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Glioblastomas are aggressive primary brain tumors with an inherent resistance to T cell-centric immunotherapy due to their low mutational burden and immunosuppressive tumor microenvironment. Here we report that fractionated radiotherapy of preclinical glioblastoma models induce a tenfold increase in T cell content. Orthogonally, spatial imaging mass cytometry shows T cell enrichment in human recurrent tumors compared with matched primary glioblastoma. In glioblastoma-bearing mice, α-PD-1 treatment applied at the peak of T cell infiltration post-radiotherapy results in a modest survival benefit compared with concurrent α-PD-1 administration. Following α-PD-1 therapy, CD103+ regulatory T cells (Tregs) with upregulated lipid metabolism accumulate in the tumor microenvironment, and restrain immune checkpoint blockade response by repressing CD8+ T cell activation. Treg targeting elicits tertiary lymphoid structure formation, enhances CD4+ and CD8+ T cell frequency and function and unleashes radio-immunotherapeutic efficacy. These results support the rational design of therapeutic regimens limiting the induction of immunosuppressive feedback pathways in the context of T cell immunotherapy in glioblastoma.

(-)-Epigallocatechin gallate (EGCG) is prone to microbial metabolism when reaching the colon. This study aimed to develop a human physiologically based kinetic (PBK) model for EGCG, with sub-models for its colonic metabolites gallic acid and pyrogallol. Results show that the developed PBK model could adequately predict in vivo time-dependent blood concentrations of EGCG after either the single or repeated oral administration of EGCG under both fasting and non-fasting conditions. The predicted in vivo blood Cmax of EGCG indicates that the Nrf2 activation is limited, while concentrations of its metabolites in the intestinal tract may reach levels that are higher than that of EGCG and also high enough to activate Nrf2 gene transcription. Taken together, combining in vitro data with a human PBK model allowed the prediction of a dose-response curve for EGCG-induced Nrf2-mediated gene expression in humans and provided insights into the contribution of gut microbial metabolites to this effect.

BACKGROUND: Elderly patients undergoing vascular surgery are at a risk of developing postoperative delirium, which is associated with high mortality. Delirium prevention is difficult and is investigated in surgical patients from various specialisms, but little is known about delirium prevention in vascular surgery. For this reason we performed a systematic review on strategies for delirium prevention in patients undergoing elective surgery for peripheral arterial disease or for an aneurysm of the abdominal aorta. METHODS: This systematic review included studies describing strategies for preventing delirium in patients undergoing elective surgery for peripheral arterial disease or for an aneurysm of the abdominal aorta. The search was conducted using the keywords 'vascular surgery,' 'prevention,' and 'delirium' and was last run on October 21, 2021 in the electronic databases PubMed, MEDLINE, Embase, Web of Science, the Cochrane library, and Emcare. Risk of bias was assessed using the Cochrane risk of bias tool for randomized controlled trials and the ROBINS-1 tool for observational studies. RESULTS: Four studies including 565 patients were included in the systematic review. A significant decrease in the incidence of delirium was reported by a study investigating the effect of comprehensive geriatric assessments within patients undergoing surgery for an aneurysm of the abdominal aorta or lower limb bypass surgery (24% in the control group vs. 11% in the intervention group, P = 0.018) and in the total group of a study evaluating the effect of outpatient clinic multimodal prehabilitation for patients with an aneurysm of the abdominal aorta (11.7% in the control group vs. 8.2% in the intervention group, P = 0.043, Odds Ratio = 0.56). A nonsignificant decrease in delirium incidence was described for patients receiving a multidisciplinary quality improvement at the vascular surgical ward (21.4% in the control group vs. 14.6% in the intervention group, P = 0.17). The study concerning the impact of the type of anesthesia on delirium in 11 older vascular surgical patients, of which 3 developed delirium, did not differentiate between the different types of anesthesia the patients received. CONCLUSIONS: Despite the high and continuous increasing incidence of delirium in the growing elderly vascular population, little is known about effective preventive strategies. An approach to address multiple risk factors simultaneously seems to be promising in delirium prevention, whether through multimodal prehabilitation or comprehensive geriatric assessments. Several strategies including prehabilitation programs have been proven to be successful in other types of surgery and more research is required to evaluate effective preventive strategies and prehabilitation programs in vascular surgical patients. ispartof: ANNALS OF VASCULAR SURGERY vol:85 pages:433-443 ispartof: location:Netherlands status: published

