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The immunopathophysiological mechanisms underlying chronic inflammatory demyelinating polyneuropathy (CIDP) in an individual patient are largely unknown. Better understanding of these mechanisms may aid development of biomarkers and targeted therapies. Both B- and T-cell dominant mechanisms have been implicated. We therefore investigated whether B-cell and T-cell receptor (BCR/TCR) repertoires might function as immunological biomarkers in CIDP. In this prospective cohort study, we longitudinally sampled peripheral blood of CIDP patients in three different phases of CIDP: starting induction treatment (IT), starting withdrawal from IVIg maintenance treatment (MT), and patients in remission (R). BCR and TCR repertoires were analyzed using RNA based high throughput sequencing. In baseline samples, the number of total clones, the number of dominant BCR and TCR clones and their impact on the repertoire was similar for patients in the IT, MT, and remission groups compared with healthy controls. Baseline samples in the IT or MT did not predict treatment response or potential relapse at follow-up. Treatment responders in the IT group showed a potential IVIg-induced increase in the number of dominant BCR clones and their impact at follow-up (baseline1.0 [IQR 1.0-2.8] vs. 6 m 3.5 [0.3-6.8]; P

International audience; We present ComBiNet, a visualization, query, and comparison system for exploring bipartite multivariate dynamic social networks. Historians and sociologists study social networks constructed from textual sources mentioning events related to people, such as marriage acts, birth certificates, and contracts. We model this type of data using bipartite multivariate dynamic networks to maintain a representation faithful to the original sources while not too complex. Relying on this data model, ComBiNet allows exploring networks using both visual and textual queries using the Cypher language, the two being synchronized to specify queries using the most suitable modality; simple queries are easy to express visually and can be refined textually when they become complex. These queries are used for applying topological and attribute-based selection on the network. Query results are visualized in the context of the whole network and over a geographical map for geolocalized entities. We also present the design of our interaction techniques for querying social networks to visually compare the selections in terms of topology, measures, and attribute distributions. We validate the query and comparison systems by showing how they have been used to answer historical questions and by explaining how they have been improved through a usability study conducted with historians.

Colorectal cancer; Driver gene; Mutant allele fraction Càncer colorectal; Gen conductor; Fracció d'al·lel mutant Cáncer colorrectal; Gen conductor; Fracción de alelo mutante Sequencing of tumors is now routine and guides personalized cancer therapy. Mutant allele fractions (MAFs, or the 'mutation dose') of a driver gene may reveal the genomic structure of tumors and influence response to targeted therapies. We performed a comprehensive analysis of MAFs of driver alterations in unpaired primary and metastatic colorectal cancer (CRC) at our institution from 2010 to 2015 and studied their potential clinical relevance. Of 763 CRC samples, 622 had detailed annotation on overall survival in the metastatic setting (OSmet) and 89 received targeted agents matched to KRAS (MEK inhibitors), BRAF (BRAF inhibitors), or PIK3CA mutations (PI3K pathway inhibitors). MAFs of each variant were normalized for tumor purity in the sample (adjMAFs). We found lower adjMAFs for BRAFV600E and PIK3CA than for KRAS, NRAS, and BRAF non-V600 variants. TP53 and BRAFV600E adjMAFs were higher in metastases as compared to primary tumors, and high KRAS adjMAFs were found in CRC metastases of patients with KRAS wild-type primary tumors previously exposed to EGFR antibodies. Patients with RAS- or BRAFV600E -mutated tumors, irrespective of adjMAFs, had worse OSmet. There was no significant association between adjMAFs and time to progression on targeted therapies matched to KRAS, BRAF, or PIK3CA mutations, potentially related to the limited antitumor activity of the employed drugs (overall response rate of 4.5%). In conclusion, the lower BRAFV600E and PIK3CA adjMAFs in subsets of primary CRC tumors indicate subclonality of these driver genes. Differences in adjMAFs between metastases and primary tumors suggest that approved therapies may result in selection of BRAFV600E - and KRAS-resistant clones and an increase in genomic heterogeneity with acquired TP53 alterations. Despite significant differences in prognosis according to mutations in driver oncogenes, adjMAFs levels did not impact on survival and did not help predict benefit with matched targeted agents in the metastatic setting.

Early data suggested that CC-115, a clinical molecule, already known to inhibit the mammalian target of rapamycin kinase (TORK) and DNA-dependent protein kinase (DNA-PK) may have additional targets beyond TORK and DNA-PK. Therefore, we aimed to identify such target(s) and investigate a potential therapeutic applicability. Functional profiling of 141 cancer cell lines revealed inhibition of kinase suppressor of morphogenesis in genitalia 1 (SMG1), a key regulator of the RNA degradation mechanism nonsense-mediated mRNA decay (NMD), as an additional target of CC-115. CC-115 treatment showed a dose-dependent increase of SMG1-mediated NMD transcripts. A subset of cell lines, including multiple myeloma (MM) cell lines sensitive to the endoplasmic reticulum stress-inducing compound thapsigargin, were highly susceptible to SMG1 inhibition. CC-115 caused the induction of UPR transcripts and cell death by mitochondrial apoptosis, requiring the presence of BAX/BAK and caspase activity. Superior antitumor activity of CC-115 over TORK inhibitors in primary human MM cells and three xenograft mouse models appeared to be via inhibition of SMG1. Our data support further development of SMG1 inhibitors as possible therapeutics in MM.

Aims and Objectives: Studies in adult medicine have shown that physicians base testing decisions on the patient's clinical condition but also consider other factors, including local practice or patient expectations. In pediatrics, physicians and parents jointly decide on behalf of a (young) child. This might demand more explicit and more complex deliberations, with sometimes conflicting interests. We explored pediatricians' considerations in diagnostic test ordering and the factors that influence their deliberation. Method: We performed in-depth, semistructured interviews with a purposively selected heterogeneous sample of 20 Dutch pediatricians. We analyzed transcribed interviews inductively using a constant comparative approach, and clustered data across interviews to derive common themes. Results: Pediatricians perceived test-related burden in children higher compared with adults, and reported that avoiding an unjustified burden causes them to be more restrictive and deliberate in test ordering. They felt conflicted when parents desired testing or when guidelines recommended diagnostic tests pediatricians perceived as unnecessary. When parents demanded testing, they would explore parental concern, educate parents about harms and alternative explanations of symptoms, and advocate watchful waiting. Yet they reported sometimes performing tests to appease parents or to comply with guidelines, because of feared personal consequences in the case of adverse outcomes. Conclusion: We obtained an overview of the considerations that are weighed in pediatric test decisions. The comparatively strong focus on prevention of harm motivates pediatricians to critically appraise the added value of testing and drivers of low-value testing. Pediatricians' relatively restrictive approach to testing could provide an example for other disciplines. Improved guidelines and physician and patient education could help to withstand the perceived pressure to test.

