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Real-time echocardiographic monitoring of blood flow in the ductus venosus and hepatic vein was undertaken during perinatal transition with intact umbilical cord of term born infants. Antegrade flow increased during inspiration, preferentially directing blood flow from the ductus venosus into the right atrium.Objective To investigate the effect of spontaneous breathing on venous return in term infants during delayed cord clamping at birth. Methods Echocardiographic ultrasound recordings were obtained directly after birth in healthy term-born infants. A subcostal view was used to obtain an optimal view of the inferior vena cava (IVC) entering the right atrium, including both the ductus venosus (DV) and the hepatic vein (HV). Colour Doppler was used to assess flow direction and flow velocity. Recordings continued until the umbilical cord was clamped and were stored in digital format for offline analyses. Results Ultrasound recordings were obtained in 15 infants, with a median (IQR) gestational age of 39.6 (39.0-40.9) weeks and a birth weight of 3560 (3195-4205) g. Flow was observed to be antegrade in the DV and HV in 98% and 82% of inspirations, respectively, with flow velocity increasing in 74% of inspirations. Retrograde flow in the DV was observed sporadically and only occurred during expiration. Collapse of the IVC occurred during 58% of inspirations and all occurred caudal to the DV inlet (100%). Conclusion Spontaneous breathing was associated with collapse of the IVC and increased antegrade DV and HV flow velocity during inspiration. Therefore, inspiration appears to preferentially direct blood flow from the DV into the right atrium. This indicates that inspiration could be a factor driving placental transfusion in infants.

Cardiac involvement is the main cause of death in Becker muscular dystrophy (BMD). Identification of left ventricular (LV) function is crucial, but standard echocardiographic measurements such as LV ejection fraction (LVEF) might not be sensitive enough to detect early myocardial dysfunction. We explored the value of LV global longitudinal strain (GLS) as a more accurate echocardiographic parameter to detect and monitor LV dysfunction in BMD. Furthermore, we studied possible factors associated with LV dysfunction and progression. A total of 40 patients with BMD (age 39.0 +/- 13.2 years) and 21 matched controls were included. Clinical variables, pulmonary tests, serum biomarkers, and echocardiograms were collected at baseline and after 2 years. LV systolic function was assessed by LVEF and LV GLS; a significant progression in LV dysfunction was defined as an absolute LV GLS deterioration >= 15%. Responsiveness to cardiac disease progression was determined using standardized response means. Patients showed impaired LVEF and LV GLS compared with controls (p

Objectives To evaluate the feasibility of automatic longitudinal analysis of consecutive biparametric MRI (bpMRI) scans to detect clinically significant (cs) prostate cancer (PCa). Methods This retrospective study included a multi-center dataset of 1513 patients who underwent bpMRI (T2 + DWI) between 2014 and 2020, of whom 73 patients underwent at least two consecutive bpMRI scans and repeat biopsies. A deep learning PCa detection model was developed to produce a heatmap of all PIRADS ≥ 2 lesions across prior and current studies. The heatmaps for each patient’s prior and current examination were used to extract differential volumetric and likelihood features reflecting explainable changes between examinations. A machine learning classifier was trained to predict from these features csPCa (ISUP > 1) at the current examination according to biopsy. A classifier trained on the current study only was developed for comparison. An extended classifier was developed to incorporate clinical parameters (PSA, PSA density, and age). The cross-validated diagnostic accuracies were compared using ROC analysis. The diagnostic performance of the best model was compared to the radiologist scores. Results The model including prior and current study (AUC 0.81, CI: 0.69, 0.91) resulted in a higher (p = 0.04) diagnostic accuracy than the current only model (AUC 0.73, CI: 0.61, 0.84). Adding clinical variables further improved diagnostic performance (AUC 0.86, CI: 0.77, 0.93). The diagnostic performance of the surveillance AI model was significantly better (p = 0.02) than of radiologists (AUC 0.69, CI: 0.54, 0.81). Conclusions Our proposed AI-assisted surveillance of prostate MRI can pick up explainable, diagnostically relevant changes with promising diagnostic accuracy. Key Points • Sequential prostate MRI scans can be automatically evaluated using a hybrid deep learning and machine learning approach. • The diagnostic accuracy of our csPCa detection AI model improved by including clinical parameters.

Background: Hypertrophic cardiomyopathy (HCM) is a complex disease partly explained by the effects of individual gene variants on sarcomeric protein biomechanics. At the cellular level, HCM mutations most commonly enhance force production, leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure–function relationships, there is still much to be learned about the mechanisms that link altered cardiac energetics to HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics represent a common pathophysiologic pathway in HCM. Methods: We performed a comprehensive multiomics profile of the molecular (transcripts, metabolites, and complex lipids), ultrastructural, and functional components of HCM energetics using myocardial samples from 27 HCM patients and 13 normal controls (donor hearts). Results: Integrated omics analysis revealed alterations in a wide array of biochemical pathways with major dysregulation in fatty acid metabolism, reduction of acylcarnitines, and accumulation of free fatty acids. HCM hearts showed evidence of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and phosphocreatine) and a reduction in mitochondrial genes involved in creatine kinase and ATP synthesis. Accompanying these metabolic derangements, electron microscopy showed an increased fraction of severely damaged mitochondria with reduced cristae density, coinciding with reduced citrate synthase activity and mitochondrial oxidative respiration. These mitochondrial abnormalities were associated with elevated reactive oxygen species and reduced antioxidant defenses. However, despite significant mitochondrial injury, HCM hearts failed to upregulate mitophagic clearance. Conclusions: Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in patients with HCM. These results highlight potential new drug targets for attenuation of the clinical disease through improving metabolic function and reducing mitochondrial injury.

ImportanceInadequate sleep negatively affects patients' physical health, mental well-being, and recovery. Nonpharmacologic interventions are recommended as first-choice treatment. However, studies evaluating the interventions are often of poor quality and show equivocal results.ObjectiveTo assess whether the implementation of nonpharmacologic interventions is associated with improved inpatient night sleep.Design, Setting, and ParticipantsIn a nonrandomized controlled trial, patients were recruited on the acute medical unit and medical and surgical wards of a Dutch academic hospital. All adults who spent exactly 1 full night in the hospital were recruited between September 1, 2019, and May 31, 2020 (control group), received usual care. Patients recruited between September 1, 2020, and May 31, 2021, served as the intervention group. The intervention group received earplugs, an eye mask, and aromatherapy. Nurses received sleep-hygiene training, and in the acute medical unit, the morning medication and vital sign measurement rounds were postponed from the night shift to the day shift. All interventions were developed in collaboration with patients, nurses, and physicians.Main Outcomes and MeasuresSleep was measured using actigraphy and the Dutch-Flemish Patient-Reported Outcomes Measurement Information System sleep disturbance item bank. Other outcomes included patient-reported sleep disturbing factors and the use of sleep-enhancing tools.ResultsA total of 374 patients were included (222 control, 152 intervention; median age, 65 [IQR, 52-74] years). Of these, 331 were included in the analysis (195 [59%] men). Most patients (138 [77%] control, 127 [84%] intervention) were in the acute medical unit. The total sleep time was 40 minutes longer in the intervention group (control: median, 6 hours and 5 minutes [IQR, 4 hours and 55 minutes to 7 hours and 4 minutes]; intervention: 6 hours and 45 minutes [IQR, 5 hours and 47 minutes to 7 hours and 39 minutes]; P am [IQR, 6:00 am to 7:22 am]; intervention, 7:00 am [IQR, 6:30-7:30 am]; P P Conclusions and RelevanceThe findings of this study suggest that sleep of hospitalized patients may be significantly improved with nonpharmacologic interventions. Postponement of morning vital sign checks and medication administration rounds from the night to the day shift may be a useful way to achieve this.Trial RegistrationNetherlands Trial Registry Identifier: NL7995

The aim of the present study was to examine construct validity and reliability of the German reactive proactive aggression questionnaire (RPQ) in a sample of delinquent boys ( N = 156). A confirmatory factor analysis with a two-factor model of reactive and proactive aggression showed a good fit to the data. The factor structure of the original RPQ could be fully replicated in the German translation, and Cronbach’s alphas were good for both subscales. Concurrent validity of the RPQ was demonstrated by significant correlations with the subscales of the inventory of callous unemotional traits. In future studies, the German RPQ can be used to assess reactive and proactive aggression in judicial and forensic psychiatric care in Germany. The present findings also provide support for the use of the RPQ in cross-cultural comparisons.

Functional Somatic Symptoms (FSS) are physical symptoms that cannot be attributed to underlying pathology. Their severity is often measured with sum scores on questionnaires; however, this may not adequately reflect FSS severity in subgroups of patients. We aimed to identify the items of the somatization section of the Composite International Diagnostic Interview that best discriminate FSS severity levels, and to assess their functioning in sex and age subgroups. We applied the two-parameter logistic model to 19 items in a population-representative cohort of 962 participants. Subsequently, we examined differential item functioning (DIF). “Localized (muscle) weakness” was the most discriminative item of FSS severity. “Abdominal pain” consistently showed DIF by sex, with males reporting it at higher FSS severity. There was no consistent DIF by age, however, “Joint pain” showed poor discrimination of FSS severity in older adults. These findings could be helpful for the development of better assessment instruments for FSS, which can improve both future research and clinical care.