Background: The division of care responsibilities between parents and children with type 1 diabetes, and an optimal transfer of responsibilities from parent to child over time are assumed to be key for optimal diabetes outcomes during childhood and adolescence. However, an overview of instruments assessing this division as well as their psychometric qualities is currently lacking. Objective: The study aims to 1) identify all existing instruments, 2) evaluate their psychometric properties, and 3) provide an overview of scoring methods. Methods: Pubmed and PsycINFO were searched using a priori-defined search string. Peerreviewed studies in English using an instrument assessing the division of diabetes care responsibilities between children (6-18 years) and parents were included. In total, 84 of 725 articles qualified, covering 62 unique samples. Results: Thirteen questionnaires were identified. The Diabetes Family Responsibility Questionnaire (DFRQ) was most frequently used across studies. Instructions, content and number of tasks, response options, and scoring methods varied across questionnaires. Recent studies often adapted questionnaires, contributing to the heterogeneity across measures. Overall, reporting and quality of psychometric properties was suboptimal. Conclusion: The division of diabetes care responsibilities can be operationalized with various instruments, each having its strengths and weaknesses but all with limited psychometric support. To measure the division of diabetes care responsibilities more adequately, an updated version of the popular DFRQ or a new scale needs to be developed and evaluated.

Background: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden. Methods: We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599. Findings: Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled and randomly assigned to active treatment (n=119) or placebo (n=117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group vs 21 [18%] of 117 in the placebo group; hazard ratio 0middot81, 95% CI 0middot45 to 1middot48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean between-group difference in Health Assessment Questionnaire disability index over 2 years: -0middot09, 95% CI -0middot16 to -0middot03; p=0middot0042). Similarly, pain (on scale 0-100, mean between-group difference: -8, 95% CI -12 to -4; p < 0middot0001), morning stiffness of joints (-12, -16 to -8; p < 0middot0001), presenteeism (-8%, -13 to -3; p=0middot0007), and MRI-detected joint inflammation (-1middot4 points, -2middot0 to -0middot9; p < 0middot0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate. Interpretation: Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Moral sensitivity and moral reasoning are essential competencies biomedical researchers have to develop to make ethical decisions in their daily practices. Previous research has shown that these competencies can be developed through ethics education. However, it is unclear which underlying mechanisms best support the development of these competencies. In this article we argue that the development of moral sensitivity and moral reasoning can be fostered through teaching strategies that tap into students’ moral imagination. We describe how moral imagination can stimulate the development of these competencies through three different merits of moral imagination. Moral imagination can help students to 1) transfer and apply abstract moral concepts to concrete situations and contexts, 2) explore the perspective of others, 3) explore and foresee the moral consequences of different decisions and actions. We explain these three merits of moral imagination in the context of biomedical research and present a theoretical model for how these merits can be used to stimulate the development of moral sensitivity and moral reasoning. Furthermore, we describe multiple teaching strategies for biomedical curricula that tap into the three merits of moral imagination. These teaching strategies can inspire teachers to design ethics education that activates students’ moral imagination for the development of moral sensitivity and moral reasoning.

Disruptive behavior in adolescents is burdensome and may continue into adulthood if left unidentified. The strengths and difficulties questionnaire (SDQ) can screen for disruptive behavior, but its psychometric properties in high-risk samples and ability to predict delinquency warrant further investigation. In 1022 adolescents, we investigated the predictive validity (on average 1.9 years after screening) of the self-reported SDQ on disruptive behavior disorders and delinquency, measured with multi-informant questionnaires and structured interviews. We compared three scoring methods: total, subscale, and dysregulation profile scoring. In this high-risk sample, SDQ subscale scores predicted disruptive behavior outcomes best. Predictive values for the specific types of delinquency were small. Concluding, the SDQ can be used in high-risk settings for early identification of youth with disruptive behavior.