Publisher Copyright: © 2023 The Authors. Functional Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society. The arrangement of plant species within a landscape influences pollination via changes in pollinator movement trajectories and plant-pollinator encounter rates. Yet the combined effects of landscape composition and pollinator traits (especially specialisation) on pollination success remain hard to quantify empirically.We used an individual-based model to explore how landscape and pollinator specialisation (degree) interact to influence pollination. We modelled variation in the landscape by generating gradients of plant species intermixing-from no mixing to complete intermixing. Furthermore, we varied the level of pollinator specialisation by simulating plant-pollinator (six to eight species) networks of different connectance. We then compared the impacts of these drivers on three proxies for pollination: visitation rate, number of consecutive visits to the focal plant species and expected number of plants pollinated.We found that the spatial arrangements of plants and pollinator degree interact to determine pollination success, and that the influence of these drivers on pollination depends on how pollination is estimated. For most pollinators, visitation rate increases in more plant mixed landscapes. Compared to the two more functional measures of pollination, visitation rate overestimates pollination service. This is particularly severe in landscapes with high plant intermixing and for generalist pollinators. Interestingly, visitation rate is less influenced by pollinator traits (pollinator degree and body size) than are the two functional metrics, likely because 'visitation rate' ignores the order in which pollinators visit plants. However, the visitation sequence order is crucial for the expected number of plants pollinated, since only prior visits to conspecific individuals can contribute to pollination. We show here that this order strongly depends on the spatial arrangements of plants, on pollinator traits and on the interaction between them.Taken together, our findings suggest that visitation rate, the most commonly used proxy for pollination in network studies, should be complemented with more functional metrics which reflect the frequency with which individual pollinators revisit the same plant species. Our findings also suggest that measures of landscape structure such as plant intermixing and density-in combination with pollinators' level of specialism-can improve estimates of the probability of pollination.

Aim: Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction is limited. Methods and results: We analysed HCRU in relation to left ventricular ejection fraction (LVEF) phenotypes, clinical features and in-hospital and 12-month outcomes in 16 943 patients hospitalized for HF in a worldwide registry. HFrEF was more prevalent (53%) than HFmrEF (17%) or HFpEF (30%). Patients with HFmrEF and HFpEF were older, more often women, with milder symptoms and more comorbidities, but differences were not pronounced. HCRU was high in all three groups; two or more in- and out-of-hospital services were required by 51%, 49% and 52% of patients with HFrEF, HFmrEF and HFpEF, respectively, and intensive care unit by 41%, 41% and 37%, respectively. Hospitalization length was similar (median, 8 days). Discharge prescription of neurohormonal inhibitors was

Network theory offers innovative tools to explore the complex ecological mechanisms regulating species associations and interactions. Although interest in ecological networks has grown steadily during the last two decades, the application of network approaches has been unequally distributed across different study systems: while some kinds of interactions (e.g. plant–pollinator and host–parasite) have been extensively investigated, others remain relatively unexplored. Among the latter, aquatic macrophyte–animal associations in coastal environments have been largely neglected, despite their major role in littoral ecosystems. The ubiquity of macrophyte systems, their accessibility and multi-faceted ecological, economical and societal importance make macrophyte–animal systems an ideal subject for ecological network science. In fact, macrophyte–animal networks offer an aquatic counterpart to terrestrial plant–animal networks. In this review, we show how the application of network analysis to aquatic macrophyte–animal associations has the potential to broaden our understanding of how coastal ecosystems function. Network analysis can also provide a key to understanding how such ecosystems will respond to on-going and future threats from anthropogenic disturbance and environmental change. For this, we: (i) identify key issues that have limited the application of network theory and modelling to aquatic animal– macrophyte associations; (ii) illustrate through examples based on empirical data how network analysis can offer new insights on the complexity and functioning of coastal ecosystems; and (iii) provide suggestions for how to design future studies and establish this new research line into network ecology.

Background: Low-dose UV treatment has been shown to be effective in mild psoriasis. However, the prolonged use of this treatment modality may raise concerns about its safety. These concerns are mainly focused on potential carcinogenic risks and overuse of this treatment modality. Objectives: This study was set out to evaluate possible carcinogenic risks of prolonged low-dose phototherapy. Methods: Three groups of psoriasis patients were evaluated: patients with local treatment only (n = 15); low-dose UV treatment at home for at least 18 months (n = 39); and patients with conventional NB-UVB (n = 8). Patients underwent visual inspection for signs of photoageing, and p53, CPDs and γH2AX were measured in skin biopsies. Patients undergoing low-dose phototherapy answered a survey about their recent patterns of use in a survey. Results: In the skin biopsies, low-dose UV treatment caused a lower amount of CPDs (p =.016) and p53 (p =.015) than NB-UVB. γH2AX did not show a significant difference. Self-report in patients undergoing low-dose phototherapy showed only one case of overuse (2.7%). Visual skin inspection showed no difference in signs of photoageing in the three groups. Conclusion: Prolonged treatment with low-dose UV for 18 months appears at least as safe as a course of conventional NB-UVB.

Special Issue: The ENIGMA Consortium: the first 10 years., Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3–90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes., European Community's Seventh Framework Programme, Grant/Award Numbers: 278948, 602450, 603016, 602805; US National Institute of Child Health and Human Development, Grant/Award Numbers: RO1HD050735, 1009064, 496682; QIMR Berghofer Medical Research Institute and the Centre for Advanced Imaging, University of Queensland; ICTSI NIH/NCRR, Grant/Award Number: RR025761; European Community's Horizon 2020 Programme, Grant/Award Numbers: 667302, 643051; Vici Innovation Program, Grant/Award Numbers: #91619115, 016-130-669; NWO Brain & Cognition Excellence Program, Grant/Award Number: 433-09-229; Biobanking and Biomolecular Resources Research Infrastructure (Netherlands) (BBMRI-NL); Spinozapremie, Grant/Award Number: NWO-56-464-14192; Biobanking and Biomolecular Resources Research Infrastructure, Grant/Award Numbers: 184.033.111, 184.021.007; Netherlands Organization for Health Research and Development (ZonMW), Grant/Award Numbers: 480-15-001/674, 024.001.003, 911-09-032, 056-32-010, 481-08-011, 016-115-035, 31160008, 400-07-080, 400-05-717, 451-04-034, 463-06-001, 480-04-004, 904-61-193, 912-10-020, 985-10-002, 904-61-090; NIMH, Grant/Award Number: R01 MH090553; Geestkracht programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Grant/Award Numbers: NWO/SPI 56-464-14192, NWO-MagW 480-04-004, 433-09-220, NWO 51.02.062, NWO 51.02.061; National Center for Advancing Translational Sciences, National Institutes of Health, Grant/Award Number: UL1 TR000153; National Center for Research Resources; National Center for Research Resources at the National Institutes of Health, Grant/Award Numbers: NIH 1U24 RR025736-01, NIH 1U24 RR021992; NIH Institutes contributing to the Big Data to Knowledge; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Numbers: U54EB020403, G0500092; National Institute of Mental Health, Grant/Award Numbers: R01MH117014, R01MH042191; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; Swedish Research Council, Grant/Award Numbers: 523-2014-3467, 2017-00949, 521-2014-3487; South-Eastern Norway Health Authority; the Research Council of Norway, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Icahn School of Medicine at Mount Sinai; Seventh Framework Programme (FP7/2007-2013), Grant/Award Number: 602450; National Institutes of Health, Grant/Award Numbers: R01 MH116147, R01 MH113619, R01 MH104284; South London and Maudsley NHS Foundation Trust; the National Institute for Health Research (NIHR)

