A New Set of in Silico Tools to Support the Interpretation of ATM Missense Variants Using Graphical Analysis

Establishing the pathogenic nature of variants in ATM, a gene associated with breast cancer and other hereditary cancers, is crucial for providing patients with adequate care. Unfortunately, achieving good variant classification is still difficult. To address this challenge, we extended the range of in silico tools with a series of graphical tools devised for the analysis of computational evidence by health care professionals. We propose a family of fast and easy-to-use graphical representations in which the impact of a variant is considered relative to other pathogenic and benign variants. To illustrate their value, the representations are applied to three problems in variant interpretation. The assessment of computational pathogenicity predictions showed that the graphics provide an intuitive view of pre-diction reliability, complementing and extending conventional numerical reliability indexes. When applied to variant of unknown significance populations, the representations shed light on the nature of these variants and can be used to prioritize variants of unknown significance for further studies. In a third application, the graphics were used to compare the two versions of the ATM-adapted American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines, obtaining valuable information on their relative virtues and weaknesses. Finally, a server [ATMision (ATM missense in silico interpretation online)] was generated for users to apply these representations in their variant interpretation problems, to check the ATM-adapted guidelines' criteria for computational evidence on their variant(s) and access different sources of information. (J Mol Diagn 2024, 26: 17-28; https://doi.org/10.1016/j.jmoldx.2023.09.009

Impact of Arterial Stiffness on All-Cause Mortality in Patients Hospitalized With COVID-19 in Spain

Older age and cardiovascular comorbidities are well-known risk factors for all-cause mortality in patients with coronavirus disease 2019 (COVID-19). Hypertension and age are the 2 principal determinants of arterial stiffness (AS). This study aimed to estimate AS in patients with COVID-19 requiring hospitalization and analyze its association with all-cause in-hospital mortality. This observational, retrospective, multicenter cohort study analyzed 12 170 patients admitted to 150 Spanish centers included in the SEMI-COVID-19 Network. We compared AS, defined as pulse pressure ≥60 mm Hg, and clinical characteristics between survivors and nonsurvivors. Mean age was 67.5 (±16.1) years and 42.5% were women. Overall, 2606 (21.4%) subjects died. Admission systolic blood pressure (BP) <120 and ≥140 mm Hg was a predictor of higher all-cause mortality (23.5% and 22.8%, respectively, P<0.001), compared with systolic BP between 120 and 140 mm Hg (18.6%). The 4379 patients with AS (36.0%) were older and had higher systolic and lower diastolic BP. Multivariate analysis showed that AS and systolic BP <120 mm Hg significantly and independently predicted all-cause in-hospital mortality (adjusted odds ratio [ORadj]: 1.27, P=0.0001; ORadj: 1.48, P=0.0001, respectively) after adjusting for sex (males, ORadj: 1.6, P=0.0001), age tertiles (second and third tertiles, ORadj: 2.0 and 4.7, P=0.0001), Charlson Comorbidity Index (second and third tertiles, ORadj: 4.8 and 8.6, P=0.0001), heart failure, and previous and in-hospital antihypertensive treatment. Our data show that AS and admission systolic BP <120 mm Hg had independent prognostic value for all-cause mortality in patients with COVID-19 requiring hospitalization

Methodology applied in the study of the language development in children with early detection of neonatal hearing loss.