The purpose of this study was to directly assess (patho)physiology of intraventricular hemodynamic interplay between four-dimensional flow cardiovascular magnetic resonance imaging (4D Flow MRI)-derived vorticity with kinetic energy (KE) and viscous energy loss (EL) over the cardiac cycle and their association to ejection fraction (EF) and stroke volume (SV). Fifteen healthy subjects and thirty Fontan patients underwent whole heart 4D Flow MRI. Ventricular vorticity, KE, and EL were computed over systole (vorticity_volavg systole, KEavg systole, and ELavg systole) and diastole (vorticity_volavg diastole, KEavg diastole, and ELavg diastole). The association between vorticity_vol and KE and EL was tested by Spearman correlation. Fontan patients were grouped to normal and impaired EF groups. A significant correlation was found between SV and vorticity in healthy subjects (systolic: r = 0.84, P < 0.001; diastolic: r = 0.81, P < 0.001) and in Fontan patients (systolic: r = 0.61, P < 0.001; diastolic: r = 0.54, P = 0.002). Healthy subjects showed positive correlation between vorticity_vol versus KE (systole: r = 0.96, P < 0.001; diastole: r = 0.90, P < 0.001) and EL (systole: r = 0.85, P < 0.001; diastole: r = 0.84, P < 0.001). Fontan patients showed significantly elevated vorticity_vol compared with healthy subjects (vorticity_volavg systole: 3.1 [2.3–3.9] vs. 1.7 [1.3–2.4] L/s, P < 0.001; vorticity_volavg diastole: 3.1 [2.0–3.7] vs. 2.1 [1.6–2.8] L/s, P = 0.002). This elevated vorticity in Fontan patients showed strong association with KE (systole: r = 0.91, P < 0.001; diastole: r = 0.85, P < 0.001) and EL (systole: r = 0.82, P < 0.001; diastole: r = 0.89, P < 0.001). Fontan patients with normal EF showed significantly higher vorticity_volavg systole and ELavg systole, but significantly decreased KE avg diastole, in the presence of normal SV, compared with healthy subjects. Healthy subjects show strong physiological hemodynamic interplay between vorticity with KE and EL. Fontan patients demonstrate a pathophysiological hemodynamic interplay characterized by correlation of elevated vorticity with KE and EL in the presence of maintained normal stroke volume. Altered vorticity and energetic hemodynamics are found in the presence of normal EF in Fontan patients. NEW & NOTEWORTHY Physiologic intraventricular hemodynamic interplay/coupling is present in the healthy left ventricle between vorticity versus viscous energy loss and kinetic energy from four-dimensional flow cardiovascular magnetic resonance imaging (4D Flow MRI). Conversely, Fontan patients present compensatory pathophysiologic hemodynamic coupling by an increase in intraventricular vorticity that positively correlates to viscous energy loss and kinetic energy levels in the presence of maintained normal stroke volume. Altered vorticity and energetics are found in the presence of normal ejection fraction in Fontan patients.

1.5–8% of older adults live in nursing homes (NHs), presenting a high prevalence of frailty and polypharmacy. To investigate the association of frailty with polypharmacy and drug prescription patterns in a sample of European Nursing Home (NH) residents. Cross-sectional study based on the data from the Services and Health for Elderly in Long TERm care (SHELTER) study. 4121 NH residents in Europe and Israel. Residents’ clinical, cognitive, social, and physical status were evaluated with the InterRAI LTCF tool, which allows comprehensive, standardized evaluation of persons living in NH. Polypharmacy and hyperpolypharmacy were defined as the concurrent use of ≥ 5 and ≥ 10 medications. Frailty was defined according to the FRAIL-NH scale. Of 4121 participants, 46.6% were frail (mean age 84.6 ± 9.2 years; 76.4% female). Polypharmacy and hyperpolypharmacy were associated with a lower likelihood of frailty (Odds Ratio = 0.72; 95% CI = 0.59–0.87 and OR = 0.75; 95% CI = 0.60–0.94, respectively). Patterns of drug prescriptions were different between frail and non-frail residents. Symptomatic drugs (laxatives, paracetamol, and opioids) were more frequently prescribed among frail residents, while preventive drugs (bisphosphonates, vitamin D, and acetylsalicylic acid) were more frequently prescribed among non-frail residents. Frailty is associated with less polypharmacy and with higher prevalence of symptomatic drugs use among NH residents. Further studies are needed to define appropriateness of drug prescription in frail individuals.

The development, homeostasis, and repair of intrahepatic and extrahepatic bile ducts are thought to involve distinct mechanisms including proliferation and maturation of cholangiocyte and progenitor cells. This study aimed to characterize human extrahepatic cholangiocyte organoids (ECO) using canonical Wnt-stimulated culture medium previously developed for intrahepatic cholangiocyte organoids (ICO). Paired ECO and ICO were derived from common bile duct and liver tissue, respectively. Characterization showed both organoid types were highly similar, though some differences in size and gene expression were observed. Both ECO and ICO have cholangiocyte fate differentiation capacity. However, unlike ICO, ECO lack the potential for differentiation towards a hepatocyte-like fate. Importantly, ECO derived from a cystic fibrosis patient showed no CFTR channel activity but normal chloride channel and MDR1 transporter activity. In conclusion, this study shows that ECO and ICO have distinct lineage fate and that ECO provide a competent model to study extrahepatic bile duct diseases like cystic fibrosis.

Supplemental Digital Content is available in the text., Background: Inherited cardiac conditions present with a wide range of symptoms and may even result in sudden cardiac death. Relatives of probands with a confirmed pathogenic genetic variant are advised predictive DNA testing to enable prevention and treatment. In 2 previous cohort studies of 115 probands with a pathogenic variant, family uptake of genetic counseling was assessed in the first year(s) after test result disclosure to the proband. This study assesses uptake in these cohorts in the 14 to 23 years following disclosure. Methods: Uptake was determined retrospectively using patient records. First-degree relatives, and second-degree relatives of a deceased first-degree relative suspected of having an inherited cardiac condition, were considered eligible. Results: Of 717 eligible relatives (598 first-degree and 119 second-degree relatives), 60% attended genetic counseling. Most of them (68.6%) attended genetic counseling in the first year. A total of 98.4% of counseled relatives pursued predictive DNA testing. A total of 49.2% was identified as carrier. Median time between disclosure to the proband and counseling of relatives was 6 months (range: 0–187 months). Attending genetic counseling was observed more frequently in first-degree relatives, female relatives, primary arrhythmia syndromes, relatives with manifest inherited cardiac condition, relatives without children and families with sudden cardiac death in first-degree relatives

No abstract available Keywords: Apolipoprotein H; B2GPI; Biomarkers; Critical care; ICU; SIRS; Sepsis.

Post-transplant diabetes mellitus (PTDM) is a frequent complication post-heart transplantation (HT), however long-term prevalence studies are missing. The aim of this study was to determine the prevalence and determinants of PTDM as well as prediabetes long-term post-HT using oral glucose tolerance tests (OGTT). Also, the additional value of OGTT compared to fasting glucose and glycated hemoglobin (HbA1c) was investigated. All patients > 1 year post-HT seen at the outpatient clinic between August 2018 and April 2021 were screened with an OGTT. Patients with known diabetes, an active infection/rejection/malignancy or patients unwilling or unable to undergo OGTT were excluded. In total, 263 patients were screened, 108 were excluded. The included 155 patients had a median age of 54.3 [42.2–64.3] years, and 63 (41%) were female. Median time since HT was 8.5 [4.8–14.5] years. Overall, 51 (33%) had a normal range, 85 (55%) had a prediabetes range and 19 (12%) had a PTDM range test. OGTT identified prediabetes and PTDM in more patients (18% and 50%, respectively), than fasting glucose levels and HbA1c. Age at HT (OR 1.03 (1.00–1.06), p = 0.044) was a significant determinant of an abnormal OGTT. Prediabetes as well as PTDM are frequently seen long-term post-HT. OGTT is the preferred screening method.

Background In women with unexplained infertility, tubal flushing with oil-based contrast during hysterosalpingography (HSG) increases ongoing pregnancy and subsequent live birth rates when compared to tubal flushing with water-based contrast. It is currently unclear whether an HSG with oil-based contrast also results in more ongoing pregnancies and live births in women of advanced age, women with ovulation disorders, and women with potential tubal pathology when compared to an HSG with water-based contrast. Methods We plan an international, multicentre, open-label, randomized controlled trial (RCT) studying three groups of infertile women who have an indication for tubal patency testing according to their treating physician and additionally; (1) are 39 years of age or older, (2) have an ovulation disorder or (3) have a high risk for tubal pathology based on their medical history. Women with an allergy for iodinated contrast medium are excluded, as are women with diabetes, hyperprolactinemia or untreated hyper- or hypothyroidism, and women with a partner with severe male infertility. After informed consent, women will be randomly allocated to the intervention, tubal flushing with the use of oil-based contrast during HSG or the control group, tubal flushing with the use of water-based contrast during HSG in a 1:1 ratio by the web-based system Castor. The primary endpoint will be ongoing pregnancy leading to live birth with conception within six months after randomization. Secondary outcomes are other pregnancy outcomes, used fertility treatments, adverse events and cost-effectiveness. Based on the expected ongoing pregnancy rate of 17% in the control group and 27% in the intervention group, the sample size will be 930 women (465 per group). Study inclusion is expected to be complete in four years. Discussion This multicentre RCT will establish whether, for women of advanced age, women with ovulatory disease, and women who have a high risk for tubal pathology, there is a fertility enhancing effect of tubal flushing with oil-based contrast during HSG and whether the use of this contrast medium is cost-effective. Trial Registration The study was prospectively registered in the Netherlands Trial Register on August 1st 2019 as ‘H2Oil2’ (reference number NL7925, https://www.trialregister.nl/trial/7925).