Background: Individuals from families at high-risk for type 2 diabetes mellitus (T2DM) are also at high risk for hypertension (HTN) and cardiovascular disease. Studies identifying lifestyle patterns (LPs) combining dietary, physical activity or sedentary variables and examining their possible role with respect to developing blood pressure (BP) are limited. The present study aimed to examine the association of different LPs with BP levels in families at high risk for T2DM in Europe. Methods: In total, 1844 adults (31.6% males) at high-risk for T2DM across six European countries were included in this cross-sectional study using data from the baseline assessment of the Feel4Diabetes Study. BP measurements and dietary and physical activity assessments were conducted, and screen times were surveyed. LPs were revealed with principal component analysis of various data regarding diet, physical activity, screen time and smoking. Results: Three LPs were identified. LP3 (high consumption of sweet and salty snacks, sugar sweetened soft drinks and juices, and high amount of screen time) was positively associated with diastolic BP (B, 0.52; 95% confidence interval = 0.05–0.99) and the existence of HTN (odds ratio = 1.12; 95% confidence interval = 1.00–1.25). Participants in the highest tertile of LP3 spent mean 3 h of screen time, consumed 1.5 portions of sweet and/or salty snacks and 1 L of soft drinks on a daily basis, were associated with 12% higher risk of HTN. Conclusions: Focusing on the combination of eating and lifestyle behaviours may more accurately identify, and therefore guide preventive measures tailored to the specific needs of high-risk populations.

Introduction: We investigated changes in self- and study partner?reported self-perceived cognitive decline in relation to amyloid pathology and clinical progression, in a sample of cognitively normal individuals. Methods: A total of 404 participants (63???9 years, 44% female) and their study partners completed the Cognitive Change Index (CCI) yearly (0.7?6.8 follow-up years; n visits?=?1436). Baseline and longitudinal associations between (change in) CCI scores, amyloid, and clinical progression were modeled in linear mixed models and Cox regressions. Results: CCI?study partner scores of amyloid-positive individuals increased over time (B?=?1.79, 95% confidence interval [CI]?=?[0.51, 3.06]), while CCI?self scores remained stable (B?=??0.45, 95% CI?=?[?1.77, 0.87]). Ten-point higher baseline CCI?study partner (hazard ratio [HR]?=?1.75, 95% CI?=?[1.30, 2.36]) and CCI?self scores (HR?=?1.90, 95% CI?=?[1.40, 2.58]) were associated with an approximately 2-fold increased risk of progression to mild cognitive impairment or dementia. Discussion: Study partner?reported but not self-perceived complaints increase over time in amyloid-positive individuals, supporting the value of longitudinal study partner report, even in initially cognitively normal individuals.

Introduction: Distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) is challenging due to overlapping presentations. We adapted a Web-based test tool, cCOG, by adding a visuospatial task and a brief clinical survey and assessed its ability to differentiate between DLB and AD. Methods: We included 110 patients (n = 30 DLB, n = 32 AD dementia, and n = 48 controls with subjective cognitive decline (SCD)). Full cCOG comprises six cognitive subtasks and a survey addressing self-reported DLB core and autonomic features. First, we compared cCOG cognitive tasks to traditional neuropsychological tasks for all diagnostic groups and clinical questions to validated assessments of clinical features in DLB only. Then, we studied the performance of cCOG cognitive tasks and clinical questions, separately and combined, in differentiating diagnostic groups. Results: cCOG cognitive tasks and clinical survey had moderate to strong correlations to standard neuropsychological testing (.61≤ rs ≤.77) and to validated assessments of clinical features (.41≤ rs ≤.65), except for fluctuations and REM-sleep behavior disorder (RBD) (rs =.32 and rs =.10). Full cCOG, including both cognitive tasks and brief survey had a diagnostic accuracy (acc) of 0.82 [95% CI 0.73–0.89], with good discrimination of DLB versus AD (acc 0.87 [0.76–0.95]) and DLB versus controls (acc 0.94 [0.86–0.98]). Conclusion: We illustrated that cCOG aids in distinguishing DLB and AD patients by using remote assessment of cognition and clinical features. Our findings pave the way to a funneled, harmonized diagnostic process among memory clinics and, eventually, a more timely and accurate diagnosis of DLB and AD.

Contains fulltext : 238920.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Hyperemesis gravidarum (HG) complicates 1% of pregnancies and has a major impact on maternal quality of life and well-being. We know very little about HG's long-term impact after an affected pregnancy, including recurrence rates in future pregnancies, which is essential information for women considering subsequent pregnancies. In this study, we aimed to prospectively measure the recurrence rate of HG and the number of postponed and terminated subsequent pregnancies due to HG. We also aimed to evaluate if there were predictive factors that could identify women at increased risk for HG recurrence, and postponing and terminating subsequent pregnancies. MATERIAL AND METHODS: We conducted a prospective cohort study. A total of 215 women admitted for HG to public hospitals in the Netherlands were enrolled in the original MOTHER randomized controlled trial and associated observational cohort. Seventy-three women were included in this follow-up study. Data were collected through an online questionnaire. Recurrent HG was defined as vomiting symptoms accompanied by any of the following: multiple medication use, weight loss, admission, tube feeding or if nausea and vomiting symptoms were severe enough to affect life and/or work. Outcome measures were recurrence, postponing, and termination rates due to HG. Univariable logistic regression analysis was used to identify predictive factors associated with HG recurrence, and postponing and terminating subsequent pregnancies. RESULTS: Thirty-five women (48%) became pregnant again of whom 40% had postponed their pregnancy due to HG. HG recurred in 89% of pregnancies. One woman terminated and eight women (23%) considered terminating their pregnancy because of recurrent HG. Twenty-four out of 38 women did not get pregnant again because of HG in the past. Univariable logistic regression analysis identifying possible predictive factors found that having a western background was associated with having weight loss due to recurrent HG in subsequent pregnancies (odds ratio 12.9, 95% CI 1.3-130.5, p = 0.03). CONCLUSIONS: High rates of HG recurrence and a high number of postponed pregnancies due to HG were observed. Women can be informed of a high chance of recurrence to enable informed family planning.