Introducción y objetivo: Dado que el potencial discapacitante que causa la deficiencia auditiva neonatal disminuye con una detección e intervención tempranas, hemos elaborado un proyecto de investigación, con el que nos proponemos conocer el grado de desarrollo del lenguaje de los niños y niñas que procedentes del cribado auditivo universal, han sido diagnosticados/as por nosotros de hipoacusia prelingual en estos últimos 15 años y analizar las variables determinantes y las que son modificables. El objeto de esta comunicación consistirá en presentar la metodología que vamos a utilizar. Método: Partimos de los datos almacenados en nuestro Servicio de ORL, que comprende a 282 niños con hipoacusia. Hemos tenido la oportunidad de crear un grupo de investigación en el que coincidimos especialistas de la audición infantil y del lenguaje, por lo que contamos con medios suficientes para el estudio. Resultados: Describimos los elementos que configuran este proyecto, en relación al equipo de trabajo y a su desarrollo. Tras aplicar unos criterios de exclusión/inclusión, hemos seleccionado a un grupo de 45 niños entre 3 y 15 años, definiendo sus características auditivas. Mediante pruebas específicas, adaptadas a la edad, estudiaremos los diferentes aspectos del lenguaje; y a través de una entrevista estructurada realizada a los padres, intentaremos determinar las variables que influyen en el proceso re-habilitador. Finalmente, los datos serán analizados estadísticamente. Discusión: La variabilidad y la escasa prevalencia de la hipoacusia infantil, dificultan la realización de estudios con población suficiente para obtener resultados estadísticamente significativos. Sin embargo, creemos que el grupo de niños seleccionado y la metodología utilizada nos permitirán conocer mejor las variables influyentes en el desarrollo del lenguaje. Conclusiones: El programa de cribado auditivo universal ha permitido una intervención más precoz, lo que debería mejorar los niveles de lenguaje de los niños detectados/as con hipoacusia. Aunque el desarrollo normalizado de la comunicación depende de otros factores difíciles de determinar, a través del protocolo presentado pretendemos equiparar estos resultados, validando el proceso de cribado/diagnóstico e intervención de nuestro medio.Introduction and objective: Given that the disabling potential causing neonatal hearing impairment decreases with early detection and intervention, we have drawn up a research project, with which we intend to know the degree of development of the language of children and girls than from the universal hearing screening, have been diagnosed for us of prelingual hearing loss in the last 15 years and analyze the determining variables and which are modifiable. The object of this communication will be to present the methodology that we use. Method: We assume the data stored on our ENT service, including 282 children with hearing loss. We have had the opportunity to create a research group in which we agree ENT and language specialists so we have resources sufficient for the study. Results: We describe the elements that make up this project in relation to the team and to its development. After applying inclusion/exclusion criteria, we have selected a group of 45 children between 3 and 15 years, defining their auditory characteristics. Through specific tests, adapted to the age, we will study the different aspects of the language; and through a structured interview parents, we try to determine the variables that influence the rehabilitator process. Finally, the data will be analyzed statistically. Discussion: The variability and the low prevalence of infant hearing loss, make it difficult studies with sufficient population to obtain statistically significant results. However, we believe that the group of children and the methodology selected will allow us to learn more about the influential in the development of the language variables. Conclusions: The hearing screening program allowed us to earlier intervention, which should improve the levels of language of children detected with hearing loss. Although the standard development of communication depends on other factors difficult to determine, through the presented protocol we equate these findings, validating the process of screening/diagnosis and intervention of our environment

Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Metodología aplicada en el estudio del desarrollo del lenguaje en niños con detección temprana de la hipoacusia neonatal

Introduction and objective: Given that the disabling potential causing neonatal hearing impairment decreases with early detection and intervention, we have drawn up a research project, with which we intend to know the degree of development of the language of children and girls than from the universal hearing screening, have been diagnosed for us of prelingual hearing loss in the last 15 years and analyze the determining variables and which are modifiable. The object of this communication will be to present the methodology that we use. Method: We assume the data stored on our ENT service, including 282 children with hearing loss. We have had the opportunity to create a research group in which we agree ENT and language specialists so we have resources sufficient for the study. Results: We describe the elements that make up this project in relation to the team and to its development. After applying inclusion/exclusion criteria, we have selected a group of 45 children between 3 and 15 years, defining their auditory characteristics. Through specific tests, adapted to the age, we will study the different aspects of the language; and through a structured interview parents, we try to determine the variables that influence the rehabilitator process. Finally, the data will be analyzed statistically. Discussion: The variability and the low prevalence of infant hearing loss, make it difficult studies with sufficient population to obtain statistically significant results. However, we believe that the group of children and the methodology selected will allow us to learn more about the influential in the development of the language variables. Conclusions: The hearing screening program allowed us to earlier intervention, which should improve the levels of language of children detected with hearing loss. Although the standard development of communication depends on other factors difficult to determine, through the presented protocol we equate these findings, validating the process of screening/diagnosis and intervention of our environment.Introducción y objetivo: Dado que el potencial discapacitante que causa la deficiencia auditiva neonatal disminuye con una detección e intervención tempranas, hemos elaborado un proyecto de investigación, con el que nos proponemos conocer el grado de desarrollo del lenguaje de los niños y niñas que procedentes del cribado auditivo universal, han sido diagnosticados/as por nosotros de hipoacusia prelingual en estos últimos 15 años y analizar las variables determinantes y las que son modificables. El objeto de esta comunicación consistirá en presentar la metodología que vamos a utilizar. Método: Partimos de los datos almacenados en nuestro Servicio de ORL, que comprende a 282 niños con hipoacusia. Hemos tenido la oportunidad de crear un grupo de investigación en el que coincidimos especialistas de la audición infantil y del lenguaje, por lo que contamos con medios suficientes para el estudio. Resultados: Describimos los elementos que configuran este proyecto, en relación al equipo de trabajo y a su desarrollo. Tras aplicar unos criterios de exclusión/inclusión, hemos seleccionado a un grupo de 45 niños entre 3 y 15 años, definiendo sus características auditivas. Mediante pruebas específicas, adaptadas a la edad, estudiaremos los diferentes aspectos del lenguaje; y a través de una entrevista estructurada realizada a los padres, intentaremos determinar las variables que influyen en el proceso re-habilitador. Finalmente, los datos serán analizados estadísticamente. Discusión: La variabilidad y la escasa prevalencia de la hipoacusia infantil, dificultan la realización de estudios con población suficiente para obtener resultados estadísticamente significativos. Sin embargo, creemos que el grupo de niños seleccionado y la metodología utilizada nos permitirán conocer mejor las variables influyentes en el desarrollo del lenguaje. Conclusiones: El programa de cribado auditivo universal ha permitido una intervención más precoz, lo que debería mejorar los niveles de lenguaje de los niños detectados/as con hipoacusia. Aunque el desarrollo normalizado de la comunicación depende de otros factores difíciles de determinar, a través del protocolo presentado pretendemos equiparar estos resultados, validando el proceso de cribado/diagnóstico e intervención de nuestro medio