Aim This study explores the relationship between in vivo 4D flow cardiovascular magnetic resonance (CMR) derived blood flow energetics in the total cavopulmonary connection (TCPC), exercise capacity and CMR-derived liver fibrosis/congestion. Background The Fontan circulation, in which both caval veins are directly connected with the pulmonary arteries (i.e. the TCPC) is the palliative approach for single ventricle patients. Blood flow efficiency in the TCPC has been associated with exercise capacity and liver fibrosis using computational fluid dynamic modelling. 4D flow CMR allows for assessment of in vivo blood flow energetics, including kinetic energy (KE) and viscous energy loss rate (EL). Methods Fontan patients were prospectively evaluated between 2018 and 2021 using a comprehensive cardiovascular and liver CMR protocol, including 4D flow imaging of the TCPC. Peak oxygen consumption (VO2) was determined using cardiopulmonary exercise testing (CPET). Iron-corrected whole liver T1 (cT1) mapping was performed as a marker of liver fibrosis/congestion. KE and EL in the TCPC were computed from 4D flow CMR and normalized for inflow. Furthermore, blood flow energetics were compared between standardized segments of the TCPC. Results Sixty-two Fontan patients were included (53% male, 17.3 ± 5.1 years). Maximal effort CPET was obtained in 50 patients (peak VO2 27.1 ± 6.2 ml/kg/min, 56 ± 12% of predicted). Both KE and EL in the entire TCPC (n = 28) were significantly correlated with cT1 (r = 0.50, p = 0.006 and r = 0.39, p = 0.04, respectively), peak VO2 (r = − 0.61, p = 0.003 and r = − 0.54, p = 0.009, respectively) and % predicted peak VO2 (r = − 0.44, p = 0.04 and r = − 0.46, p = 0.03, respectively). Segmental analysis indicated that the most adverse flow energetics were found in the Fontan tunnel and left pulmonary artery. Conclusions Adverse 4D flow CMR derived KE and EL in the TCPC correlate with decreased exercise capacity and increased levels of liver fibrosis/congestion. 4D flow CMR is promising as a non-invasive screening tool for identification of patients with adverse TCPC flow efficiency.

Anxiety disorders are a common problem in adolescent mental health. Previous studies have investigated only a limited number of risk factors for the development of anxiety disorders concurrently. By investigating multiple factors simultaneously, a more complete understanding of the etiology of anxiety disorders can be reached. Therefore, we assessed preadolescent socio-demographic, familial, psychosocial, and biological factors and their association with the onset of anxiety disorders in adolescence. This study was conducted among 1584 Dutch participants of the TRacking Adolescents’ Individual Lives Survey (TRAILS). Potential risk factors were assessed at baseline (age 10–12), and included socio-demographic (sex, socioeconomic status), familial (parental anxiety and depression), psychosocial (childhood adversity, temperament), and biological (body mass index, heart rate, blood pressure, cortisol) variables. Anxiety disorders were assessed at about age 19 years through the Composite International Diagnostic Interview (CIDI). Univariate and multivariate logistic regression analyses were performed with onset of anxiety disorder as a dependent variable and the above-mentioned putative risk factors as predictors. Of the total sample, 25.7% had a lifetime diagnosis of anxiety disorder at age 19 years. Anxiety disorders were twice as prevalent in girls as in boys. Multivariate logistic regression analysis showed that being female (OR = 2.38, p

Objectives Psychosocial factors have been hypothesized to increase the risk of cancer. This study aims (1) to test whether psychosocial factors (depression, anxiety, recent loss events, subjective social support, relationship status, general distress, and neuroticism) are associated with the incidence of any cancer (any, breast, lung, prostate, colorectal, smoking‐related, and alcohol‐related); (2) to test the interaction between psychosocial factors and factors related to cancer risk (smoking, alcohol use, weight, physical activity, sedentary behavior, sleep, age, sex, education, hormone replacement therapy, and menopausal status) with regard to the incidence of cancer; and (3) to test the mediating role of health behaviors (smoking, alcohol use, weight, physical activity, sedentary behavior, and sleep) in the relationship between psychosocial factors and the incidence of cancer. Methods The psychosocial factors and cancer incidence (PSY‐CA) consortium was established involving experts in the field of (psycho‐)oncology, methodology, and epidemiology. Using data collected in 18 cohorts (N = 617,355), a preplanned two‐stage individual participant data (IPD) meta‐analysis is proposed. Standardized analyses will be conducted on harmonized datasets for each cohort (stage 1), and meta‐analyses will be performed on the risk estimates (stage 2). Conclusion PSY‐CA aims to elucidate the relationship between psychosocial factors and cancer risk by addressing several shortcomings of prior meta‐analyses., Psychosocial factors and cancer incidence (PSY‐CA) consortium endeavor to understand the role of several different psychosocial factors—including depression and anxiety—in the onset of cancer. The study will employ the use of individual participant data meta‐analyses, combining results from several large, international cohorts with longitudinal designs. Furthermore, PSY‐CA aims to elucidate the role of health behaviors in the relationship between psychosocial factors and cancer risk.

Objectives With the spread of COVID-19, the Netherlands implemented a policy to keep citizens physically distanced. We hypothesize that consequent reduction in the frequency of social contacts, personal losses, and the experience of general threats in society reduced well-being. Methods Data were collected from 1,679 Dutch community-dwelling participants aged 65–102 years comprising a longitudinal online panel. Social and emotional loneliness and mental health were measured in May 2020, that is, 2 months after the implementation of the measures, and earlier in October and November 2019. Results In this pandemic, the loneliness of older people increased, but mental health remained roughly stable. The policy measures for physical distancing did not cause much social isolation but personal losses, worries about the pandemic, and a decline in trust in societal institutions were associated with increased mental health problems and especially emotional loneliness. Discussion The consequences of long-term social isolation and well-being must be closely monitored.

Background: Self-limited (familial) infantile epilepsy (S(F)IE), formerly known as benign (familial) infantile convulsions (13(F)1C), is an infantile cluster epilepsy with in rule a complete recovery. This form of epilepsy is most often caused by variations in the PRRT2 gene (OMIM #605751). Aim: To describe the clinical and genetic spectrum of sudden onset clusters of focal seizures in infancy. Methods: We retrospectively reviewed all individuals, who presented with unprovoked infantile seizures and selected all infants who had unprovoked clustered focal seizures between 1 and 20 months of age. We described the clinical and genetic spectrum of this cohort. Results: The data of 23 patients from 21 families were collected. All had an initial diagnosis of S(F)IE which was adjusted in 5 individuals. In 12 individuals a pathogenic variation in PRRT2 gene or complete deletion was identified. Pathogenic variants in PCDHI9 and KCNQ2 were found in respectively 3 and 1 individuals. One individual had a non-pathogenic variant in ATP1A3 and in 6 others no variants were identified. The mean cluster duration was 2.9 days (range 1-13) (see Table 1). Twelve infants had only one cluster. All patients had focal motor or non-motor seizures, in 12 (52%) followed by bilateral (tonic) clonic seizures. Positive family history was present in 74% of individuals. In 11/12 (92%) tested families, >= 1 family member carried the pathogenic PRRT2 variant. Age of seizure onset (ASO) averaged 6.2 months (range 2-20 months). Age of latest seizure averaged 16 months (range 2-92). In several interictal EEG (electroencephalogram) recordings multifocal spikes or spike-wave abnormalities were detected. Ictal EEG recordings detected primary focal abnormalities. Conclusion: We described 23 individuals with unprovoked cluster(s) of focal seizures at infancy. It appears to be a heterogeneous group. Half of them had a pathogenic variation in PRRT2 gene. Most had only one cluster of seizures. When clusters reoccur frequently, when seizures are more therapy-resistant and when seizures persist beyond the age of 2 years, another diagnosis or causative gene is likely. (C) 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Supplemental Digital Content is available in the text., Background. Previous studies on the association between cytomegalovirus (CMV) infection and cardiac allograft vasculopathy (CAV) were conducted on patients transplanted in the prevalganciclovir prophylaxis era. The aim of our study is to evaluate this relation in heart transplantation (HTx) recipients treated according to current prophylactic and immunosuppressive regimens. Methods. This single-center retrospective study included all consecutive adult patients that underwent HTx between January 1, 2000, and May 31, 2018. Clinically relevant CMV infection was defined as either plasma CMV DNAemia ≥ 1000 IU/mL with/without clinical symptoms or

