Innovative electrode and chip designs for transendothelial electrical resistance measurements in organs-on-chips.

Many different epithelial and endothelial barriers in the human body ensure the proper functioning of our organs by controlling which substances can pass from one side to another. In recent years, organs-on-chips (OoC) have become a popular tool to study such barriers in vitro. To assess the proper functioning of these barriers, we can measure the transendothelial electrical resistance (TEER) which indicates how easily ions can cross the cell layer when a current is applied between electrodes on either side. TEER measurements are a convenient method to quantify the barrier properties since it is a non-invasive and label-free technique. Direct integration of electrodes for TEER measurements into OoC allows for continuous monitoring of the barrier, and fixed integration of the electrodes improves the reproducibility of the measurements. In this review, we will give an overview of different electrode and channel designs that have been used to measure the TEER in OoC. After giving some insight into why biological barriers are an important field of study, we will explain the theory and practice behind measuring the TEER in in vitro systems. Next, this review gives an overview of the state of the art in the field of integrated electrodes for TEER measurements in OoC, with a special focus on alternative chip and electrode designs. Finally, we outline some of the remaining challenges and provide some suggestions on how to overcome these challenges.

The benefit of adding polygenic risk scores, lifestyle factors, and breast density to family history and genetic status for breast cancer risk and surveillance classification of unaffected women from germline CHEK2 c.1100delC families.

To determine the changes in surveillance category by adding a polygenic risk score based on 311 breast cancer (BC)-associated variants (PRS311), questionnaire-based risk factors and breast density on personalized BC risk in unaffected women from Dutch CHEK2 c.1100delC families. In total, 117 unaffected women (58 heterozygotes and 59 non-carriers) from CHEK2 families were included. Blood-derived DNA samples were genotyped with the GSAMDv3-array to determine PRS311. Lifetime BC risk was calculated in CanRisk, which uses data from the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Women, were categorized into three surveillance groups. The surveillance advice was reclassified in 37.9 % of heterozygotes and 32.2 % of non-carriers after adding PRS311. Including questionnaire-based risk factors resulted in an additional change in 20.0 % of heterozygotes and 13.2 % of non-carriers; and a subanalysis showed that adding breast density on top shifted another 17.9 % of heterozygotes and 33.3 % of non-carriers. Overall, the majority of heterozygotes were reclassified to a less intensive surveillance, while non-carriers would require intensified surveillance. The addition of PRS311, questionnaire-based risk factors and breast density to family history resulted in a more personalized BC surveillance advice in CHEK2-families, which may lead to more efficient use of surveillance.

The degree of safety behaviors to a safety stimulus predicts development of threat beliefs.

Safety behaviors are behavioral responses that aim to prevent or minimize an imminent threat when confronting a feared stimulus. Despite its adaptive purpose, preliminary evidence suggests that unnecessary safety behaviors to a safety stimulus induce threat beliefs to it. By allowing participants to engage in safety behaviors dimensionally, this study tested whether the degree of safety behaviors to a safety stimulus predicts the subsequent level of threat expectancies to it. To this end, participants first acquired safety behaviors to a threat-related stimulus (A). Safety behaviors then became available only for one safety stimulus (C), but not to another safety stimulus (B). After engaging in safety behaviors to C, participants exhibited greater threat expectancies to C compared to B, albeit with a small effect size. Importantly, the degree of safety behaviors predicted an increase in threat expectancies. The current findings suggest that safety behaviors to safety stimuli are linked to the development of threat beliefs.

Childhood maltreatment and adulthood victimization: An evidence-based model.