Impact of late presentation of HIV infection on short-, mid- and long-term mortality and causes of death in a multicenter national cohort : 2004-2013

To analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004-2013). Cox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 < 350 cells/ml or AIDS. Of 7165 new HIV diagnoses, 46.9% (CI:45.7-48.0) were LP, 240 patients died.First-year mortality was the highest (aHR = 10.3[CI:5.5-19.3]); between 1 and 4 years post-diagnosis, aHR = 1.9(1.2-3.0); an

Association Between Use of Enhanced Recovery After Surgery Protocol and Postoperative Complications in Total Hip and Knee Arthroplasty in the Postoperative Outcomes Within Enhanced Recovery After Surgery Protocol in Elective Total Hip and Knee Arthroplasty Study (POWER2)

[Importance] The Enhanced Recovery After Surgery (ERAS) care protocol has been shown to improve outcomes compared with traditional care in certain types of surgery.[Objective] To assess the association of use of the ERAS protocols with complications in patients undergoing elective total hip arthroplasty (THA) and total knee arthroplasty (TKA).[Design, Setting, and Participants] This multicenter, prospective cohort study included patients recruited from 131 centers in Spain from October 22 through December 22, 2018. All consecutive adults scheduled for elective THA or TKA were eligible for inclusion. Patients were stratified between those treated in a self-designated ERAS center (ERAS group) and those treated in a non-ERAS center (non-ERAS group). Data were analyzed from June 15 through September 15, 2019.[Exposures] Total hip or knee arthroplasty and perioperative management. Sixteen individual ERAS items were assessed in all included patients, whether they were treated at a center that was part of an established ERAS protocol or not.[Main Outcomes and Measures] The primary outcome was postoperative complications within 30 days after surgery. Secondary outcomes included length of stay and mortality.[Results] During the 2-month recruitment period, 6146 patients were included (3580 women [58.2%]; median age, 71 [interquartile range (IQR), 63-76] years). Of these, 680 patients (11.1%) presented with postoperative complications. No differences were found in the number of patients with overall postoperative complications between ERAS and non-ERAS groups (163 [10.2%] vs 517 [11.4%]; odds ratio [OR], 0.89; 95% CI, 0.74-1.07; P = .22). Fewer patients in the ERAS group had moderate to severe complications (73 [4.6%] vs 279 [6.1%]; OR, 0.74; 95% CI, 0.56-0.96; P = .02). The median overall adherence rate with the ERAS protocol was 50.0% (IQR, 43.8%-62.5%), with the rate for ERAS facilities being 68.8% (IQR, 56.2%-81.2%) vs 50.0% (IQR, 37.5%-56.2%) at non-ERAS centers (P < .001). Among the patients with the highest and lowest quartiles of adherence to ERAS components, the patients with the highest adherence had fewer overall postoperative complications (144 [10.6%] vs 270 [13.0%]; OR, 0.80; 95% CI, 0.64-0.99; P < .001) and moderate to severe postoperative complications (59 [4.4%] vs 143 [6.9%]; OR, 0.62; 95% CI, 0.45-0.84; P < .001) and shorter median length of hospital stay (4 [IQR, 3-5] vs 5 [IQR, 4-6] days; OR, 0.97; 95% CI, 0.96-0.99; P < .001).[Conclusions and Relevance] An increase in adherence to the ERAS program was associated with a decrease in postoperative complications, although only a few ERAS items were individually associated with improved outcomes.This study was supported by institutional and/or departmental sources. The Postoperative Outcomes Within Enhanced Recovery After Surgery Protocol in Elective Total Hip and Knee Arthroplasty (POWER2) study was supported by the Spanish Perioperative Audit and Research Network (REDGERM