Purpose: To investigate the pathobiological origin of local relapse after chemoradiotherapy, we studied genetic relationships of primary tumors (PT) and local relapses (LR) of patients treated with chemoradiotherapy. Experimental Design: First, low-coverage whole genome sequencing was performed on DNA from 44 biopsies of resected head and neck squamous cell carcinoma (HNSCC) specimens (median 3 biopsies/tumor) to assess suitability of copy number alterations (CNAs) as biomarker for genetic relationships. CNAs were compared within and between tumors and an algorithm was developed to assess genetic relationships with consideration of intratumor heterogeneity. Next, this CNA-based algorithm was combined with target enrichment sequencing of genes frequently mutated in HNSCC to assess the genetic relationships of paired tumors and LRs of patients treated with chemoradiotherapy. Results: Genetic relationship analysis using CNAs could accurately (96%) predict tumor biopsy pairs as patient-matched or independent. However, subsequent CNA analysis of PTs and LRs after chemoradiotherapy suggested genetic relationships in only 20% of cases, and absence in 80%. Target enrichment sequencing for mutations confirmed absence of any genetic relationship in half of the paired PTs and LRs. Conclusions: There are minor variations in CNA profiles within different areas of HNSCC tumors and many between independent tumors, suggesting that CNA profiles could be exploited as a marker of genetic relationship. Using CNA profiling and mutational analysis of cancer driver genes, relapses after chemoradiotherapy appear to be partially genetically related to the corresponding PTs, but seem often genetically unrelated. This remarkable observation warrants further studies and will impact therapeutic innovations and prognostic modeling when using index tumor characteristics.

Synthetic cross-linked collagen-related peptide (CRP-XL) is a glycoprotein VI (GPVI) receptor activator for platelet activation. This triple helical peptide, widely used in platelet function tests, is synthesized and cross-linked through cysteine residues at its N-terminus and C-terminus. Currently, there is only one laboratory, which is capable to produce this valuable peptide for clinical applications. In an attempt to provide a standardized alternative for CRP-XL, we developed a synthetic triple helical collagen peptide (STH-CP) with the same primary sequence as CRP-XL (GPC-(GPO)10-GPCG-amide)3, which was both on the C-terminus and on the N-terminus fixed on a scaffold with a binding side for each of the three peptides. The performance of STH-CP on platelet function was studied using flow cytometry and compared with CRP-XL. We found that platelet activation pattern in response to STH-CP and CRP-XL is similar, although the STH-CP requires sixfold higher concentrations to activate platelets to the same state. The intra-assay percent coefficient of variation of STH-CP and CRP-XL were both Our findings show that this new STH-CP is a stable and potent platelet GPVI agonist which can induce the same reproducible platelet activation as CRP-XL and that STH-CP can be considered as a good alternative for CRP-XL.

5-Fluorouracil (5-FU) is a chemotherapeutic drug commonly used for the treatment of solid cancers. It is proposed that 5-FU interferes with nucleotide synthesis and incorporates into DNA, which may have a mutational impact on both surviving tumor and healthy cells. Here, we treat intestinal organoids with 5-FU and find a highly characteristic mutational pattern that is dominated by T>G substitutions in a CTT context. Tumor whole genome sequencing data confirms that this signature is also identified in vivo in colorectal and breast cancer patients who have received 5-FU treatment. Taken together, our results demonstrate that 5-FU is mutagenic and may drive tumor evolution and increase the risk of secondary malignancies. Furthermore, the identified signature shows a strong resemblance to COSMIC signature 17, the hallmark signature of treatment-naive esophageal and gastric tumors, which indicates that distinct endogenous and exogenous triggers can converge onto highly similar mutational signatures., 5-Fluorouracil (5-FU) is a commonly used chemo drug to treat cancer patients. Using in vitro 5-FU treated organoids and in vivo 5-FU treated human cancer data, the authors describe a 5-FU mutational signature that is similar to COSMIC signature 17 frequently observed in untreated cancers

BACKGROUND: The Diagnostic and Statistical Manual of Mental Disorders, version 5 (DSM-5) definition of agoraphobia (AG) as an independent diagnostic entity makes it timely to re-examine the epidemiology of AG. Study objective was to present representative data on the characteristics of individuals who meet DSM-IV criteria for AG (AG without a history of panic disorder [PD] and PD with AG) but not DSM-5 criteria, DSM-5 but not DSM-IV criteria, or both sets of criteria. METHODS: Population-based surveys from the World Mental Health Survey Initiative including adult respondents (n = 136,357) from 27 countries across the world. The Composite International Diagnostic Interview was used to assess AG and other disorders. RESULTS: Lifetime and 12-month prevalence estimates of DSM-5 AG (1.5% and 1.0%) were comparable to DSM-IV (1.4% and 0.9%). Of respondents meeting criteria in either system, 57.1% met criteria in both, while 24.2% met criteria for DSM-5 only and 18.8% for DSM-IV only. Severe role impairment due to AG was reported by a lower proportion of respondents who met criteria only for DSM-IV AG (30.4%) than those with both DSM-5 and DSM-IV AG (44.0%; χ 21 = 4.7; P = 0.031). The proportion of cases with any comorbidity was lower among respondents who met criteria only for DSM-IV AG (78.7%) than those who met both sets (92.9%; χ 21 = 14.5; P

Aim:In patients after atrioventricular septal defect correction, altered geometry leads to a changed position and subsequent flow over the left ventricular outflow tract. We hypothesised that this altered flow may influence haemodynamics in the ascending aorta.Methods:In total, 30 patients after atrioventricular septal defect correction (age 27.6 ± 12.8 years) and 28 healthy volunteers (age 24.8 ± 13.7 years) underwent 4D flow cardiovascular magnetic resonance. Left ventricular ejection fraction and mean and peak wall shear stress calculated at ascending aortic peak systole were obtained from cardiovascular magnetic resonance. Left ventricular outflow tract data including velocity and diameter were obtained from echocardiography.Results:Patients showed a higher mean (911 ± 173 versus 703 ± 154 mPa, p = 0.001) and peak ascending aortic wall shear stress (1264 ± 302 versus 1009 ± 240 mPa, p = 0.001) compared to healthy volunteers. Increased blood flow velocities over the left ventricular outflow tract (1.49 ± 0.30 m/s versus 1.22 ± 0.20 m/s, p < 0.001) correlated well with mean and peak ascending aortic wall shear stress (r = 0.67, p < 0.001 and r = 0.77, p < 0.001).Conclusion:After atrioventricular septal defect correction, increased wall shear stress was observed, which correlated to velocities over the left ventricular outflow tract. These findings imply that altered outflow tract geometry contributes to changed aortic haemodynamics.

IMPORTANCE Individuals with mental disorders often develop comorbidityover time. Past studies of comorbidity have often restricted analyses to a subset of disorders and few studies have provided absolute risks of later comorbidity.OBJECTIVES To undertake a comprehensive study of comorbidity within mental disorders, by providing temporally ordered age-and sex-specific pairwise estimates between the major groups of mental disorders, and to develop an interactive website to visualize all results and guide future research and clinical practice.DESIGN, SETTING. AND PARTICIPANTS This population-based cohort study included all individuals born in Denmark between January 1, 190 0, and December 31, 2015, and living in the country between January 1, 20 0 0, and December 31, 2016. The analyses were conducted between June 2017 and May 2018.MAIN OUTCOMES AND MEASURES Danish health registers were used to identify mental disorders, which were examined within the broad 10-level International Statistical Classification of Diseases and Related Health Problems, lOth Revision, subchapter groups (eg, codes F00-F09 and F10-F19). For each temporally ordered pair of disorders, overall and lagged hazard ratios and 95% Cls were calculated using Cox proportional hazards regress on models. Absolute risks were estimated using competing risks survival analyses. Estimates for each sex were generated.RESULTS A total of 5 940 778 persons were Included in this study (2 958 293 men and 2 982 485 women; mean [SD] age at beginning of follow-up, 32.1[25.4] years). They were followed up for 83.9 million person-years. All mental disorders were associated with an increased risk of all other mental disorders when adjusting for sex, age, and calendar time (hazard ratios ranging from 2.0 [95% CI, 1.7-2.4] for prior intellectual disabilities and later eating disorders to 48.6 [95% Cl, 46.6-50.7] for prior developmental disorders and later intellectual disabilities). The hazard ratios were temporally patterned, with higher estimates during the first year after the onset of the first disorder, but with persistently elevated rates during the entire observation period. Some disorders were associated with substantial absolute risks of developing specific later disorders (eg, 30.6% [95% CI, 29.3%-32.0%] of men and 38.4% [95% CI, 37.5%-39.4%] of women with a diagnosis of mood disorders before age 20 years developed neurotic disorders within the following 5 years).CONCLUSIONS AND RELEVANCE Comorbidity within mental disorders is pervasive, and the risk persists over time. This study provides disorder-, sex-, and age-specific relative and absolute risks of the comorbidity of mental disorders. Web-based interactive data visualization tools are provided for clinical utility.