There is ample evidence showing that childhood maltreatment increases two to three fold the risk of victimization in adulthood. Various risk factors, including posttraumatic stress disorder (PTSD) symptoms, dissociation, self-blame, and alcohol abuse are related to revictimization. Although previous research examined associations between risk factors for revictimization, the evidence is limited and the proposed models mostly include a handful of risk factors. Therefore, it is critical to investigate a more comprehensive model explaining the link between childhood maltreatment and adulthood (re)victimization. Accordingly, this study tested a data-driven theoretical path model consisting of 33 variables (and their associations) that could potentially enhance understanding of factors explaining revictimization. Cross-sectional data derived from a multi-wave study were used for this investigation. Participants (N = 2156, age mean = 19.94, SD = 2.89) were first-year female psychology students in the Netherlands and New Zealand, who responded to a battery of questionnaires and performed two computer tasks. The path model created by structural equation modelling using modification indices showed that peritraumatic dissociation, PTSD symptoms, trauma load, loneliness, and drug use were important mediators. Attachment styles, maladaptive schemas, meaning in life, and sex motives connected childhood maltreatment to adulthood victimization via other factors (i.e., PTSD symptoms, risky sex behavior, loneliness, emotion dysregulation, and sex motives). The model indicated that childhood maltreatment was associated with cognitive patterns (e.g., anxious attachment style), which in turn were associated with emotional factors (e.g., emotion dysregulation), and then with behavioral factors (e.g., risky sex behavior) resulting in revictimization. The findings of the study should be interpreted in the light of the limitations. In particular, the cross-sectional design of the study hinders us from ascertaining that the mediators preceded the outcome variable.

Mejora en el manejo de la sospecha del síndrome aórtico agudo en urgencias mediante un algoritmo clínico y el estudio de factores predictivos / Improvement in the management of suspected acute aortic syndrome in the emergency room through a clinical algorithm and study of predictive factors

Antecedentes y objetivo: El síndrome aórtico agudo (SAA) es poco frecuente y difícil de diagnosticar, con una gran variabilidad en su cuadro clínico inicial. Los objetivos son: 1) desarrollar un algoritmo informático, o un sistema de apoyo a las decisiones clínicas (SADC), para el manejo y la solicitud de estudios de diagnóstico por imagen en el servicio de Urgencias, en concreto de una tomografía computarizada (TC) de la aorta, ante la sospecha de SAA, 2) determinar el efecto de la implantación de este sistema, y 3) determinar los factores asociados a un diagnóstico radiológico positivo que mejoren la capacidad predictiva de los hallazgos de la TC de aorta. Material y métodos: Tras desarrollar e implementar un algoritmo basado en la evidencia, se estudiaron casos de sospecha de SAA. Se utilizó el test de la χ2 para analizar la asociación entre las variables incluidas en el algoritmo y el diagnóstico radiológico, con 3 categorías: sin hallazgos relevantes, positivo para SAA y diagnósticos alternativos. Resultados: Se identificaron 130 solicitudes; 19 (14,6%) tenían SAA y 34 (26,2%) tenían otra patología aguda. De las 19 con SAA, 15 habían sido estratificadas como de alto riesgo y 4 como de riesgo intermedio. La probabilidad de SAA era 3,4 veces mayor en los pacientes con aneurisma aórtico conocido (p=0,021, IC del 95%: 1,2-9,6) y 5,1 veces mayor en los pacientes con un soplo de insuficiencia vascular aórtica de novo(p=0,019, IC del 95 %: 1,3-20,1). La probabilidad de tener una enfermedad aguda grave alternativa fue 3,2 veces mayor en los pacientes con hipotensión o choque (p=0,02, IC del 95 %: 1,2-8,5). Conclusión: El uso de un SADC en el servicio de Urgencias puede ayudar a optimizar el diagnóstico del SAA. Se demostró que la presencia de un aneurisma aórtico conocido y de insuficiencia valvular aórtica de nueva aparición aumentan significativamente la probabilidad de SAA. Se necesitan más estudios para establecer una regla de predicción clínica.(AU)