Background Childhood obesity is a chronic disease with negative physical and psychosocial health consequences. To manage childhood overweight and obesity, integrated care as part of an integrated approach is needed. To realise implementation of this integrated care, practical guidance for policy and practice is needed. The aim of this study is to describe the development of a Dutch national model of integrated care for childhood overweight and obesity and accompanying materials for policy and practice. Methods The development of the national model was led by a university-based team in collaboration with eight selected Dutch municipalities who were responsible for the local realisation of the integrated care and with frequent input from other stakeholders. Learning communities were organised to exchange knowledge, experiences and tools between the participating municipalities. Results The developed national model describes the vision, process, partners and finance of the integrated care. It sets out a structure that provides a basis for local integrated care that should facilitate support and care for children with overweight or obesity and their families. The accompanying materials are divided into materials for policymakers to support local realisation of the integrated care and materials for healthcare professionals to support them in delivering the needed support and care. Conclusions The developed national model and accompanying materials can contribute to improvement of support and care for children with overweight or obesity and their families, and thereby help improve the health, quality of life and societal participation of these children. Further implementation of the evidence- and practice-based integrated care while evaluating on the way is needed.

T-cell redirecting bispecific antibodies hold high promise for treatment of B-cell malignancies. B-cell maturation antigen (BCMA) exhibits high expression on normal and malignant mature B cells including plasma cells, which can be enhanced by inhibition of γ-secretase. BCMA is considered a validated target in multiple myeloma but whether mature B-cell lymphomas can be targeted by the BCMAxCD3 T-cell redirector teclistamab is currently unknown. BCMA expression on B-cell non–Hodgkin lymphoma and primary chronic lymphocytic leukemia (CLL) cells was assessed by flow cytometry and/or IHC. To assess teclistamab efficacy, cells were treated with teclistamab in presence of effector cells with/without γ-secretase inhibition. BCMA could be detected on all tested mature B-cell malignancy cell lines, while expression levels varied per tumor type. γ-secretase inhibition universally increased BCMA surface expression. These data were corroborated in primary samples from patients with Waldenstrom's macroglobulinemia, CLL, and diffuse large B-cell lymphoma. Functional studies with the B-cell lymphoma cell lines revealed teclistamab-mediated T-cell activation, proliferation, and cytotoxicity. This was independent of the level of BCMA expression, but generally lower in mature B-cell malignancies compared with multiple myeloma. Despite low BCMA levels, healthy donor T cells and CLL-derived T cells induced lysis of (autologous) CLL cells upon addition of teclistamab. These data show that BCMA is expressed on various B-cell malignancies and that lymphoma cell lines and primary CLL can be targeted using teclistamab. Further studies to understand the determinants of response to teclistamab are required to identify which other diseases might be suitable for teclistamab targeting.Significance:Besides reported BCMA expression on multiple myeloma, we demonstrate BCMA can be detected and enhanced using γ-secretase inhibition on cell lines and primary material of various B-cell malignancies. Furthermore, using CLL we demonstrate that low BCMA-expressing tumors can be targeted efficiently using the BCMAxCD3 DuoBody teclistamab.

Supplementary Table 1. CLL Patient characteristics. Supplementary Table 2. Healthy donor characteristics. Supplementary Table 3. MM patient characteristics. Supplementary Figure 1. γ-secretase inhibition increases BCMA levels but does not affect viability of B-cell malignancy cell lines. Supplementary Figure 2. γ-secretase inhibition does not affect viability CLL cells. Supplementary Figure 3. BCMAxCD3 DuoBody® induces activation, degranulation, and cytokine secretion by T cells in the presence of B cell malignancy cell lines. Supplementary Figure 4. BCMAxCD3 DuoBody® induces autologous killing of MM cells.