Long scan times prohibit a widespread clinical applicability of 4D flow MRI in Fontan patients. As pulsatility in the Fontan pathway is minimal during the cardiac cycle, acquiring non-ECG gated 3D flow MRI may result in a reduction of scan time while accurately obtaining time-averaged clinical parameters in comparison with 2D and 4D flow MRI. Thirty-two Fontan patients prospectively underwent 2D (reference), 3D and 4D flow MRI of the Fontan pathway. Multiple clinical parameters were assessed from time-averaged flow rates, including the right-to-left pulmonary flow distribution (main endpoint) and systemic-to-pulmonary collateral flow (SPCF). A ten-fold reduction in scan time was achieved [4D flow 15.9 min (SD 2.7 min) and 3D flow 1.6 min (SD 7.8 s), p

BackgroundStudies on herpes zoster (HZ) incidence in solid organ transplant (SOT) recipients report widely varying numbers. We investigated HZ incidence, severity, and risk factors in recipients of four different SOTs, with a follow-up time of 6–14 years.MethodsRecords of 1,033 transplant recipients after first heart (HTx: n = 211), lung (LuTx: n = 121), liver (LiTx: n = 258) and kidney (KTx: n = 443) transplantation between 2000 and 2014 were analyzed for VZV-PCR, clinical signs of HZ, and complications.ResultsHZ was diagnosed in 108 of 1,033 patients (10.5%): 36 HTx, 17 LuTx, 15 LiTx, and 40 KTx recipients. Overall HZ incidence rate after HTx (30.7 cases/1,000 person–years (PY)), LuTx (38.8 cases/1,000 PY), LiTx (22.7 cases/1,000 PY) and KTx (14.5 cases/1,000 PY) was significantly higher than in the general 50–70 year population. Multivariable analysis demonstrated age ≥50 years at transplantation (p = 0.038, RR 1.536), type of organ transplant (overall p = 0.002; LuTx p = 0.393; RR 1.314; LiTx p = 0.011, RR 0.444; KTx p = 0.034, RR 0.575), CMV prophylaxis (p = 0.043, RR 0.631) and type of anti-rejection therapy (overall p = 0.020; methylprednisolone p = 0.008, RR 0.475; r-ATG p = 0.64, RR1.194) as significant risk factors. Complications occurred in 33 of 108 (31%) patients (39% of HTx, 47% of LuTx, 20% of LiTx, 20% of KTx): post-herpetic neuralgia, disseminated disease, and cranial nerve involvement.ConclusionHZ incidence and severity in SOT recipients are most pronounced after heart and lung transplantation, in older patients, and when CMV prophylaxis is lacking.

Cardiac diseases and sudden cardiac death (SCD) are more prevalent in individuals diagnosed with schizophrenia compared to the general population, with especially coronary artery disease (CAD) as the major cardiovascular cause of death. Antipsychotic medications, genetics, and lifestyle factors may contribute to the increased SCD in individuals with schizophrenia. The role of antipsychotic medications and lifestyle factors have been widely investigated, while the genetic predisposition to inherited cardiac diseases in schizophrenia is poorly understood. In this study, we examined 100 genes associated with inherited cardiomyopathies and cardiac channelopathies in 97 deceased individuals diagnosed with schizophrenia for the prevalence of genetic variants associated with SCD. The deceased individuals had various causes of death and were included in the SURVIVE project, a prospective, autopsy-based study of mentally ill individuals in Denmark. This is the first study of multiple inherited cardiac disease-related genes in deceased individuals with diagnosed schizophrenia to shed light on the genetic predisposition to SCD in individuals with schizophrenia. We found no evidence for an overrepresentation of rare variants with high penetrance in inherited cardiac diseases, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG) consensus guidelines. However, we found that the deceased individuals had a statistically significantly increased polygenic burden caused by variants in the investigated heart genes compared to the general population. This indicates that common variants with smaller effects in heart genes may play a role in schizophrenia.

Objective: Fibrin is considered to strengthen thrombus formation via integrin αIIbβ3, but recent findings indicate that fibrin can also act as ligand for platelet glycoprotein VI. Approach and Results: To investigate the thrombus-forming potential of fibrin and the roles of platelet receptors herein, we generated a range of immobilized fibrin surfaces, some of which were cross-linked with factor XIIIa and contained VWF-BP (von Willebrand factor-binding peptide). Multicolor microfluidics assays with whole-blood flowed at high shear rate (1000 s −1 ) indicated that the fibrin surfaces, regardless of the presence of factor XIIIa or VWF-BP, supported platelet adhesion and activation (P-selectin expression), but only microthrombi were formed consisting of bilayers of platelets. Fibrinogen surfaces produced similar microthrombi. Markedly, tiggering of coagulation with tissue factor or blocking of thrombin no more than moderately affected the fibrin-induced microthrombus formation. Absence of αIIbβ3 in Glanzmann thrombasthenia annulled platelet adhesion. Blocking of glycoprotein VI with Fab 9O12 substantially, but incompletely reduced platelet secretion, Ca 2+ signaling and aggregation, while inhibition of Syk further reduced these responses. In platelet suspension, glycoprotein VI blockage or Syk inhibition prevented fibrin-induced platelet aggregation. Microthrombi on fibrin surfaces triggered only minimal thrombin generation, in spite of thrombin binding to the fibrin fibers. Conclusions: Together, these results indicate that fibrin fibers, regardless of their way of formation, act as a consolidating surface in microthrombus formation via nonredundant roles of platelet glycoprotein VI and integrin αIIbβ3 through signaling via Syk and low-level Ca 2+ rises.

Funder: BBSRC studentship, Identifying causative variants in cis-regulatory elements (CRE) in neurodevelopmental disorders has proven challenging. We have used in vivo functional analyses to categorize rigorously filtered CRE variants in a clinical cohort that is plausibly enriched for causative CRE mutations: 48 unrelated males with a family history consistent with X-linked intellectual disability (XLID) in whom no detectable cause could be identified in the coding regions of the X chromosome (chrX). Targeted sequencing of all chrX CRE identified six rare variants in five affected individuals that altered conserved bases in CRE targeting known XLID genes and segregated appropriately in families. Two of these variants, FMR1CRE and TENM1CRE, showed consistent site- and stage-specific differences of enhancer function in the developing zebrafish brain using dual-color fluorescent reporter assay. Mouse models were created for both variants. In male mice Fmr1CRE induced alterations in neurodevelopmental Fmr1 expression, olfactory behavior and neurophysiological indicators of FMRP function. The absence of another likely causative variant on whole genome sequencing further supported FMR1CRE as the likely basis of the XLID in this family. Tenm1CRE mice showed no phenotypic anomalies. Following the release of gnomAD 2.1, reanalysis showed that TENM1CRE exceeded the maximum plausible population frequency of a XLID causative allele. Assigning causative status to any ultra-rare CRE variant remains problematic and requires disease-relevant in vivo functional data from multiple sources. The sequential and bespoke nature of such analyses renders them time-consuming and challenging to scale for routine clinical use.

Background: D-dimer concentrations in people living with HIV (PLHIV) on combination antiretroviral therapy (cART) are increased and have been linked to mortality. D-dimer is a biomarker of in vivo coagulation. In contrast to reports on D-dimer, data on coagulation capacity in PLHIV are conflicting. In this study, we assessed the effect of cART and inflammation on coagulation capacity. Setting: We explored coagulation capacity using calibrated thrombin generation (TG) and linked this to persistent inflammation and cART in a cross-sectional study including PLHIV with viral suppression and uninfected controls. Methods: We used multivariate analyses to identify independent factors influencing in vivo coagulation (D-dimer) and ex vivo coagulation capacity (TG). Results: Among 208 PLHIV, 94 (45%) were on an abacavir-containing regimen. D-dimer levels (219.1 vs 170.5 ng/mL, P = 0.001) and inflammatory makers (sCD14, sCD163, and high-sensitive C-reactive protein) were increased in PLHIV compared with those in controls (n = 56). PLHIV experienced lower TG (reflected by endogenous thrombin potential [ETP]) when compared with controls, after correction for age, sex, and antiretroviral therapy. Abacavir use was independently associated with increased ETP. Prothrombin concentrations were strongly associated with ETP and lower in PLHIV on a non-abacavir-containing regimen compared with those in controls, suggesting consumption as a possible mechanism for HIV-associated reduction in TG. D-dimer concentrations were associated with inflammation, but not TG. Conclusions: Abacavir use was associated with increased TG and could serve as an additional factor in the reported increase in thrombotic events during abacavir use. Increased exposure to triggers that propagate coagulation, such as inflammation, likely underlie increased D-dimer concentrations found in most PLHIV.