International audience; Robust statistical data modelling under potential model mis-specification often requires leaving the parametric world for the nonparametric. In the latter, parameters are infinite dimensional objects such as functions, probability distributions or infinite vectors. In the Bayesian nonparametric approach, prior distributions are designed for these parameters, which provide a handle to manage the complexity of nonparametric models in practice. However, most modern Bayesian nonparametric models seem often out of reach to practitioners, as inference algorithms need careful design to deal with the infinite number of parameters. The aim of this work is to facilitate the journey by providing computational tools for Bayesian nonparametric inference. The article describes a set of functions available in the R package BNPdensity in order to carry out density estimation with an infinite mixture model, including all types of censored data. The package provides access to a large class of such models based on normalized random measures, which represent a generalization of the popular Dirichlet process mixture. One striking advantage of this generalization is that it offers much more robust priors on the number of clusters than the Dirichlet. Another crucial advantage is the complete flexibility in specifying the prior for the scale and location parameters of the clusters, because conjugacy is not required. Inference is performed using a theoretically grounded approximate sampling methodology known as the Ferguson & Klass algorithm. The package also offers several goodness of fit diagnostics such as QQ-plots, including a cross-validation criterion, the conditional predictive ordinate. The proposed methodology is illustrated on a classical ecological risk assessment method called the Species Sensitivity Distribution (SSD) problem, showcasing the benefits of the Bayesian nonparametric framework.

When performing a systematic review, researchers screen the articles retrieved after a broad search strategy one by one, which is time-consuming. Computerised support of this screening process has been applied with varying success. This is partly due to the dependency on large amounts of data to develop models that predict inclusion. In this paper, we present an approach to choose which data to use in model training and compare it with established approaches. We used a dataset of 50 Cochrane diagnostic test accuracy reviews, and each was used as a target review. From the remaining 49 reviews, we selected those that most closely resembled the target review's clinical topic using the cosine similarity metric. Included and excluded studies from these selected reviews were then used to develop our prediction models. The performance of models trained on the selected reviews was compared against models trained on studies from all available reviews. The prediction models performed best with a larger number of reviews in the training set and on target reviews that had a research subject similar to other reviews in the dataset. Our approach using cosine similarity may reduce computational costs for model training and the duration of the screening process.

Background Experimental studies show that high‐sodium intake affects the innate immune system, among others with increased circulating granulocytes. Whether this relationship exists on a population level and whether this relates to disease outcomes is unclear. We aimed to test the hypotheses that (1) sodium intake is associated with granulocytes on a population level; (2) granulocytes are associated with the presence of hypertension and both cardiovascular and renal outcomes; and (3) the relation between high‐sodium intake and these outcomes is mediated by granulocytes. Methods and Results We performed an analysis in 13 804 participants from the prospective EPIC (European Prospective Investigation into Cancer)‐Norfolk cohort, with a mean age of 58 years and median follow‐up of 19.3 years. Analyses were carried out using calculated estimated sodium intake and sodium‐to‐potassium ratios from spot urines at baseline. The main outcomes were hypertension at baseline, and composite cardiovascular (mortality or cardiovascular events) and renal (mortality or renal events) outcomes during follow‐up. Sodium intake and urine sodium‐to‐potassium ratio were positively associated with circulating granulocyte concentrations after adjustment for confounders (β=0.03; P =0.028 and β=0.06; P Conclusions Sodium intake is positively associated with circulating granulocyte concentrations, and higher granulocyte concentrations associate with worse long‐term cardiovascular and renal outcomes. Given the recently established immune‐modulating effects of sodium and the role of immune cells in both cardiovascular and renal disease, causality for this pathway may need consideration in further studies.

Atopic dermatitis is associated with work productivity loss. Little is known about how patients perceive their work ability and quality of working life, and how this is affected by treatment. Our primary objective was to investigate work ability and quality of working life at baseline and during treatment in the long term. A registry‐embedded prospective observational cohort study was conducted consisting of patients with atopic dermatitis starting dupilumab in routine clinical care. The instruments used were the Work Ability Index (WAI; questions 1, 2, and 3) and the Quality of Working Life Questionnaire (QWLQ). Ninety‐three patients were included of whom 72 were (self‐)employed (77%). From baseline to 48 weeks, the mean WAI‐1 score (general work ability, range 0–10) improved from 6.8 (±2.0) to 7.9 (±1.3), WAI‐2 (physical work ability, range 1–5) from 3.7 (±0.9) to 4.3 (±0.7), and WAI‐3 (mental/emotional work ability, range 1–5) from 3.4 (±0.9) to 3.9 (±0.8) (p = 0.001, p = 0.005, p

Background: Noninvasive diagnostic methods are urgently required in disease stratification and monitoring in nonalcoholic fatty liver disease (NAFLD). Multiparametric magnetic resonance imaging (MRI) is a promising technique to assess hepatic steatosis, inflammation, and fibrosis, potentially enabling noninvasive identification of individuals with active and advanced stages of NAFLD. Purpose: To examine the diagnostic performance of multiparametric MRI for the assessment of disease severity along the NAFLD disease spectrum with comparison to histological scores. Study Type: Prospective, cohort. Population: Thirty-seven patients with NAFLD. Field Strength/Sequence: Multiparametric MRI at 3.0 T consisted of magnetic resonance (MR) spectroscopy (MRS) with multi-echo stimulated-echo acquisition mode, magnitude-based and three-point Dixon using a two-dimensional multi-echo gradient echo, MR elastography (MRE) using a generalized multishot gradient-recalled echo sequence and intravoxel incoherent motion (IVIM) using a multislice diffusion weighted single-shot echo-planar sequence. Assessment: Histological steatosis grades were compared to proton density fat fraction measured by MRS (PDFF MRS), magnitude-based MRI (PDFF MRI-M), and three-point Dixon (PDFF Dixon), as well as FibroScan® controlled attenuation parameter (CAP). Fibrosis and disease activity were compared to IVIM and MRE. FibroScan® liver stiffness measurements were compared to fibrosis levels. Diagnostic performance of all imaging parameters was determined for distinction between simple steatosis and nonalcoholic steatohepatitis (NASH). Statistical Tests: Spearman's rank test, Kruskal–Wallis test, Dunn's post-hoc test with Holm-Bonferroni P-value adjustment, receiver operating characteristic curve analysis. A P-value

Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses., This article provides real‐world European data on the results of relapsed/refractory large B‐cell lymphoma patients treated with tisagenlecleucel.