Background and objective: Acute aortic syndrome (AAS) is uncommon and difficult to diagnose, with great variability in clinical presentation. To develop a computerized algorithm, or clinical decision support system (CDSS), for managing and requesting imaging in the emergency department, specifically computerized tomography of the aorta (CTA), when there is suspicion of AAS, and to determine the effect of implementing this system. To determine the factors associated with a positive radiological diagnosis that improve the predictive capacity of CTA findings. Materials and methods: After developing and implementing an evidence-based algorithm, we studied suspected cases of AAS. Chi-squared test was used to analyze the association between the variables included in the algorithm and radiological diagnosis, with 3 categories: no relevant findings, positive for AAS, and alternative diagnoses. Results: 130 requests were identified; 19 (14.6%) had AAS and 34 (26.2%) had a different acute pathology. Of the 19 with AAS, 15 had been stratified as high risk and 4 as intermediate risk. The probability of AAS was 3.4 times higher in patients with known aortic aneurysm (P=.021, 95% CI 1.2–9.6) and 5.1 times higher in patients with a new aortic regurgitation murmur (P=.019, 95% CI 1.3–20.1). The probability of having an alternative severe acute pathology was 3.2 times higher in patients with hypotension or shock (P=.02, 95% CI 1.2–8.5). Conclusion: The use of a CDSS in the emergency department can help optimize AAS diagnosis. The presence of a known aortic aneurysm and new-onset aortic regurgitation were shown to significantly increase the probability of AAS. Further studies are needed to establish a clinical prediction rule.(AU)

Are liver contour and bone fusion comparable to fiducials for IGRT in liver SBRT?

Introduction: Liver stereotactic body radiotherapy (SBRT) is increasingly being used to treat tumours. The purpose of this study was to compare the differences in patient positioning when using implanted fiducials as surrogates compared to alternative methods based on liver contour or bone registration. Material and methods: Eighteen patients treated with SBRT who underwent a fiducial placement procedure were included. Fiducial guidance was our gold standard to guide treatment in this study. After recording the displacements, when fusing the planning CT and CBCT performed in the treatment unit using fiducials, liver contour and bone reference, the differences between fiducials and liver contour and bone reference were calculated. Data from 88 CBCT were analyzed. The correlation between the displacements found with fiducials and those performed based on the liver contour and the nearest bone structure as references was determined. The mean, median, variance, range and standard deviation of the displacements with each of the fusion methods were obtained. µ, Æ©, and σ values and margins were obtained. Results: Lateral displacements of less than 3 mm with respect to the gold standard in 92% vs. 62.5% of cases using liver contour and bone references, respectively, with 93.2% vs. 65.9% in the AP axis and SI movement in 69.3% vs. 51.1%. The errors µ, σ and Æ© of the fusions with hepatic contour and bone reference in SI were 0.26 mm, 4 mm and 3 mm, and 0.8 mm, 5 mm and 3 mm respectively. Conclusion: Our study showed that displacements were smaller with the use of hepatic contour compared to bone reference and comparable to those obtained with the use of fiducials in the lateral, AP and SI motion axes. This would justify that hepatic contouring can be a guide in the treatment of patients in the absence of fiducials.

Improvement in the management of suspected acute aortic syndrome in the emergency room through a clinical algorithm and study of predictive factors.

BACKGROUND AND OBJECTIVE: Acute aortic syndrome (AAS) is uncommon and difficult to diagnose, with great variability in clinical presentation. To develop a computerized algorithm, or clinical decision support system (CDSS), for managing and requesting imaging in the emergency department, specifically computerized tomography of the aorta (CTA), when there is suspicion of AAS, and to determine the effect of implementing this system. To determine the factors associated with a positive radiological diagnosis that improve the predictive capacity of CTA findings. MATERIALS AND METHODS: After developing and implementing an evidence-based algorithm, we studied suspected cases of AAS. Chi-squared test was used to analyze the association between the variables included in the algorithm and radiological diagnosis, with 3 categories: no relevant findings, positive for AAS, and alternative diagnoses. RESULTS: 130 requests were identified; 19 (14.6%) had AAS and 34 (26.2%) had a different acute pathology. Of the 19 with AAS, 15 had been stratified as high risk and 4 as intermediate risk. The probability of AAS was 3.4 times higher in patients with known aortic aneurysm (P = .021, 95% CI 1.2-9.6) and 5.1 times higher in patients with a new aortic regurgitation murmur (P = .019, 95% CI 1.3-20.1). The probability of having an alternative severe acute pathology was 3.2 times higher in patients with hypotension or shock (P = .02, 95% CI 1.2-8.5). CONCLUSION: The use of a CDSS in the emergency department can help optimize AAS diagnosis. The presence of a known aortic aneurysm and new-onset aortic regurgitation were shown to significantly increase the probability of AAS. Further studies are needed to establish a clinical prediction rule.

Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.

Predictors associated with mortality of veno-venous extracorporeal membrane oxygenation therapy.

Background: The use of veno-venous extracorporeal membrane oxygenation (V-V ECMO) has rapidly increased in recent years. Today, applications of V-V ECMO include a variety of clinical conditions such as acute respiratory distress syndrome (ARDS), bridge to lung transplantation and primary graft dysfunction after lung transplantation. The purpose of the present study was to investigate in-hospital mortality of adult patients undergoing V-V ECMO therapy and to determine independent predictors associated with mortality. Methods: This retrospective study was conducted at the University Hospital Zurich, a designated ECMO center in Switzerland. Data was analyzed of all adult V-V ECMO cases from 2007 to 2019. Results: In total, 221 patients required V-V ECMO support (median age 50 years, 38.9% female). In-hospital mortality was 37.6% and did not statistically vary significantly between indications (P=0.61): 25.0% (1/4) for primary graft dysfunction after lung transplantation, 29.4% (5/17) for bridge to lung transplantation, 36.2% (50/138) for ARDS and 43.5% (27/62) for other pulmonary disease indications. Cubic spline interpolation showed no effect of time on mortality over the study period of 13 years. Multiple logistic regression modelling identified significant predictor variables associated with mortality: age [odds ratio (OR), 1.05; 95% confidence interval (CI): 1.02-1.07; P=0.001], newly detected liver failure (OR, 4.83; 95% CI: 1.27-20.3; P=0.02), red blood cell transfusion (OR, 1.91; 95% CI: 1.39-2.74; P<0.001) and platelet concentrate transfusion (OR, 1.93; 95% CI: 1.28-3.15; P=0.004). Conclusions: In-hospital mortality of patients receiving V-V ECMO therapy remains relatively high. Patients' outcomes have not improved significantly in the observed period. We identified age, newly detected liver failure, red blood cell transfusion and platelet concentrate transfusion as independent predictors associated with in-hospital mortality. Incorporating such mortality predictors into decision making with regards to V-V ECMO use may increase its effectiveness and safety and may translate into better outcomes.

Breast cancer genomes from CHEK2 c.1100delC mutation carriers lack somatic TP53 mutations and display a unique structural variant size distribution profile.