Objective To prevent osteoporotic fractures in nursing home residents a combination of bisphosphonates, calcium and vitamin D is recommended. This study assessed the prevalence of pharmacological osteoporosis prevention in nursing home residents from eight countries, and assessed its association with patient characteristics. Design Cross-sectional analyses of the SHELTER study data. We assessed the overall prevalence of osteoporosis medication (OM) use (vitamin D, calcium and bisphosphonates) in residents stratified for falls and fractures over last 30 days, health instability with high mortality risk, cognitive impairment, and dependence in walking. Setting and Participants Nursing home residents in the Czech Republic, England, Finland, France, Germany, Italy, The Netherlands and Israel. Results Of 3832 eligible residents, vitamin D, calcium and bisphosphonates were used by 16.2%, 10.4%, and 4.5% respectively. All 3 classes of OM together were used by 1.5% of all residents. Of residents with a recent fracture, 9.5% used a bisphosphonate (2.7% all 3 OMs). In patients with recent falls, 20.8% used vitamin D and 15.3% calcium. In residents with severe cognitive impairment, 15.5% used vitamin D and 9.3% used calcium. Of the bisphosphonate users, 33.7% also used both vitamin D and calcium, 25.8% used only calcium in addition and 17.4% only vitamin D in addition. The use of any OM varied widely across countries, from 66.8% in Finland to 3.0% in Israel. Conclusions and Implications We found substantial pharmacological under-treatment of prevention of osteoporosis in residents with recent falls, fractures and dependence in walking. Only two-thirds of bisphosphonate users also took a vitamin D–calcium combination, despite guideline recommendations. On the other hand, possible over-treatment was found in residents with high mortality risk in whom preventive pharmacotherapy might not have still been appropriate. The prevalence of pharmacological prevention of osteoporosis differed substantially between countries. Efforts are needed to improve pharmacotherapy in residents.

Background Patients who have undergone the Fontan procedure are at high risk of circulatory failure. In an exploratory analysis we aimed to determine the prognostic value of blood biomarkers in a young cohort who have undergone the Fontan procedure. Methods and Results In multicenter prospective studies patients who have undergone the Fontan procedure underwent blood sampling, cardiopulmonary exercise testing, and stress cardiac magnetic resonance imaging. Several biomarkers including NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), GDF‐15 (growth differentiation factor 15), Gal‐3 (galectin‐3), ST2 (suppression of tumorigenicity 2), DLK‐1 (protein delta homolog 1), FABP‐4 (fatty acid‐binding protein 4), IGFBP‐1 (insulin‐like growth factor‐binding protein 1), IGFBP‐7, MMP‐2 (matrix metalloproteinase 2), and vWF (von Willebrand factor) were assessed in blood at 9.6 (7.1–12.1) years after Fontan completion. After this baseline study measurement, follow‐up information was collected on the incidence of adverse cardiac events, including cardiac death, out of hospital cardiac arrest, heart transplantation (listing), cardiac reintervention (severe events), hospitalization, and cardioversion/ablation for arrhythmias was collected and the relation with blood biomarkers was assessed by Cox proportional hazard analyses. The correlation between biomarkers and other clinical parameters was evaluated. We included 133 patients who have undergone the Fontan procedure, median age 13.2 (25th, 75th percentile 10.4–15.9) years, median age at Fontan 3.2 (2.5–3.9) years. After a median follow‐up of 6.2 (4.9–6.9) years, 36 (27.1%) patients experienced an event of whom 13 (9.8%) had a severe event. NT‐proBNP was associated with (all) events during follow‐up and remained predictive after correction for age, sex, and dominant ventricle (hazard ratio, 1.89; CI, 1.32–2.68). The severe event‐free survival was better in patients with low levels of GDF‐15 ( P =0.005) and vWF ( P =0.008) and high levels of DLK‐1 ( P =0.041). There was a positive correlation (β=0.33, P =0.003) between DLK‐1 and stress cardiac magnetic resonance imaging functional reserve. Conclusions NT‐proBNP, GDF‐15, vWF, DLK‐1, ST‐2 FABP‐4, and IGFBP‐7 levels relate to long‐term outcome in young patients who have undergone the Fontan procedure.

Previous research shows that crises can have both negative and positive mental health effects on the population. The current study explored these effects in the context of the COVID-19 pandemic after relaxation of governmental measures. An online survey was administered among a representative sample of the Dutch population (n = 1519) in June 2020, ten weeks after the peak of COVID-19 had passed, and five weeks after restrictions were relaxed. Participants were asked about mental health, adverse events during COVID-19, and about any positive effects of the pandemic. Most participants (80%, n = 1207) reported no change in mental health since the COVID-19 pandemic. This was also the case among respondents who had experienced an adverse event. Protective factors of mental health were being male and high levels of positive mental well-being. Risk factors were emotional loneliness and the experience of adverse life events. Social loneliness was positively associated with stable mental health, stressing the importance of meaningful relationships. Note that 58% of participants reported positive effects of the pandemic, the most common of which were rest, working from home, and feeling more socially connected. In summary, 10 weeks after the start of the crisis, and 5 weeks after relaxation of the restrictions, most people remained stable during the crisis, and were even able to report positive effects.

Of all tuberculosis (TB) cases, 1% affects the central nervous system (CNS), with a mortality rate of up to 60%. Our aim is to fill the 'key gap' in TBM research by analyzing brain specimens in a unique historical cohort of 84 patients, focusing on granuloma formation. We describe three different types: non-necrotizing, necrotizing gummatous, and necrotizing abscess type granuloma. Our hypothesis is that these different types of granuloma are developmental stages of the same pathological process. All types were present in each patient and were mainly localized in the leptomeninges. Intra-parenchymal granulomas were less abundant than the leptomeningeal ones and mainly located close to the cerebrospinal fluid (subpial and subependymal). We found that most of the intraparenchymal granulomas are an extension of leptomeningeal lesions which is the opposite of the classical Rich focus theory. We present a 3D-model to facilitate further understanding of the topographic relation of granulomas with leptomeninges, brain parenchyma and blood vessels. We describe innate and adaptive immune responses during granuloma formation including the cytokine profiles. We emphasize the presence of leptomeningeal B-cell aggregates as tertiary lymphoid structures. Our study forms a basis for further research in neuroinflammation and infectious diseases of the CNS, especially TB.

Background Hemodynamic aorta parameters can be derived from 4D flow MRI, but this requires lumen segmentation. In both commercially available and research 4D flow MRI software tools, lumen segmentation is mostly (semi-)automatically performed and subsequently manually improved by an observer. Since the segmentation variability, together with 4D flow MRI data and image processing algorithms, will contribute to the reproducibility of patient-specific flow properties, the observer's lumen segmentation reproducibility and repeatability needs to be assessed. Purpose To determine the interexamination, interobserver reproducibility, and intraobserver repeatability of aortic lumen segmentation on 4D flow MRI. Study type Prospective and retrospective. Population A healthy volunteer cohort of 10 subjects who underwent 4D flow MRI twice. Also, a clinical cohort of six subjects who underwent 4D flow MRI once. Field strength/sequence 3T; time-resolved three-directional and 3D velocity-encoded sequence (4D flow MRI). Assessment The thoracic aorta was segmented on the 4D flow MRI in five systolic phases. By positioning six planes perpendicular to a segmentation's centerline, the aorta was divided into five segments. The volume, surface area, centerline length, maximal diameter, and curvature radius were determined for each segment. Statistical tests To assess the reproducibility, the coefficient of variation (COV), Pearson correlation coefficient (r), and intraclass correlation coefficient (ICC) were calculated. Results The interexamination and interobserver reproducibility and intraobserver repeatability were comparable for each parameter. For both cohorts there was very good reproducibility and repeatability for volume, surface area, and centerline length (COV = 10-32%, r = 0.54-0.95 and ICC = 0.65-0.99), excellent reproducibility and repeatability for maximal diameter (COV = 3-11%, r = 0.94-0.99, ICC = 0.94-0.99), and good reproducibility and repeatability for curvature radius (COV = 25-62%, r = 0.73-0.95, ICC = 0.84-0.97). Data conclusion This study demonstrated no major reproducibility and repeatability limitations for 4D flow MRI aortic lumen segmentation. Level of evidence 3 TECHNICAL EFFICACY STAGE: 2.

DNA copy number alterations (CNAs) are frequent in cancer, and recently developed CNA signatures revealed their value in molecular tumor stratification for patient prognosis and platinum resistance prediction in ovarian cancer. Head and neck squamous cell carcinoma (HNSCC) is also characterized by high CNAs. In this study, we determined CNA in 173 human papilloma virus‐negative HNSCC from a Dutch multicenter cohort by low‐coverage whole genome sequencing and tested the prognostic value of seven cancer‐derived CNA signatures for these cisplatin‐ and radiotherapy‐treated patients. We find that a high CNA signature 1 (s1) score is associated with low values for all other signatures and better patient outcomes in the Dutch cohorts and The Cancer Genome Atlas HNSCC data set. High s5 and s7 scores are associated with increased distant metastasis rates and high s6 scores with poor overall survival. High cumulative cisplatin doses result in improved outcomes in chemoradiotherapy‐treated HNSCC patients. Here we find that tumors high in s1 or low in s6 are most responsive to a change in cisplatin dose. High s5 values, however, significantly increase the risk for metastasis in patients with low cumulative cisplatin doses. Together this suggests that the processes causing these CNA signatures affect cisplatin response in HNSCC. In conclusion, CNA signatures derived from a different cancer type were prognostic and associated with cisplatin response in HNSCC, suggesting they represent underlying molecular processes that define patient outcome., What's new? DNA copy number alterations (CNA) reflect the involvement of crucial mutational processes in cancer and has the potential to inform tumor molecular stratification for precision medicine. While CNA signatures have been developed in ovarian cancer, their application in other cancers remains elusive. Here, the authors demonstrate the applicability of ovarian cancer CNA signatures in head and neck squamous cell carcinoma (HNSCC), which is also characterized by high CNA numbers, treated with radiotherapy and cisplatin. Several of the CNA signatures exhibited a prognostic role in two independent HNSCC cohorts that was dependent on cisplatin treatment and the anatomical subsite.