Contains fulltext : 233789.pdf (Publisher’s version ) (Open Access) AIMS: In non-ischaemic dilated cardiomyopathy (DCM), concomitant right ventricular (RV) dysfunction is frequently observed. This study sought to determine the correlation of RV dysfunction with several cardiac magnetic resonance (CMR) imaging characteristics in patients with DCM, and the prognostic value of RV dysfunction on all-cause mortality and ventricular arrhythmias (VA) was evaluated. METHODS AND RESULTS: Consecutive patients with DCM and left ventricular (LV) dysfunction (ejection fraction

The role of antihypertensives, especially Renin–Angiotensin–Aldosterone System inhibitors, is still debatable in COVID‐19‐related severity and outcome. Therefore, we search for a more global analysis of antihypertensive medication in relation to SAS‐CoV‐2 severity using prescription data worldwide. The association between the percentage use of different types of antihypertensive medications and mortality rates due to a SARS‐CoV‐2 infection during the first 3 weeks of the pandemic was analyzed using random effects linear regression models for 30 countries worldwide. Higher percentages of prescribed angiotensin receptor blockers (ARBs) (β, 95% confidence interval [CI]; −0.02 [−0.04 to −0.0012]; p = .042) and calcium channel blockers (CCBs) (β, 95% CI; −0.023 [−0.05 to −0.0028]; p = .0304) were associated with a lower first 3‐week SARS‐CoV‐2‐related death rate, whereas a higher percentage of prescribed angiotensin‐converting enzyme inhibitors (ACEis) (β, 95% CI; 0.03 [0.0061–0.05]; p = .0103) was associated with a higher first 3‐week death rate, even when adjusted for age and metformin use. There was no association between the amount of prescribed beta‐blockers (BBs) and diuretics (Diu) and the first 3‐week death rate. When analyzing the combination of drugs that is used by at least 50% of antihypertensive users, within the different countries, countries with the lowest first 3‐week death rates had at least an angiotensin receptor blocker as one of the most often prescribed antihypertensive medications (ARBs/CCBs: [β, 95% CI; −0.02 [−0.03 to −0.004]; p = .009], ARBs/BBs: [β, 95% CI; −0.03 [−0.05 to −0.006]; p = .01]). Finally, countries prescribing high‐potency ARBs had lower first 3‐week ARBs. In conclusion, ARBs and CCB seem to have a protective effect against death from SARS‐CoV‐2 infection., Highlights Higher percentages of prescribed angiotensin receptor blockers and calcium channel blockers were associated with a lower first 3‐week SARS‐CoV‐2‐related death rate.Higher percentage of prescribed angiotensin‐converting enzyme was associated with a higher first 3‐week death rates.Countries with the lowest first 3‐week death rates had at least an angiotensin receptor blocker as one of the most often prescribed antihypertensive medications.

Disease modelling plays a fundamental role in biomedical research, even more in virology where the virus depends strictly on its host for replication. Although animal models are extensively used in virology, there is an increasing demand for animal-free research. Therefore, during this transition, it is crucial to learn and take advantage of animal research to better implement new emerging models. In this study, we aim to systematically review the translation from animal models to humans for the well-characterized viral disease polio, as a reference for novel in vitro models in virology. We found a high risk of bias in the included studies and a large diversity of animal models. Moreover, we showed that animal models for studying poliovirus pathogenesis are mainly discrimination models focusing on specific aspects of the disease allowing an insightful understanding of the complex poliovirus infection. Our review underlines the importance of proper standardization of new emerging models and a careful interpretation of the results from discrimination models.

Objective: To assess the psychometric properties of 8 pediatric Patient-Reported Outcomes Measurement Information System (PROMIS) item banks in a clinical sample of children with juvenile idiopathic arthritis (JIA). Methods: A total of 154 Dutch children (mean ± SD age 14.4 ± 3.0 years; range 8–18 years) with JIA completed 8 pediatric version 1.0 PROMIS item banks (anger, anxiety, depressive symptoms, fatigue, pain interference, peer relationships, physical function mobility, physical function upper extremity) twice and the Pediatric Quality of Life Inventory (PedsQL) and the Childhood Health Assessment Questionnaire (C-HAQ) once. Structural validity of the item banks was assessed by fitting a graded response model (GRM) and inspecting GRM fit (comparative fit index [CFI], Tucker-Lewis index [TLI], and root mean square error of approximation [RMSEA]) and item fit (S-X2 statistic). Convergent validity (with PedsQL/C-HAQ subdomains) and discriminative validity (active/inactive disease) were assessed. Reliability of the item banks, short forms, and computerized adaptive testing (CAT) was expressed as the SE of theta (SE[θ]). Test–retest reliability was assessed using intraclass correlation coefficients (ICCs) and smallest detectable change. Results: All item banks had sufficient overall GRM fit (CFI >0.95, TLI >0.95, RMSEA 2 P > 0.001). High correlations (>0.70) were found between most PROMIS T scores and hypothesized PedsQL/C-HAQ (sub)domains. Mobility, pain interference, and upper extremity item banks were able to discriminate between patients with active and inactive disease. Regarding reliability, PROMIS item banks outperformed legacy instruments. Post hoc CAT simulations outperformed short forms. Test–retest reliability was strong (ICC >0.70) for all full-length item banks and short forms, except for the peer relationships item bank. Conclusion: The pediatric PROMIS item banks displayed sufficient psychometric properties for Dutch children with JIA. PROMIS item banks are ready for use in clinical research and practice for children with JIA.

Background:Psychotropic drugs are frequently prescribed to people with dementia in nursing homes although severe adverse events and side effects are common. Less is known about the prevalence and types of psychotropic drug prescription in primary care for people with dementia.Objective:This study examined the prevalence of psychotropic drug prescriptions in primary care among persons with dementia from the year of diagnosis onwards.Methods:A longitudinal observational study using electronic health record (EHR) data was conducted. People with dementia were selected from EHR data of 451 general practices in the Netherlands. Age and gender-adjusted psychotropic drug prescription rates were calculated per 1000 person-years from the year the dementia diagnosis was first recorded in general practice up to 8 years after diagnosis.Results:Data of 15,687 patients were analyzed. The prescription rate of psychotropic drugs (not including antidementia drugs) was 420 per 1000 person-years (95% CI 409; 431) in the first year after the recorded dementia diagnosis, which increased to 801 per 1000 person-years (95% CI 649; 989) in the eighth year. The most frequently prescribed drugs were antidepressants, antipsychotics, and antidementia drugs, followed by anxiolytics, hypnotics, and antiepileptics.Conclusions:After a dementia diagnosis is recorded in general practice, the prevalence of psychotropic drug prescriptions is substantial and increases steadily during the disease trajectory of persons with dementia. Although the (in)appropriateness of prescribing was not assessed, these insights may stimulate primary care clinicians to (re)consider their prescription policy of psychotropics for people with dementia more carefully.