Supplemental Material and Methods. Supplemental Figure S1. Cell cycle analysis in FA and sporadic HNSCC cell lines upon ICL treatment. Supplemental Figure S2. FANCM protein expression is absent in FaDu cells. Supplemental Figure S3. Overview of possible pathogenic variants in genes that are frequently altered in HNSCC. Supplemental Figure S4. PARP inhibitor resistance and normal RAD51 focus formation in VU-SCC-147. Supplemental Figure S5. Cell line UPCI-SCC-154 is sensitive to cisplatin. Supplemental Figure S6. Cell line VU-SCC-41 is mutated in PSC5A. Supplemental Figure S7. Mutational inactivation of STAG2 in cell line VU-SCC-78. Supplemental Table 1. Separate panel of 39 sporadic HNSCC cell lines.

Anne L Meulenbroek,1 Miriam C Faes,2 Stefanie R van Mil,1 MG Buimer,1 Hans GW de Groot,1 Eelco J Veen,1 Gwan H Ho,1 Leandra JM Boonman-de Winter,3,4 Jolanda de Vries,5,6 Rebecca van Gorkom,1 Fleur Toonders,1 Rene van Alphen,7 Karolien van Overveld,8 Nathalie Verbogt,1 Ewout W Steyerberg,9 Lijckle van der Laan1,10 1Department of Surgery, Amphia Hospital, Breda, the Netherlands; 2Department of Geriatrics, Amphia Hospital, Breda, the Netherlands; 3Department of Scientific Research, Amphia Hospital, Breda, the Netherlands; 4Admiraal de Ruyter Ziekenhuis, Goes, the Netherlands; 5Department of Medical and Clinical Psychology, Tilburg University, Tilburg, the Netherlands; 6Board, Admiraal de Ruyter Hospital, Goes, the Netherlands; 7Department of Physical Therapy, Amphia Hospital, Breda, the Netherlands; 8Department of Dieticians, Amphia Hospital, Breda, the Netherlands; 9Department of Biomedical Data Sciences, Leiden University Medical Centre, Leiden, the Netherlands; 10Department of Cardiovascular Science, University Hospitals Leuven, Leuven, BelgiumCorrespondence: Anne L Meulenbroek, Department of Surgery, Amphia Hospital, Molengracht 21, Breda, 4818 CK, the Netherlands, Tel +31 76 595 3157, Fax +31 76 595 3818, Email AMeulenbroek1@amphia.nlObjective: Chronic limb threatening ischemia is the final stage of peripheral arterial disease. Current treatment is based on revascularization to preserve the leg. In the older, hospitalized chronic limb threatening ischemia patient, delirium is a frequent and severe complication after revascularization. Delirium leads to an increased length of hospital stay, a higher mortality rate and a decrease in quality of life. Currently, no specific guidelines to prevent delirium in chronic limb threatening ischemia patients exist. We aim to evaluate the effect of a multicomponent, multidisciplinary prehabilitation program on the incidence of delirium in chronic limb threatening ischemia patients ≥ 65 years.Design: A prospective observational cohort study to investigate the effects of the program on the incidence of delirium will be performed in a large teaching hospital in the Netherlands. This manuscript describes the design of the study and the content of this specific prehabilitation program.Methods: Chronic limb threatening ischemia patients ≥ 65 years that require revascularization will participate in the program. This program focuses on optimizing the patient’s overall health and includes delirium risk assessment, nutritional optimization, home-based physical therapy, iron infusion in case of anaemia and a comprehensive geriatric assessment in case of frailty. The primary outcome is the incidence of delirium. Secondary outcomes include quality of life, amputation-free survival, length of hospital stay and mortality. Exclusion criteria are the requirement of acute treatment or patients who are mentally incompetent to understand the procedures of the study or to complete questionnaires. A historical cohort from the same hospital is used as a control group.Discussion: This study will clarify the effect of a prehabilitation program on delirium incidence in chronic limb threatening ischemia patients. New insights will be obtained on optimizing a patient’s preoperative mental and physical condition to prevent postoperative complications, including delirium.Trial: This protocol is registered at the Netherlands National Trial Register (NTR) number: NL9380.Keywords: chronic limb threatening ischemia, vascular surgical procedures, delirium, delirium/prevention and control, prehabilitation