Introduction: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for cardiovascular events, particularly following an acute exacerbation (AE-COPD). Exacerbations are associated with increased systemic inflammation, which may drive coagulation. This prospective cohort study aimed to determine how an AE-COPD affects platelet activation, the endothelium, plasmatic coagulation and fibrinolysis, and its association with systemic inflammation.Materials and methods: Fifty-two patients with an AE-COPD were included. Blood samples at admission, at day 3 of treatment and at convalescence were available for 32 patients. Platelet-monocyte complex (PMC) formation, monocyte Mac-1 expression and platelet (re)activity (P-selectin expression, alpha IIb133 activation) were measured by flow cytometry. Von Willebrand Factor (VWF), thrombin generation (TG) and clot lysis time (CLT) were determined as measures of endothelial activation, plasmatic coagulation and fibrinolysis, respectively.Results: Exacerbations were associated with increased PMCs (MFI 31.3 vs 23.8, p = 0.004) and Mac-1 (MFI 38.2 vs 34.8, p = 0.006) compared to convalescence, but not with changes in platelet (re)activity. VWF (antigen, activity, active fraction) and TG (peak, ETP and velocity index) were all significantly higher during AE-COPD compared to convalescence. PMCs, Mac-1, VWF and TG were positively associated with systemic inflammation (CRP). CLT was prolonged in AE-COPD patients with systemic inflammation. Moreover, platelet hyperreactivity on admission was associated with an increased risk for exacerbation relapse.Conclusions: Acute exacerbations are associated with an inflammation-associated prothrombotic state, characterized by increased PMCs, endothelial activation and plasmatic coagulation. Our findings provide direction for future studies on biomarkers predicting the risk of exacerbation relapse and cardiovascular events.

Aims Epidemiological studies indicate that individuals with one type of mental disorder have an increased risk of subsequently developing other types of mental disorders. This study aimed to undertake a comprehensive analysis of pair-wise lifetime comorbidity across a range of common mental disorders based on a diverse range of population-based surveys. Methods The WHO World Mental Health (WMH) surveys assessed 145 990 adult respondents from 27 countries. Based on retrospectively-reported age-of-onset for 24 DSM-IV mental disorders, associations were examined between all 548 logically possible temporally-ordered disorder pairs. Overall and time-dependent hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. Absolute risks were estimated using the product-limit method. Estimates were generated separately for men and women. Results Each prior lifetime mental disorder was associated with an increased risk of subsequent first onset of each other disorder. The median HR was 12.1 (mean = 14.4; range 5.2–110.8, interquartile range = 6.0–19.4). The HRs were most prominent between closely-related mental disorder types and in the first 1–2 years after the onset of the prior disorder. Although HRs declined with time since prior disorder, significantly elevated risk of subsequent comorbidity persisted for at least 15 years. Appreciable absolute risks of secondary disorders were found over time for many pairs. Conclusions Survey data from a range of sites confirms that comorbidity between mental disorders is common. Understanding the risks of temporally secondary disorders may help design practical programs for primary prevention of secondary disorders.

PIWI-interacting RNAs (piRNAs) target transcripts by sequence complementarity serving as guides for RNA slicing in animal germ cells. The piRNA pathway is increasingly recognized as critical for essential cellular functions such as germline development and reproduction. In the Anopheles gambiae ovary, as much as 11% of piRNAs map to protein-coding genes. Here we show that ovarian mRNAs and long non-coding RNAs (lncRNAs) are processed into piRNAs that can direct other transcripts into the piRNA biogenesis pathway. Targeting piRNAs fuel transcripts either into the ping-pong cycle of piRNA amplification or into the machinery of phased piRNA biogenesis, thereby creating networks of inter-regulating transcripts. RNAs of the same network share related genomic repeats. These repeats give rise to piRNAs, which target other transcripts and lead to a cascade of concerted RNA slicing. While ping-pong networks are based on repeats of several hundred nucleotides, networks that rely on phased piRNA biogenesis operate through short ∼40-nucleotides long repeats, which we named snetDNAs. Interestingly, snetDNAs are recurring in evolution from insects to mammals. Our study brings to light a new type of a conserved regulatory pathway, the snetDNA-pathway, by which short sequences can include independent genes and lncRNAs in the same biological pathway.AUTHOR SUMMARYSmall RNA molecules are essential actors in silencing mobile genetic elements in animal germ cells. The 24-29-nucleotide-long Piwi-interacting RNAs (piRNAs) target transcripts by sequence complementarity serving as guides for RNA slicing. Mosquitoes of the Anopheles gambiae species complex are the principal vectors of malaria, and research on their germline is essential to develop new strategies of vector control by acting on reproduction. In the Anopheles gambiae ovary as much as 11% of piRNAs originate from protein-coding genes. We identified piRNAs which are able to target transcripts from several distinct genes or long non-coding RNAs (lncRNAs), bringing together genic transcripts and lncRNAs in a same regulation network. piRNA targeting induces transcript slicing and production of novel piRNAs, which then target other mRNAs and lncRNAs leading again to piRNA processing, thus resulting in a cascade of RNA slicing and piRNA production. Each network relies on piRNAs originating from repeated genetic elements, present in all transcripts of the same network. Some of these repeats are very short, only ∼40-nucleotides long. We identified similar repeats in all 43 animal species that we analysed, including mosquitoes, flies, arachnidae, snail, mouse, rat and human, suggesting that such regulation networks are recurrent, possibly conserved, in evolutionary history.

Objective: This systematic review and meta-analysis aimed to clarify the association between social anxiety and affective (AE) and cognitive empathy (CE). Methods: 1442 studies from PsycINFO, Medline, and EMBASE (inception-January 2020) were systematically reviewed. Included studies (N = 48) either predicted variance in empathy using social anxiety scores or compared empathy scores between socially anxious individuals and a control group. Results: Social anxiety and AE were statistically significantly positively associated, k = 14, r= .103 (95%CI [.003, .203]), z =2.03, p =.043. Sex (QM (2) = 18.79, p< .0001), and type of measures (QM (1 = 7.34, p =.007) moderated the association. Correlations were significant for male samples (rmale= .316, (95%CI [.200, .432])) and studies using self-report measures (rself-report = .162 (95%CI [.070, .254])). Overall, social anxiety and CE were not significantly associated, k=52, r =-.021 (95%CI [-.075, .034]), z= -0.74, p = .459. Sample type moderated the association (QM (1)= 5.03, p

This article provides norms for general taboo, personal taboo, insult, valence, and arousal for 672 Dutch words, including 202 taboo words. Norms were collected using a 7-point Likert scale and based on ratings by psychology students from the Erasmus University Rotterdam in The Netherlands. The sample consisted of 87 psychology students (58 females, 29 males). We obtained high reliability based on split-half analyses. Our norms show high correlations with arousal and valence ratings collected by another Dutch word-norms study (Moors et al.,, Behavior Research Methods, 45, 169–177, 2013). Our results show that the previously found quadratic relation (i.e., U-shaped pattern) between valence and arousal also holds when only taboo words are considered. Additionally, words rated high on taboo tended to be rated low on valence, but some words related to sex rated high on both taboo and valence. Words that rated high on taboo rated high on insult, again with the exception of words related to sex many of which rated low on insult. Finally, words rated high on taboo and insult rated high on arousal. The Dutch Taboo Norms (DTN) database is a useful tool for researchers interested in the effects of taboo words on cognitive processing. The data associated with this paper can be accessed via the Open Science Framework ( https://osf.io/vk782/ ).

BackgroundImprovement in depression within the first 2 weeks of antidepressant treatment predicts good outcomes, but non-improvers can still respond or remit, whereas improvers often do not.AimsWe aimed to investigate whether early improvement of individual depressive symptoms better predicts response or remission.MethodWe obtained individual patient data of 30 trials comprising 2184 placebo-treated and 6058 antidepressant-treated participants. Primary outcome was week 6 response; secondary outcomes were week 6 remission and week 12 response and remission. We compared models that only included improvement in total score by week 2 (total improvement model) with models that also included improvement in individual symptoms.ResultsFor week 6 response, the area under the receiver operating characteristic curve and negative and positive predictive values of the total improvement model were 0.73, 0.67 and 0.74 compared with 0.77, 0.70 and 0.71 for the item improvement model. Model performance decreased for week 12 outcomes. Of predicted non-responders, 29% actually did respond by week 6 and 43% by week 12, which was decreased from the baseline (overall) probabilities of 51% by week 6 and 69% by week 12. In post hoc analyses with continuous rather than dichotomous early improvement, including individual items did not enhance model performance.ConclusionsExamining individual symptoms adds little to the predictive ability of early improvement. Additionally, early non-improvement does not rule out response or remission, particularly after 12 rather than 6 weeks. Therefore, our findings suggest that routinely adapting pharmacological treatment because of limited early improvement would often be premature.Declaration of interestNone.