Background Alterations in the GBA gene (NM_000157.3) are the most important genetic risk factor for Parkinson's disease (PD). Biallelic GBA mutations cause the lysosomal storage disorder Gaucher's disease. The GBA variants p.E365K and p.T408M are associated with PD but not with Gaucher's disease. The pathophysiological role of these variants needs to be further explored. Objective This study analyzed clinical, neuropsychological, metabolic, and neuroimaging phenotypes of patients with PD carrying the GBA variants p.E365K and p.T408M. Methods GBA was sequenced in 56 patients with mid-stage PD. Carriers of GBA variants were compared with noncarriers regarding clinical history and symptoms, neuropsychological features, metabolomics, and multimodal neuroimaging. Blood plasma gas chromatography coupled to mass spectrometry, 6-[18 F]fluoro-L-Dopa positron emission tomography (PET), [18 F]fluorodeoxyglucose PET, and resting-state functional magnetic resonance imaging were performed. Results Sequence analysis detected 13 heterozygous GBA variant carriers (7 with p.E365K, 6 with p.T408M). One patient carried a GBA mutation (p.N409S) and was excluded. Clinical history and symptoms were not significantly different between groups. Global cognitive performance was lower in variant carriers. Metabolomic group differences were suggestive of more severe PD-related alterations in carriers versus noncarriers. Both PET scans showed signs of a more advanced disease; [18 F]fluorodeoxyglucose PET and functional magnetic resonance imaging showed similarities with Lewy body dementia and PD dementia in carriers. Conclusions This is the first study to comprehensively assess (neuro-)biological phenotypes of GBA variants in PD. Metabolomics and neuroimaging detected more significant group differences than clinical and behavioral evaluation. These alterations could be promising to monitor effects of disease-modifying treatments targeting glucocerebrosidase metabolism. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

© 2020 The Authors. Journal of Orthopaedic Research® published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.Mechanical stress determines bone mass and structure. It is not known whether mechanical loading affects expression of bone regulatory genes in a combined deficiency of estrogen and vitamin D. We studied the effect of mechanical loading on the messenger RNA (mRNA) expression of bone regulatory genes during vitamin D and/or estrogen deficiency. We performed a single bout in vivo axial loading with 14 N peak load, 2 Hz frequency and 360 cycles in right ulnae of nineteen weeks old female control Wistar rats with or without ovariectomy (OVX), vitamin D deficiency and the combination of OVX and vitamin D deficiency (N = 10/group). Total bone RNA was isolated 6 hours after loading, and mRNA expression was detected of Mepe, Fgf23, Dmp1, Phex, Sost, Col1a1, Cyp27b1, Vdr, and Esr1. Serum levels of 25(OH)D, 1,25(OH)2D and estradiol were also measured at this time point. The effect of loading, vitamin D and estrogen deficiency and their interaction on bone gene expression was tested using a mixed effect model analysis. Mechanical loading significantly increased the mRNA expression of Mepe, and Sost, whereas it decreased the mRNA expression of Fgf23 and Esr1. Mechanical loading showed a significant interaction with vitamin D deficiency with regard to mRNA expression of Vdr and Esr1. Mechanical loading affected gene expression of Mepe, Fgf23, Sost, and Esr1 independently of vitamin D or estrogen, indicating that mechanical loading may affect bone turnover even during vitamin D deficiency and after menopause.

Aims:\ud Several studies have shown that older patients with heart failure with reduced ejection fraction (HFrEF) are undertreated. The aim of this study was to evaluate the association of up‐titration of angiotensin‐converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB) and beta‐blockers on outcome across the age spectrum in HFrEF patients.\ud \ud Methods and results:\ud We analysed HFrEF patients on sub‐optimal doses of ACEI/ARB and/or beta‐blockers from the BIOSTAT‐CHF study stratified by age. Patients underwent a 3‐month up‐titration period. We used inverse probability weighting to adjust for the likelihood of successful up‐titration to determine the association of achieved dose with mortality and/or heart failure hospitalisation, testing for an interaction with age. Over a median follow‐up of 21 months in 1720 HFrEF patients (76.5% male, mean age 67 years), the primary outcome occurred in 558 patients. Increased percentage of target dose of ACEI/ARB and beta‐blocker achieved at 3 months were both significantly associated with reduced incidence of the primary outcome, [ACEI‐ARB: hazard ratio (HR) per 12.5% increase in dose: 0.92, 95% confidence interval (CI) 0.91–0.94, P

Objective To develop a core outcome set for trials on the treatment of hyperemesis gravidarum (HG). Design Identification of outcomes is followed by a modified Delphi survey combined with a consensus development meeting and a consultation round. Setting An international web-based survey combined with a consensus development meeting. Population Stakeholders including researchers; women with lived experience of HG and their families; obstetric health professionals; and other health professionals. Methods We used systematic review, semi-structured patient interviews, closed group sessions and Steering Committee input to identify potential core outcomes. We conducted two web-based survey rounds, followed by a face-to-face consensus development meeting and a web-based consultation round. Main outcome measures A core outcome set for research on HG. Results Fifty-six potential outcomes were identified. The modified Delphi process was completed by 125 stakeholders, the consensus development meeting by 20 stakeholders and the consultation round by 96 stakeholders. Consensus was reached in ten domains on 24 outcomes: nausea; vomiting; inability to tolerate oral fluids or food; dehydration; weight difference; electrolyte imbalance; intravenous fluid treatment; use of medication for hyperemesis gravidarum; hospital treatment; treatment compliance; patient satisfaction; daily functioning; maternal physical or mental or emotional wellbeing; short- and long-term adverse effects of treatment; maternal death; pregnancy complications; considering or actually terminating a wanted pregnancy; preterm birth; small for gestational age; congenital anomalies; neonatal morbidity and offspring death). Conclusions This core outcome set will help standardise outcome reporting in HG trials. Tweetable abstract A core outcome set for treatment of hyperemesis gravidarum in order to create high-quality evidence.