Purpose Both aggression toward others and self peak in adolescence and interpersonal violence and suicide are among the leading causes of death in young people worldwide. Individuals who show both aggression toward others and self, i.e. dual-harm, may experience the worst outcomes. The current study investigates clinical and parenting factors associated with dual-harming in adolescence, to provide new insights for prevention and treatment. Methods In a prospective cohort of adolescents, oversampled on emotional and behavioral problems (n = 1022; aged 12–17 years), we investigated co-occurrence in harm toward others and self and presented findings in an area-proportional Euler diagram. Four harm groups (no harm, other-harm, self-harm, and dual-harm) were compared on intelligence scores, general functioning, emotional and behavioral problems, substance use, parental hostility, and harsh parenting with ANCOVAs and logistic regressions. Results In adolescents that other-harmed, the risk of self-harm was 1.9 times higher than for those who did not harm others. Dual-harm adolescents reported worse overall functioning, more emotional and behavioral problems, more parental hostility and harshness, and were more likely to use substances than those who did not engage in aggressive behaviors. No evidence of differences in intelligence scores between groups were found. Conclusion These findings highlight a vulnerable group of adolescents, at risk of future suicide, violent offending, and the development of severe psychopathology. Dual-harm is a promising marker for early intervention and referral to specialized mental health professionals. Further research is needed to examine underlying pathways and risk factors associated with persistent dual-harm trajectories into adulthood.

Although cross-sectional studies have shown that the COVID-19 pandemic has negatively affected the mental health of adolescents, the effect of the pandemic on adolescents with pre-pandemic symptoms is unclear. We, therefore, tested the hypothesis that adolescents had increased emotional and behavioral problems during the lockdowns imposed during the pandemic.This study included three measurements in a prospective cohort of 1022 adolescents who were oversampled based on their high risk of developing psychopathology. Before the pandemic, we assessed depressive, anxiety, stress, oppositional defiant problems, psychotic experiences and suicidality, using the Youth Self-Report; 445 and 333 of these 1,022 adolescents subsequently completed the online questionnaire in the first lockdown (in April 2020) and in the second lockdown (in January 2021), respectively. Multilevel random intercept regression models were used to determine the change in psychiatric symptoms, including an interaction term to assess whether these changes differed based on the severity of symptoms prior to the pandemic. Throughout the pandemic, the majority of the participating adolescents reported having emotional and behavioral symptoms that were within the normal range. Moreover, the mean symptom scores for all six outcomes decreased significantly among adolescents with high clinical severity prior to the pandemic.In contrast to our original hypothesis, the effects of the COVID-19 pandemic may not necessarily be detrimental, at least among a specific subgroup of adolescents with pre-existing mental health problems. Moreover, our finding that most adolescents in this at-risk sample did not report experiencing clinically relevant symptoms during the pandemic reflects their resilience during the pandemic.

Introduction To decrease antibiotic resistance, their use as growth promoters in the agricultural sector has been largely abandoned. This may lead to decreased health due to infectious disease or microbiome changes leading to gut inflammation. Objectives We aimed to generate a m/z signature classifying chicken health in blood, and obtain biological insights from the resulting m/z signature. Methods We used direct infusion mass-spectrometry to determine a machine-learned metabolomics signature that classifies chicken health from a blood sample. We then challenged the resulting models by investigating the classification capability of the signature on novel data obtained at poultry houses in previously unseen countries using a Leave-One-Country-Out (LOCO) cross-validation strategy. Additionally, we optimised the number of mass/charge (m/z) values required to maximise the classification capability of Random Forest models, by developing a novel ranking system based on combined univariate t-test and fold-change analyses and building models based on this ranking through forward and reverse feature selection. Results The multi-country and LOCO models could classify chicken health. Both resulting 25-m/z and 3784-m/z signatures reliably classified chicken health in multiple countries. Through mummichog enrichment analysis on the large m/z signature, we found changes in amino acid metabolism, including branched chain amino acids and polyamines. Conclusion We reliably classified chicken health from blood, independent of genetic-, farm-, feed- and country-specific confounding factors. The 25-m/z signature can be used to aid development of a per-metabolite panel. The extended 3784-m/z version can be used to gain a deeper understanding of the metabolic causes and consequences of low chicken health. Together, they may facilitate future treatment, prevention and intervention.