Background Pediatric hematopoietic stem cell transplantation (HSCT) recipients are at increased risk of cardiovascular disease later in life. As HSCT survival has significantly improved, with a growing number of HSCT indications, tailored screening strategies for HSCT-related late effects are warranted. Little is known regarding the value of cardiovascular magnetic resonance (CMR) for early identification of high-risk patients after HSCT, before symptomatic cardiovascular disease manifests. This study aimed to assess CMR-derived left ventricular (LV) systolic and diastolic function, aortic stiffness and myocardial tissue characteristics in young adults who received HSCT during childhood. Methods Sixteen patients (22.1 ± 1.5 years) treated with HSCT during childhood and 16 healthy controls (22.1 ± 1.8 years) underwent 3 T CMR. LV systolic and diastolic function were measured as LV ejection fraction (LVEF), the ratio of transmitral early and late peak filling rate (E/A), the estimated LV filling pressure (E/Ea) and global longitudinal and circumferential systolic strain and diastolic strain rates, using balanced steady-state free precession cine CMR and 2D velocity-encoded CMR over the mitral valve. Aortic stiffness, myocardial fibrosis and steatosis were assessed with 2D velocity-encoded CMR, native T1 mapping and proton CMR spectroscopy (1H-CMRS), respectively. Results In the patient compared to the control group, E/Ea (9.92 ± 3.42 vs. 7.24 ± 2.29, P = 0.004) was higher, LVEF (54 ± 6% vs. 58 ± 5%, P = 0.055) and global longitudinal strain (GLS) ( -20.7 ± 3.5% vs. -22.9 ± 3.0%, P = 0.063) tended to be lower, while aortic pulse wave velocity (4.40 ± 0.26 vs. 4.29 ± 0.29 m/s, P = 0.29), native T1 (1211 ± 36 vs. 1227 ± 28 ms, P = 0.16) and myocardial triglyceride content (0.47 ± 0.18 vs. 0.50 ± 0.13%, P = 0.202) were comparable. There were no differences between patients and controls in E/A (2.76 ± 0.92 vs. 2.97 ± 0.91, P = 0.60) and diastolic strain rates. Conclusion In young adults who received HSCT during childhood, LV diastolic function was decreased (higher estimated LV filling pressure) and LV systolic function (LVEF and GLS) tended to be reduced as compared to healthy controls, whereas no concomitant differences were found in aortic stiffness and myocardial tissue characteristics. When using CMR, assessment of LV diastolic function in particular is important for early detection of patients at risk of HSCT-related cardiovascular disease, which may warrant closer surveillance.

BACKGROUNDPersons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions.METHODSWe used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses.RESULTSA total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder.CONCLUSIONSMost mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753. opens in new tab.) BACKGROUND: Persons with mental disorders are at a higher risk than the general population for the subsequent development of certain medical conditions.METHODS: We used a population-based cohort from Danish national registries that included data on more than 5.9 million persons born in Denmark from 1900 through 2015 and followed them from 2000 through 2016, for a total of 83.9 million person-years. We assessed 10 broad types of mental disorders and 9 broad categories of medical conditions (which encompassed 31 specific conditions). We used Cox regression models to calculate overall hazard ratios and time-dependent hazard ratios for pairs of mental disorders and medical conditions, after adjustment for age, sex, calendar time, and previous mental disorders. Absolute risks were estimated with the use of competing-risks survival analyses.RESULTS: A total of 698,874 of 5,940,299 persons (11.8%) were identified as having a mental disorder. The median age of the total population was 32.1 years at entry into the cohort and 48.7 years at the time of the last follow-up. Persons with a mental disorder had a higher risk than those without such disorders with respect to 76 of 90 pairs of mental disorders and medical conditions. The median hazard ratio for an association between a mental disorder and a medical condition was 1.37. The lowest hazard ratio was 0.82 for organic mental disorders and the broad category of cancer (95% confidence interval [CI], 0.80 to 0.84), and the highest was 3.62 for eating disorders and urogenital conditions (95% CI, 3.11 to 4.22). Several specific pairs showed a reduced risk (e.g., schizophrenia and musculoskeletal conditions). Risks varied according to the time since the diagnosis of a mental disorder. The absolute risk of a medical condition within 15 years after a mental disorder was diagnosed varied from 0.6% for a urogenital condition among persons with a developmental disorder to 54.1% for a circulatory disorder among those with an organic mental disorder.CONCLUSIONS: Most mental disorders were associated with an increased risk of a subsequent medical condition; hazard ratios ranged from 0.82 to 3.62 and varied according to the time since the diagnosis of the mental disorder. (Funded by the Danish National Research Foundation and others; COMO-GMC ClinicalTrials.gov number, NCT03847753.).

Aim This study aimed to evaluate the presence and prognostic value of tumor-infiltrating T cells in the tumor epithelium in advanced stage, HPV-negative head and neck squamous cell carcinoma (HNSCC) patients treated with primary chemoradiotherapy using digital pathology. Methods Pre-treatment biopsies from 80 oropharyngeal, 52 hypopharyngeal, and 29 laryngeal cancer patients were collected in a tissue microarray (TMA) and immunohistochemically stained for T-cell markers CD3, CD4, CD8, FoxP3, and PD1, and for immune checkpoint PD-L1. For each marker, the number of positive tumor-infiltrating lymphocytes (TILs) per mm2 tumor epithelium was digitally quantified and correlated to overall survival (OS), disease-free survival (DFS), and locoregional control (LRC), as well as to clinicopathological characteristics. Differences in clinical outcome were estimated using Cox proportional hazard analysis and visualized using Kaplan–Meier curves. Results The patient cohort had a 3-year OS of 58%, with a median follow-up of 53 months. None of the T-cell markers showed a correlation with OS, DFS or LRC. A low N stage was correlated to a better prognosis (OS: HR 0.39, p = 0.0028, DFS: HR 0.34, p = p = 0.008). High TIL counts were more often observed in PD-L1-positive tumors (p Conclusion This study showed an objective, digital pathology-aided method to assess TILs in the tumor epithelium. However, it did not provide evidence for a prognostic role of the presence of CD3 + , CD4 + , CD8 + , FoxP3 + , and PD1 + TILs in the tumor epithelium of advanced stage, HPV-negative HNSCC patients treated with primary chemoradiotherapy.

Skeletal muscles control posture, mobility and strength, and influence whole-body metabolism. Muscles are built of different types of myofibers, each having specific metabolic, molecular, and contractile properties. Fiber classification is, therefore, regarded the key for understanding muscle biology, (patho-) physiology. The expression of three myosin heavy chain (MyHC) isoforms, MyHC-1, MyHC-2A, and MyHC-2X, marks myofibers in humans. Typically, myofiber classification is performed by an eye-based histological analysis. This classical approach is insufficient to capture complex fiber classes, expressing more than one MyHC-isoform. We, therefore, developed a methodological procedure for high-throughput characterization of myofibers on the basis of multiple isoforms. The mean fluorescence intensity of the three most abundant MyHC isoforms was measured per myofiber in muscle biopsies of 56 healthy elderly adults, and myofiber classes were identified using computational biology tools. Unsupervised clustering revealed the existence of six distinct myofiber clusters. A comparison with the visual assessment of myofibers using the same images showed that some of these myofiber clusters could not be detected or were frequently misclassified. The presence of these six clusters was reinforced by RNA expressions levels of sarcomeric genes. In addition, one of the clusters, expressing all three MyHC isoforms, correlated with histological measures of muscle health. To conclude, this methodological procedure enables deep characterization of the complex muscle heterogeneity. This study opens opportunities to further investigate myofiber composition in comparative studies.

Background: Previous studies have suggested a bidirectional association between sleep problems and anxiety symptoms in adolescents. These studies used methods that do not separate between-person effects from within-person effects, and therefore their conclusions may not pertain to within-person mutual influences of sleep and anxiety. We examined bidirectional associations between sleep problems and anxiety during adolescence and young adulthood while differentiating between person effects from within-person effects. Methods: Data came from the Dutch TRacking Adolescents' Individual Lives Survey (TRAILS), a prospective cohort study including six waves of data spanning 15 years. Young adolescents (N = 2230, mean age at baseline 11.1 years) were followed every 2–3 years until young adulthood (mean age 25.6 years). Sleep problems and anxiety symptoms were measured by the Youth Self-Report, Adult Self-Report and Nottingham Health Profile. Temporal associations between sleep and anxiety were investigated using the random intercept cross-lagged panel model. Results: Across individuals, sleep problems were significantly associated with (β = 0.60, p < 0.001). At the within-person level, there were significant cross–sectional associations between sleep problems and anxiety symptoms at all waves (β = 0.12–0.34, p < 0.001). In addition, poor sleep predicted greater anxiety symptoms between the first and second, and between the third and fourth assessment wave. The reverse association was not statistically significant. Conclusions: Within-person associations between sleep problems and anxiety are considerably weaker than between-person associations. Yet, our findings tentatively suggest that poor sleep, especially during early and mid-adolescence, may precede anxiety symptoms, and that anxiety might be prevented by alleviating sleep problems in young adolescents.