BACKGROUND: CHEK2 c.1100delC was the first moderate-risk breast cancer (BC) susceptibility allele discovered. Despite several genomic, transcriptomic and functional studies, however, it is still unclear how exactly CHEK2 c.1100delC promotes tumorigenesis. Since the mutational landscape of a tumor reflects the processes that have operated on its development, the aim of this study was to uncover the somatic genomic landscape of CHEK2-associated BC. METHODS: We sequenced primary BC (pBC) and normal genomes of 20 CHEK2 c.1100delC mutation carriers as well as their pBC transcriptomes. Including pre-existing cohorts, we exhaustively compared CHEK2 pBC genomes to those from BRCA1/2 mutation carriers, those that displayed homologous recombination deficiency (HRD) and ER- and ER+ pBCs, totaling to 574 pBC genomes. Findings were validated in 517 metastatic BC genomes subdivided into the same subgroups. Transcriptome data from 168 ER+ pBCs were used to derive a TP53-mutant gene expression signature and perform cluster analysis with CHEK2 BC transcriptomes. Finally, clinical outcome of CHEK2 c.1100delC carriers was compared with BC patients displaying somatic TP53 mutations in two well-described retrospective cohorts totaling to 942 independent pBC cases. RESULTS: BC genomes from CHEK2 mutation carriers were most similar to ER+ BC genomes and least similar to those of BRCA1/2 mutation carriers in terms of tumor mutational burden as well as mutational signatures. Moreover, CHEK2 BC genomes did not show any evidence of HRD. Somatic TP53 mutation frequency and the size distribution of structural variants (SVs), however, were different compared to ER+ BC. Interestingly, BC genomes with bi-allelic CHEK2 inactivation lacked somatic TP53 mutations and transcriptomic analysis indicated a shared biology with TP53 mutant BC. Moreover, CHEK2 BC genomes had an increased frequency of > 1 Mb deletions, inversions and tandem duplications with peaks at specific sizes. The high chromothripsis frequency among CHEK2 BC genomes appeared, however, not associated with this unique SV size distribution profile. CONCLUSIONS: CHEK2 BC genomes are most similar to ER+ BC genomes, but display unique features that may further unravel CHEK2-driven tumorigenesis. Increased insight into this mechanism could explain the shorter survival of CHEK2 mutation carriers that is likely driven by intrinsic tumor aggressiveness rather than endocrine resistance.

Impact of institutional prophylaxis guidelines on rates of pediatric venous thromboembolism following trauma-A multicenter study from the pediatric trauma society research committee.

BACKGROUND: A paucity of data exists with regard to the incidence, management, and outcomes of venous thromboembolism (VTE) in injured children. We sought to determine the impact of institutional chemoprophylaxis guidelines on VTE rates in a pediatric trauma population. METHODS: A retrospective review of injured children (≤15 years) admitted between 2009 and 2018 at 10 pediatric trauma centers was performed. Data were gathered from institutional trauma registries and dedicated chart review. The institutions were surveyed as to whether they had chemoprophylaxis guidelines in place for high-risk pediatric trauma patients, and outcomes were compared based on the presence of guidelines using χ 2 analysis ( p < 0.05). RESULTS: There were 45,202 patients evaluated during the study period. Three institutions (28,359 patients, 63%) had established chemoprophylaxis policies during the study period ("Guidelines"); the other seven centers (16,843 patients, 37%) had no such guidelines ("Standard"). There were significantly lower rates of VTE in the Guidelines group, but these patients also had significantly fewer risk factors. Among critically injured children with similar clinical presentations, there was no difference in VTE rate. Specifically within the Guidelines group, 30 children developed VTE. The majority (17/30) were actually not indicated for chemoprophylaxis based on institutional guidelines. Still, despite protocols only one VTE patient in the guidelines group who was indicated for intervention ended up receiving chemoprophylaxis prior to diagnosis. No consistent ultrasound screening protocol was in place at any institution during the study. CONCLUSION: The presence of an institutional policy to guide chemoprophylaxis for injured children is associated with a decreased overall frequency of VTE, but this disappears when controlling for patient factors. However, the overall efficacy is impacted by a combination of deficits in guideline compliance and structure. Further prospective data are needed to help determine the ideal role for chemoprophylaxis and protocols in pediatric trauma. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Clinical applicability of the Polygenic Risk Score for breast cancer risk prediction in familial cases.

BACKGROUND: Common low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2 Dutch BC families. METHODS: We included 3918 BC cases from 3492 Dutch non-BRCA1/2 BC families and 3474 Dutch population controls. The association of the standardised PRS313 with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2 and PALB2 was known. RESULTS: The family history-adjusted PRS313 was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313 in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313 had the largest impact for CHEK2 and ATM. CONCLUSIONS: Our results support the application of the PRS313 in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.

The Negative Impact of COVID-19 in HCV, HIV, and HPV Surveillance Programs During the Different Pandemic Waves.