Additional file 2. The statistical code to simulate the study power.

Additional file 2. Literature search results.

Additional file 4. Tables.

ObjectivesTo provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field.MethodsAn international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item.ResultsThe task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3–6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations.ConclusionsThese updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.

Additional file 1. Focus group sessions topic guides.

Additional file 1. Description of planned statistical analyses for the PRWE outcome conform the ‘estimands’ framework.

Background: Truncating variants in desmoplakin ( DSP tv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSP tv cardiomyopathy. Methods: Individuals with DSP tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSP tv performed. Results: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSP tv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSP tv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P Conclusions: In the largest series of individuals with DSP tv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.

Additional file 5. Consolidated criteria for reporting qualitative studies (COREQ): 32-item checklist.

Objectives Paternal preconception health is recognized as an important contributor to pregnancy outcomes. Nonetheless, pregnancy outcomes of partners of men with inflammatory arthritis (IA) have never been studied. Our objective was to describe the pregnancy outcomes of partners of men diagnosed with IA. Methods We performed a multicentre cross-sectional retrospective study conducted in the Netherlands. Men with IA who were over 40 years old that reported at least one positive pregnancy test were included. To analyse the impact of IA on pregnancy outcomes, pregnancies were classified into two groups: pregnancies conceived after the diagnosis of IA and before the diagnosis of IA. Results In total, 408 male participants diagnosed with IA reported 897 singleton pregnancies that resulted in 794 live births. Pregnancies conceived after the diagnosis of IA had higher rate of miscarriage (12.27 vs 7.53%, P = Conclusions This is the largest study to describe the pregnancy outcomes of partners of men diagnosed with IA and the first to demonstrate that paternal IA is associated with a higher risk of miscarriage. Notwithstanding, the overall rate of miscarriage reported in our study could be comparable to previously reported population estimates.

Truncating variants in desmoplakin (Individuals withThere were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with aIn the largest series of individuals with

Water is essential for survival, but one in three individuals worldwide (2.2 billion people) lacks access to safe drinking water. Water intake requirements largely reflect water turnover (WT), the water used by the body each day. We investigated the determinants of human WT in 5604 people from the ages of 8 days to 96 years from 23 countries using isotope-tracking (2H) methods. Age, body size, and composition were significantly associated with WT, as were physical activity, athletic status, pregnancy, socioeconomic status, and environmental characteristics (latitude, altitude, air temperature, and humidity). People who lived in countries with a low human development index (HDI) had higher WT than people in high-HDI countries. On the basis of this extensive dataset, we provide equations to predict human WT in relation to anthropometric, economic, and environmental factors.

Carriers of the R14del pathogenic variant in the phospholamban (PLN) gene develop severe cardiomyopathy with extracellular adipocyte infiltration and intracellular cardiomyocyte mitochondrial disturbances. However, the basis of this metabolic dysregulation tailoring potential treatment targets is unknown. Here, we present a combined approach of transcriptional regulation analysis in human primary tissue and validation in a unique long-term (160 days) matured human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model. We demonstrate a dysregulated PPARA-mediated mitochondrial fatty acid oxidation (FAO) signalling in PLN-R14del hearts and hiPSC-CMs. PLN-R14del hiPSC-CMs also displayed a higher preference for glycolysis over FAO and presented limited flexibility in energy substrate switching leading to enhanced lipid droplet storage. By activating PPARA in PLN-R14del hiPSC-CMs using bezafibrate, we observed an improved mitochondrial structure and calcium handling function, further indicating the importance of FAO in the disease and the potential of PPARA agonists as a novel therapeutic strategy in cardiomyopathies.