específic de proteïnaEndofenotipo; Predicciones de patogenicidad; Predictor específico de proteínaEndophenotype; Pathogenicity predictions; Protein-specific predictorThe present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i.e., computational estimates of the outcomes of functional assays, can be a good option to address this bottleneck. The application of this idea to the BRCA1/2 variants in the CAGI 5-ENIGMA international challenge has shown promising results. Here, we developed this approach, exploring the predictive performances of the regression models applied to the BRCA1/2 variants for which the values of the homology-directed DNA repair and saturation genome editing assays are available. Our results first showed that we can generate endophenotype estimates using a few molecular-level properties. Second, we show that the accuracy of these estimates is enough to obtain pathogenicity predictions comparable to those of many standard tools. Third, endophenotype-based predictions are complementary to, but do not outperform, those of a Random Forest model trained using variant pathogenicity annotations instead of endophenotype values. In summary, our results confirmed the usefulness of the endophenotype approach for the pathogenicity prediction of the BRCA1/2 missense variants, suggesting different options for future improvements.This research was funded by the EU European Regional Development Fund (ERDF) through the Program Interreg V-A Spain-France-Andorra (POCTEFA), grant number EFA086/15-PIREPRED, by the Spanish Ministerio de Ciencia e Innovación, grant number PID2019-111217RB-I00, and by the Spanish Ministerio de Economía y Competitividad, grant number SAF2016-80255-R

Choosing Variant Interpretation Tools for Clinical Applications: Context Matters

Clinical variant interpretation; Healthcare costs; Pathogenicity predictionInterpretación de variantes clínicas; Costes sanitarios; Predicción de patogenicidadInterpretació de variants clíniques; Despeses sanitàries; Predicció de patogenicitatPathogenicity predictors are computational tools that classify genetic variants as benign or pathogenic; this is currently a major challenge in genomic medicine. With more than fifty such predictors available, selecting the most suitable tool for clinical applications like genetic screening, molecular diagnostics, and companion diagnostics has become increasingly challenging. To address this issue, we have developed a cost-based framework that naturally considers the various components of the problem. This framework encodes clinical scenarios using a minimal set of parameters and treats pathogenicity predictors as rejection classifiers, a common practice in clinical applications where low-confidence predictions are routinely rejected. We illustrate our approach in four examples where we compare different numbers of pathogenicity predictors for missense variants. Our results show that no single predictor is optimal for all clinical scenarios and that considering rejection yields a different perspective on classifiers.This work was supported by research grants SAF2016-80255-R from the Spanish Ministerio de Economía y Competitividad (MINECO), PID2019-111217RB-I00 and TED2021-130342B-I00 from the Spanish Ministerio de Ciencia e Innovación, and by the European Regional Development Fund (ERDF) through the Interreg program POCTEFA (Pirepred, EFA086/15)

FGF-23 levels are associated with vascular calcification, but not with atherosclerosis, in hemodialysis patients

WOS: 000372588800021PubMed ID: 26865177High fibroblast growth factor-23 (FGF-23) levels are associated with mortality and cardiovascular events in patients with chronic kidney disease. The aim of this cross-sectional study was to investigate the relationship between plasma FGF-23 levels and coronary artery calcification and carotid artery intima-media thickness (CA-IMT) in hemodialysis (HD) patients. In this cross-sectional study, plasma intact FGF-23 levels were measured in 229 patients who underwent coronary artery calcification scores (CACs) determined by multi-slice computerized tomography and CA-IMT assessed by using high-resolution color Doppler ultrasonography. Median FGF-23 was 53.5 pg/ml (IQR 30.8-249.5). Median CACs was 98 (IQR 0-531), and the frequency of patients with severe calcification (CACs > 400) was 28.8 %; 27.5 % of cases had no calcification. Mean CA-IMT was 0.78 +/- A 0.20 mm, and the presence of carotid plaques was 51 % with a mean length 2.1 mm. FGF-23 level was positively correlated with serum calcium (r = 0.337, p < 0.001), phosphate (r = 0.397, p < 0.001) and CACs (r = 0.218, p = 0.001). Neither CA-IMT nor the presence of carotid artery plaques correlated with FGF-23 levels. In adjusted ordinal regression analysis, FGF-23 level was an independent predictor for severe CACs together with age, gender, presence of diabetes, time on dialysis and CA-IMT (model r (2) = 0.44, p < 0.001). As a novel finding, the mean CACs was markedly higher in patients with FGF-23 level above median regardless of phosphate levels (p = 0.03). In HD patients, plasma FGF-23 level is superior to phosphate in the prediction of coronary artery calcification. However, FGF-23 is not associated with carotid artery atherosclerosis in HD patients