Background: The coronavirus disease 2019 (COVID-19) pandemic has been a worldwide stress test for health systems. 2 years have elapsed since the description of the first cases of pneumonia of unknown origin. This study quantifies the impact of COVID-19 in the screening program of chronic viral infections such as human papillomavirus (HPV), human immunodeficiency virus (HIV), and hepatitis C virus (HCV) along the six different pandemic waves in our population. Each wave had particular epidemiological, biological, or clinical patterns. Methods: We analyzed the number of samples for screening of these viruses from March 2020 to February 2022, the new infections detected in the pandemic period compared to the previous year, the time elapsed between diagnosis and linking to treatment and follow-up of patients, and the percentage of late HIV diagnosis. Moreover, we used the origin of the samples as a marker for quantifying the restoration of activity in primary care. Results: During the first pandemic year, the number of samples received was reduced by 26.7, 22.6, and 22.5% for molecular detection of HPV or serological HCV and HIV status respectively. The highest decrease was observed during the first wave with 70, 40, and 26.7% for HPV, HCV, and HIV. As expected, new diagnoses also decreased by 35.4, 58.2, and 40.5% for HPV, HCV, and HIV respectively during the first year of the pandemic. In the second year of the pandemic, the number of samples remained below pre-pandemic period levels for HCV (-3.6%) and HIV (-9.3%) but was slightly higher for HPV (8.0%). The new diagnoses in the second year of the pandemic were -16.1, -46.8, and -18.6% for HPV, HCV, and HIV respectively. Conclusions: Undoubtedly, an important number of new HPV, HCV, and HIV infections were lost during the COVID-19 pandemic, and surveillance programs were disrupted as a consequence of collapse of the health system. It is a priority to reinforce these surveillance programs as soon as possible in order to detect undiagnosed cases before the associated morbidity-mortality increases. New pandemic waves could increase the risk of reversing the achievements made over the last few decades.

Uncovering the Contribution of Moderate-Penetrance Susceptibility Genes to Breast Cancer by Whole-Exome Sequencing and Targeted Enrichment Sequencing of Candidate Genes in Women of European Ancestry.

Rare variants in at least 10 genes, including BRCA1, BRCA2, PALB2, ATM, and CHEK2, are associated with increased risk of breast cancer; however, these variants, in combination with common variants identified through genome-wide association studies, explain only a fraction of the familial aggregation of the disease. To identify further susceptibility genes, we performed a two-stage whole-exome sequencing study. In the discovery stage, samples from 1528 breast cancer cases enriched for breast cancer susceptibility and 3733 geographically matched unaffected controls were sequenced. Using five different filtering and gene prioritization strategies, 198 genes were selected for further validation. These genes, and a panel of 32 known or suspected breast cancer susceptibility genes, were assessed in a validation set of 6211 cases and 6019 controls for their association with risk of breast cancer overall, and by estrogen receptor (ER) disease subtypes, using gene burden tests applied to loss-of-function and rare missense variants. Twenty genes showed nominal evidence of association (p-value < 0.05) with either overall or subtype-specific breast cancer. Our study had the statistical power to detect susceptibility genes with effect sizes similar to ATM, CHEK2, and PALB2, however, it was underpowered to identify genes in which susceptibility variants are rarer or confer smaller effect sizes. Larger sample sizes would be required in order to identify such genes.

Predictors associated with mortality of extracorporeal life support therapy for acute heart failure: single-center experience with 679 patients.