Objective: What are the cost per live birth and the incremental cost of preventing a miscarriage with preimplantation genetic testing for aneuploidy (PGT-A) by polar body biopsy and array-based comprehensive genome hybridisation (aCGH) versus regular IVF/ICSI without PGT-A for infertility treatment in women 36–40 years of age?. Design: Decision tree model. Population: A randomised clinical trial on PGT-A (ESTEEM study). Methods: Two treatment strategies were compared: one cycle of IVF/ICSI with or without PGT-A. Costs and effects were analysed with this model for four different cost scenarios: high-, higher medium, lower medium and low-cost. Base case, sensitivity, threshold, and probabilistic sensitivity analyses were used to examine the cost-effectiveness implications of PGT-A. Results: PGT-A increased the cost per live birth by approximately 15% in the high-cost scenario to approximately 285% in the low-cost scenario. Threshold analysis revealed that PGT-A would need to be associated with an absolute increase in pregnancy rate by 6% to >39% or, alternatively, would need to be US$2,969 (high-cost scenario) to US$4,888 (low-cost scenario) cheaper. The incremental cost to prevent one miscarriage by PGT-A using the base case assumptions was calculated to be US$34,427 (high-cost scenario) to US$51,146 (low-cost scenario). A probabilistic sensitivity analysis showed cost-effectiveness for PGT-A from 1.9% (high-cost scenario) to 0.0% (low-cost scenario) of calculated samples. Conclusions: While avoiding unnecessary embryo transfers and miscarriages are important goals, patients and doctors need to be aware of the high-cost implications of applying PGT-A using aCGH on polar bodies. Tweetable abstract: PGT-A by polar body biopsy and comprehensive genome hybridisation increases cost per live birth and requires high financial spending per miscarriage averted.

AIMS: Heart failure (HF) patients are at high-risk of cardiovascular (CV) events, including CV death. Nonetheless, a substantial proportion of these patients die from non-CV causes. Identifying patients at higher risk for each individual event may help selecting patients for clinical trials and tailoring cardiovascular therapies. The aims of the present study are to: (i) characterize patients according to CV vs. non-CV death; (ii) develop models for the prediction of the respective events; (iii) assess the models' performance to differentiate CV from non-CV death. METHODS AND RESULTS: This study included 2309 patients with HF from the BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Competing-risk models were used to assess the best combination of variables associated with each cause-specific death. Results were validated in an independent cohort of 1738 HF patients. The best model to predict CV death included low blood pressure, estimated glomerular filtration rate ≤ 60 mL/min, peripheral oedema, previous HF hospitalization, ischaemic HF, chronic obstructive pulmonary disease, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and troponin (c-index = 0.73). The non-CV death model incorporated age > 75 years, anaemia and elevated NT-proBNP (c-index = 0.71). Both CV and non-CV death rose by quintiles of the risk scores; yet these models allowed the identification of patients in whom absolute CV death rates clearly outweigh non-CV death ones. These findings were externally replicated, but performed worse in a less severely diseased population. CONCLUSIONS: Risk models for predicting CV and non-CV death allowed the identification of patients at higher absolute risk of dying from CV causes (vs. non-CV ones). Troponin helped in predicting CV death only, whereas NT-proBNP helped in the prediction of both CV and non-CV death. These findings can be useful both for tailoring therapies and for patient selection in HF trials in order to attain CV event enrichment.

Background: Dialysis is associated with frequent hospitalisations. Studies comparing hospitalisations between peritoneal dialysis (PD) and haemodialysis (HD) report conflicting results and mostly analyse data of patients that remain on their initial dialysis modality. This cohort study compares hospitalisations between PD and HD patients taking into account transitions between modalities. Methods: The Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes collected hospitalisation data of patients who started dialysis between 2012 and 2017. Primary outcome was hospitalisation rate, analysed with a multi-state model that attributed each hospitalisation to the current dialysis modality. Results: In total, 695 patients (252 PD, 443 HD) treated in 31 Dutch hospitals were included. The crude hospitalisation rate for PD was 2.3 (± 5.0) and for HD 1.4 (± 3.2) hospitalisations per patient-year. The adjusted hazard ratio for hospitalisation rate was 1.1 (95%CI 1.02–1.3) for PD compared with HD. The risk for first hospitalisation was 1.3 times (95%CI 1.1–1.6) higher for PD compared with HD during the first year after dialysis initiation. The number of hospitalisations and number of hospital days per patient-year were significantly higher for PD. The most common causes of PD and HD hospitalisations were peritonitis (23%) and vascular access-related problems (33%). Conclusion: PD was associated with higher hospitalisation rate, higher risk for first hospitalisation and higher number of hospitalisations compared with HD. Since the PD hospitalisations were mainly caused by peritonitis, more attention to infection prevention is necessary for reducing the number of hospitalisations in the future.

Importance: The prevalence of hyperacusis and its relationship with mental and general health is unknown in a nonclinical sample. Therefore, we aimed to determine the prevalence of hyperacusis and its relation with hearing, general and mental health in a population-based study. Study Design: Prospective population-based study. Material and Methods: This study uses data from the Busselton Healthy Ageing Study (BHAS). A sample of 5,107 eligible inhabitants aged 45 to 70 years completed a detailed questionnaire and a clinical assessment. A positive answer to “Do you consider yourself sensitive or intolerant to everyday sounds” was used to indicate hyperacusis. Logistic regression was used to examine the association between hearing, mental and general health factors, and hyperacusis. Results: Of 5,107 participants, 775 (15.2%) reported hyperacusis. The majority of participants with hyperacusis reported an occasional effect on daily life (72.0%). Being female, older in age, having a lower income, physical or mental health difficulties, more severe hearing loss, and tinnitus were all associated with the presence of hyperacusis. Individuals who experience hearing impairment, poorer general or mental health have a higher possibility of hyperacusis having an effect on their daily life. Conclusions: In this community population-based cohort study, we found a prevalence of hyperacusis of 15.2%. Individuals with hearing loss, mental health problems, and lower physical health have a higher possibility of experiencing effects on their daily life associated with their hyperacusis. Unravelling the relationship between hyperacusis hearing, general and mental health can be of major importance for a better understanding of the condition and its consequences. Level of Evidence: 2 Laryngoscope, 131:E2887–E2896, 2021.

BACKGROUND: Long-term sequelae of acute pulmonary embolism (PE) include decreased quality of life (QoL). Evidence suggests that adequacy of initial anticoagulant treatment in the acute phase of venous thrombosis has a key impact on late postthrombotic complications. We hypothesize that patients with acute PE treated with edoxaban for acute PE experience have improved QoL compared to those treated with warfarin. METHODS: Patients with PE who participated in the Hokusai-VTE trial were contacted between June 2017 and September 2020 for a single long-term follow-up visit. Main outcomes were the generic and disease-specific QoL measured by the 36-Item Short Form Health Survey (SF-36) and Pulmonary Embolism Quality of Life questionnaire. RESULTS: We included 251 patients from 26 centers in eight countries, of which 129 (51%) had been assigned to edoxaban and 122 (49%) to warfarin. Patient- and thrombus-specific characteristics were similar in both groups. Mean time since randomization in the Hokusai-VTE trial was 7.0 years (standard deviation, 1.0). No relevant or statistical differences were observed in the QoL for patients treated with edoxaban compared to patients treated with warfarin. The mean difference between patients treated with edoxaban and patients with PE treated with warfarin was 0.8 (95% confidence interval [CI]. -1.6 to 3.2) for the SF-36 summary mental score and 1.6 (95% CI, -0.9 to 4.1) for summary physical score. CONCLUSION: Our findings indicate that patients with an index PE treated with edoxaban or warfarin have a similar long-term QoL. Since our study was a follow-up study from a well-controlled clinical trial setting, future studies should be designed in a daily clinical practice setting. We suggest a longitudinal design for investigation of changes in QoL over time. ispartof: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS vol:5 issue:5 ispartof: location:United States status: published