What should be the appropriate minimal duration for patient examination and evaluation in pulmonary outpatient clinics?

INTRODUCTION: Patient examinations performed in a limited time period may lead to impairment in patient and physician relationship, defective and erroneous diagnosis, inappropriate prescriptions, less common use of preventive medicine practices, poor patient satisfaction, and increased violent acts against health-care staff

COVID-19: vaccination vs. hospitalization

Objective Vaccination is the most efficient way to control the coronavirus disease 2019 (COVID-19) pandemic, but vaccination rates remain below the target level in most countries. This multicenter study aimed to evaluate the vaccination status of hospitalized patients and compare two different booster vaccine protocols. Setting Inoculation in Turkey began in mid-January 2021. Sinovac was the only available vaccine until April 2021, when BioNTech was added. At the beginning of July 2021, the government offered a third booster dose to healthcare workers and people aged > 50 years who had received the two doses of Sinovac. Of the participants who received a booster, most chose BioNTech as the third dose. Methods We collected data from 25 hospitals in 16 cities. Patients hospitalized between August 1 and 10, 2021, were included and categorized into eight groups according to their vaccination status. Results We identified 1401 patients, of which 529 (37.7%) were admitted to intensive care units. Nearly half (47.8%) of the patients were not vaccinated, and those with two doses of Sinovac formed the second largest group (32.9%). Hospitalizations were lower in the group which received 2 doses of Sinovac and a booster dose of BioNTech than in the group which received 3 doses of Sinovac. Conclusion Effective vaccinations decreased COVID-19-related hospitalizations. The efficacy after two doses of Sinovac may decrease over time; however, it may be enhanced by adding a booster dose. Moreover, unvaccinated patients may be persuaded to undergo vaccination

Can we predict patients that will not benefit from invasive mechanical ventilation? A novel scoring system in intensive care: the IMV mortality prediction score (IMPRES)

KUCUK, Ahmet Oguzhan/0000-0002-6993-0519; Kirakli, Cenk/0000-0001-6013-7330; KUCUK, Mehtap PEHLIVANLAR/0000-0003-2247-4074; Aksoy, Iskender/0000-0002-4426-3342WOS: 000504051300010PubMed: 31655511Background/aim: The present study aimed to define the clinical and laboratory criteria for predicting patients that will not benefit from invasive mechanical ventilation (IMV) treatment and determine the prediction of mortality and prognosis of these critical ill patients. Materials and methods: The study was designed as an observational, multicenter, prospective, and cross-sectional clinical study. It was conducted by 75 researchers at 41 centers in intensive care units (ICUs) located in various geographical areas of Turkey. It included a total of 1463 ICU patients who were receiving invasive mechanical ventilation (IMV) treatment. A total of 158 parameters were examined via logistic regression analysis to identify independent risk factors for mortality; using these data, the IMV Mortality Prediction Score (IMPRES) scoring system was developed. Results: The following cut-off scores were used to indicate mortality risk: 8, very high risk. There was a 26.8% mortality rate among the 254 patients who had a total IMPRES score of lower than 2. The mortality rate was 93.3% for patients with total 1M PRES scores of greater than 8 (P < 0.001). Conclusion: The present study included a large number of patients from various geographical areas of the country who were admitted to various types of ICUs, had diverse diagnoses and comorbidities, were intubated with various indications in either urgent or elective settings, and were followed by physicians from various specialties. Therefore, our data are more general and can be applied to a broader population. This study devised a new scoring system for decision-making for critically ill patients as to whether they need to be intubated or not and presents a rapid and accurate prediction of mortality and prognosis prior to ICU admission using simple clinical data