Background: Extracorporeal life support (ECLS) therapy is increasingly used for cardiac and respiratory support postcardiotomy, refractory cardiogenic shock and cardiopulmonary resuscitation. This study aims to describe in-hospital mortality of patients requiring ECLS, identify independent predictors associated with mortality and analyze changes of mortality over time. Methods: This retrospective study includes all adult ECLS cases at the University Hospital Zurich, a designated ECLS center in Switzerland, in the period 2007 to 2019. Results: ECLS therapy was required in 679 patients (median age 60 years, 27.5% female). In-hospital mortality was 55.5%. Cubic spline interpolation did not detect evidence for a change in mortality over the whole period of 13 years. In-hospital mortality significantly varied between ECLS indications: 70.7% (152/215) for postcardiotomy, 67.9% (108/159) for cardiopulmonary resuscitation, 47.0% (110/234) for refractory cardiogenic shock, and 9.9% (7/71) for lung transplantation and expansive thoracic surgery (P<0.001). Logistic regression modelling showed excellent discrimination in the receiver operating characteristic (ROC) area under the curve (AUC) of 0.89 [95% confidence interval (CI): 0.87-0.92] and identified significant mortality predictors: age, simplified acute physiology score (SAPS) II, as well as new liver failure and each allogenic blood transfusion unit given per day. ECLS after cardiopulmonary resuscitation was associated with significantly higher mortality compared to ECLS for refractory cardiogenic shock. Conclusions: In-hospital mortality of patients treated with ECLS therapy is high. Outcomes have not changed significantly in the observed period. We identified age, SAPS II, new liver failure and each allogenic blood transfusion unit given per day as independent mortality predictors. Knowledge of predictors strongly associated with in-hospital mortality may affect future decisions about ECLS indications and the respective management to use this elaborate therapy more effectively.

Ventilación mecánica en España, 1998-2016: cambios en la desconexión de la ventilación mecánica / Mechanical ventilation in Spain, 1998-2016: changes in the disconnection of mechanical ventilation

Objetivo Evaluar los cambios en la desconexión de la ventilación mecánica en España desde 1998 hasta 2016. Diseño Análisis post-hoc de 4 estudios de cohorte. Ámbito Un total de 138 UCI. Enfermos Un total de 2.141 enfermos extubados de forma programada. Intervenciones Ninguna. Variables de interés principales Demográficas, motivo de ventilación mecánica, complicaciones, métodos para la desconexión, fracaso del primer intento de desconexión, duración de la desconexión, reintubación, traqueotomía post-reintubación, estancia y mortalidad en la UCI. Resultados Se observa un aumento significativo (p<0,001) en la presión de soporte como técnica de desconexión. Ha aumentado, a lo largo del tiempo, la probabilidad ajustada de utilizar la presión de soporte progresivamente decreciente frente a una prueba de ventilación espontánea, tanto para el primer intento de desconexión (referencia estudio de 1998: odds ratio 0,99 en 2004, 0,57 en 2010 y 2,43 en 2016) como para la desconexión difícil/prolongada (referencia estudio de 1998: odds ratio 2,29 en 2004, 1,23 en 2010 y 2,54 en 2016). La proporción de extubación tras el primer intento de desconexión ha aumentado con el tiempo. Hay una disminución del tiempo dedicado a la desconexión (desde un 45% en 1998 hasta un 36% en 2016). Sin embargo, no ha disminuido la duración en la desconexión difícil/prolongada (mediana 3 días en todos los estudios, p=0,435). Conclusiones Ha habido cambios significativos en el modo de desconexión de la ventilación mecánica, con un aumento progresivo del uso de la presión de soporte. Se han observado mínimos cambios en los desenlaces (AU)

Purpose To evaluate changes in the disconnection of mechanical ventilation in Spain from 1998 to 2016. Design Post-hoc analysis of four cohort studies. Ambit 138 Spanish ICUs. Patients 2141 patients scheduled extubated. Interventions None. Variables of interest Demographics, reason for mechanical ventilation, complications, methods for disconnection, failure on the first attempt at disconnection, duration of weaning, reintubation, post-reintubation tracheotomy, ICU stay and mortality. Results There was a significant increase (p<0.001) in the use of gradual reduction of support pressure. The adjusted probability of using the gradual reduction in pressure support versus a spontaneous breathing trial has increased over time, both for the first attempt at disconnection (taking the 1998 study as a reference: odds ratio 0.99 in 2004, 0.57 in 2010 and 2.43 in 2016) and for difficult/prolonged disconnection (taking the 1998 study as a reference: odds ratio 2.29 in 2004, 1.23 in 2010 and 2.54 in 2016). The proportion of patients extubated after the first attempt at disconnection has increased over time. There is a decrease in the ventilation time dedicated to weaning (from 45% in 1998 to 36% in 2016). However, the duration in difficult/prolonged weaning has not decreased (median 3 days in all studies, p=0.435). Conclusions There have been significant changes in the mode of disconnection of mechanical ventilation, with a progressive increase in the use of gradual reduction of pressure support. No relevant changes in outcomes have been observed (AU)