Prediction of long-term outcomes of HIV-infected patients developing non-AIDS events using a multistate approach

Outcomes of people living with HIV (PLWH) developing non-AIDS events (NAEs) remain poorly defined. We aimed to classify NAEs according to severity, and to describe clinical outcomes and prognostic factors after NAE occurrence using data from CoRIS, a large Spanish HIV cohort from 2004 to 2013. Prospective multicenter cohort study. Using a multistate approach we estimated 3 transition probabilities: from alive and NAE-free to alive and NAE-experienced ("NAE development"); from alive and NAE-experienced to death ("Death after NAE"); and from alive and NAE-free to death ("Death without NAE"). We analyzed the effect of different covariates, including demographic, immunologic and virologic data, on death or NAE development, based on estimates of hazard ratios (HR). We focused on the transition "Death after NAE". 8,789 PLWH were followed-up until death, cohort censoring or loss to follow-up. 792 first incident NAEs occurred in 9.01% PLWH (incidence rate 28.76; 95% confidence interval [CI], 26.80-30.84, per 1000 patient-years). 112 (14.14%) NAE-experienced PLWH and 240 (2.73%) NAE-free PLWH died. Adjusted HR for the transition "Death after NAE" was 12.1 (95%CI, 4.90-29.89). There was a graded increase in the adjusted HRs for mortality according to NAE severity category: HR (95%CI), 4.02 (2.45-6.57) for intermediate-severity; and 9.85 (5.45-17.81) for serious NAEs compared to low-severity NAEs. Male sex (HR 2.04; 95% CI, 1.11-3.84), ag

COVID-19 in hospitalized HIV-positive and HIV-negative patients : A matched study

CatedresObjectives: We compared the characteristics and clinical outcomes of hospitalized individuals with COVID-19 with [people with HIV (PWH)] and without (non-PWH) HIV co-infection in Spain during the first wave of the pandemic. Methods: This was a retrospective matched cohort study. People with HIV were identified by reviewing clinical records and laboratory registries of 10 922 patients in active-follow-up within the Spanish HIV Research Network (CoRIS) up to 30 June 2020. Each hospitalized PWH was matched with five non-PWH of the same age and sex randomly selected from COVID-19@Spain, a multicentre cohort of 4035 patients hospitalized with confirmed COVID-19. The main outcome was all-cause in-hospital mortality. Results: Forty-five PWH with PCR-confirmed COVID-19 were identified in CoRIS, 21 of whom were hospitalized. A total of 105 age/sex-matched controls were selected from the COVID-19@Spain cohort. The median age in both groups was 53 (Q1-Q3, 46-56) years, and 90.5% were men. In PWH, 19.1% were injecting drug users, 95.2% were on antiretroviral therapy, 94.4% had HIV-RNA < 50 copies/mL, and the median (Q1-Q3) CD4 count was 595 (349-798) cells/μL. No statistically significant differences were found between PWH and non-PWH in number of comorbidities, presenting signs and symptoms, laboratory parameters, radiology findings and severity scores on admission. Corticosteroids were administered to 33.3% and 27.4% of PWH and non-PWH, respectively (P = 0.580). Deaths during admission were documented in two (9.5%) PWH and 12 (11.4%) non-PWH (P = 0.800). Conclusions: Our findings suggest that well-controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes of COVID-19 hospitalization