A meta-analysis of conditioned fear generalization in anxiety-related disorders.

Generalization of conditioned fear is adaptive in some situations but maladaptive when fear excessively generalizes to innocuous stimuli with incidental resemblance to a genuine threat cue. Recently, empirical interest in fear generalization as a transdiagnostic explanatory mechanism underlying anxiety-related disorders has accelerated. As there are now several studies of fear generalization across multiple types of anxiety-related disorders, the authors conducted a meta-analysis of studies reporting behavioral measures (subjective ratings and psychophysiological indices) of fear generalization in anxiety-related disorder vs. comparison groups. We conducted systematic searches of electronic databases (conducted from January-October 2020) for fear generalization studies involving anxiety-related disorder groups or subclinical analog groups. A total of 300 records were full-text screened and two unpublished datasets were obtained, yielding 16 studies reporting behavioral fear generalization measures. Random-effects meta-analytic models and meta-regressions were applied to the identified data. Fear generalization was significantly heightened in anxiety-related disorder participants (N = 439) relative to comparison participants (N = 428). We did not identify any significant clinical, sample, or methodological moderators. Heightened fear generalization is quantitatively supported as distinguishing anxiety-related disorder groups from comparison groups. Evidence suggests this effect is transdiagnostic, relatively robust to experimental or sample parameters, and that generalization paradigms are a well-supported framework for neurobehavioral investigations of learning and emotion in anxiety-related disorders. We discuss these findings in the context of prior fear conditioning meta-analyses, past neuroimaging investigations of fear generalization in anxiety-related disorders, and future directions and challenges for the field.

Mechanical ventilation in Spain, 1998-2016: Changes in the disconnection of mechanical ventilation.

PURPOSE: To evaluate changes in the disconnection of mechanical ventilation in Spain from 1998 to 2016. DESIGN: Post-hoc analysis of four cohort studies. AMBIT: 138 Spanish ICUs. PATIENTS: 2141 patients scheduled extubated. INTERVENTIONS: None. VARIABLES OF INTEREST: Demographics, reason for mechanical ventilation, complications, methods for disconnection, failure on the first attempt at disconnection, duration of weaning, reintubation, post-reintubation tracheotomy, ICU stay and mortality. RESULTS: There was a significant increase (p < 0.001) in the use of gradual reduction of support pressure. The adjusted probability of using the gradual reduction in pressure support versus a spontaneous breathing trial has increased over time, both for the first attempt at disconnection (taking the 1998 study as a reference: odds ratio 0.99 in 2004, 0.57 in 2010 and 2.43 in 2016) and for difficult/prolonged disconnection (taking the 1998 study as a reference: odds ratio 2.29 in 2004, 1.23 in 2010 and 2.54 in 2016). The proportion of patients extubated after the first attempt at disconnection has increased over time. There is a decrease in the ventilation time dedicated to weaning (from 45% in 1998 to 36% in 2016). However, the duration in difficult/prolonged weaning has not decreased (median 3 days in all studies, p = 0.435). CONCLUSIONS: There have been significant changes in the mode of disconnection of mechanical ventilation, with a progressive increase in the use of gradual reduction of pressure support. No relevant changes in outcomes have been observed.

Breast cancer risks associated with missense variants in breast cancer susceptibility genes.

BACKGROUND: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. METHODS: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. RESULTS: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. CONCLUSIONS: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.