Accurate assessment of burn wound depth and the associated healing potential is vital in determining the need for surgical treatment in burns. Infrared thermography measures the temperature of the burn wound noninvasively, thereby providing indirect information on its blood flow. Previous research demonstrated that a small, low-priced, handheld thermal imager has an excellent reliability, but a moderate validity for measuring burn wound healing potential. A new and more sensitive version of this convenient device has become available. The aim of this study was to evaluate the validity of thermography for measuring burn wound healing potential, compared to Laser Doppler Imaging (LDI) as a reference standard. Thermal images and LDI scans were obtained from burn wounds between 2 and 5 days postburn. Temperature differences between burned and nonburned skin (ΔT) were calculated. To evaluate validity, ΔT values were compared to the healing potential categories assessed by LDI. Two receiver operating characteristic curves were created and two ΔT cutoff values were calculated to illustrate the ability to discriminate between burn wounds that heal in a time period of less than 14 days, between 14 and 21 days, and more than 21 days. Between June and October 2018, 43 burn wounds in 32 patients were measured. ΔT cutoff values of 0.6°C (sensitivity 68%, specificity 95%) and −2.3°C (sensitivity 30%, specificity 95%) were calculated to discriminate between burn wounds that heal in 21 days, respectively. This study shows a good validity of the feasible thermal imager for the assessment of burn wound healing potential. Therefore, we consider it a promising technique to be used for triage in local hospitals and general practices, and as a valuable addition to clinical evaluation in burn centers.

Objective: To evaluate whether improvement of proprioception, pain, or dynamic knee instability mediates the effect of wearing a soft knee brace on activity limitations in patients with knee osteoarthritis (OA). Methods: We conducted an analysis of data for 44 patients with knee OA who were enrolled in a laboratory-based trial evaluating the effect of wearing a commercially available soft knee brace. Activity limitations were assessed with the 10-meter walk test and the Get Up and Go test. Knee joint proprioception was assessed by an active joint position sense test; pain was assessed on a numeric rating scale (NRS) (range 0–10); pressure pain threshold (PPT) was assessed with a hand-held pressure algometer; dynamic knee instability was expressed by the perturbation response, i.e., a measure reflecting a deviation in mean knee varus–valgus angle after a controlled mechanical perturbation on a treadmill, with respect to level walking. Mediation analysis was conducted using the product of coefficients approach. Confidence intervals were calculated with a bootstrap procedure. Results: A decrease in pain (scored on an NRS) and a decrease in dynamic knee instability mediated the effect of wearing a soft knee brace on the reduction of activity limitations (P < 0.05), while changes in proprioception and PPT did not mediate this effect (P > 0.05). Conclusion: This study shows that decreased pain and reduced dynamic knee instability are pathways by which wearing a soft knee brace decreases activity limitations in patients with knee OA.

Daily clinical practice has shown that patients are often hesitant to undergo a lumbar puncture (LP) because of unfamiliarity with the awaiting procedure and/or unrealistic ideas concerning post-LP complications. In light of increased number of LPs in diagnostic and research settings, our institute has developed an educational video for patients and caregivers in which we inform them about and prepare them for the LP procedure. This video was based on the latest literature and was developed with the help of communication experts, medical doctors, and two separate patient panels., Highlights • The use of lumbar punctures (LPs) in research and diagnostic settings is growing. • Often patients are hesitant to undergo an LP because of unfamiliarity with the procedure. • Our educational video helps inform about and prepare patients for the LP procedure.

Objective To study the effect of an intervention based on Crew Resource Management team training, including a tool for structured communication, on adverse perinatal and maternal outcomes. Design Stepped wedge. Setting The Netherlands. Population or sample Registry data of 8123 women referred from primary care to a hospital during childbirth, at >= 32.0 weeks of singleton gestation and with no congenital abnormalities, in the period 2012-15. Methods Obstetric teams of five hospitals and their surrounding primary-care midwifery practices participated in the intervention. In total, 49 team training sessions were organised for 465 care professionals (75.5% participated). Adverse perinatal and maternal outcomes before, during and after the intervention were analysed using multivariate logistic regression analyses. Main Outcome Measures Adverse Outcome Index (AOI-5), a composite measure involving; intrapartum or neonatal death, admission to neonatal intensive care unit, Apgar

As part of the Biomedical Data Translator program, the National Center for Advancing Translational Sciences (NCATS) has assembled 11 teams comprising nearly 200 team members drawn from 28 institutions. Roughly 1 year into the feasibility phase, we describe the program's conception, the rapid coalescence of teams and team members, the novel mechanisms of interaction and communication, and the emergent collaborative culture and community that we believe are driving the early success of the program.

Journal of the American Heart Association 10(4), e017405 (2021). doi:10.1161/JAHA.120.017405, Published by American Heart Association, New York, NY

International audience; We review knowledge on applications of sustained aerobic swimming as a tool to promote productivity and welfare of farmed fish species. There has been extensive interest in whether providing active species with a current to swim against can promote growth. The results are not conclusive but the studies have varied in species, life stage, swimming speed applied, feeding regime, stocking density and other factors. Therefore, much remains to be understood about mechanisms underlying findings of 'swimming-enhanced growth', in particular to demonstrate that swimming can improve feed conversion ratio and dietary protein retention under true aquaculture conditions. There has also been research into whether swimming can alleviate chronic stress, once again on a range of species and life stages. The evidence is mixed but swimming does improve recovery from acute stresses such as handling or confinement. Research into issues such as whether swimming can improve immune function and promote cognitive function is still at an early stage and should be encouraged. There is promising evidence that swimming can inhibit precocious sexual maturation in some species, so studies should be broadened to other species where precocious maturation is a problem. Swimming performance is a heritable trait and may prove a useful selection tool, especially if it is related to overall robustness. More research is required to better understand the advantages that swimming may provide to the fish farmer, in terms of production, mitigation and selection.

Rationale: Identification of peptides and proteins is a challenging task in mass spectrometry–based proteomics. Knowledge of the number of sulfur atoms can improve the identification of peptides and proteins. Methods: In this article, we propose a method for the prediction of S-atoms based on the aggregated isotope distribution. The Mahalanobis distance is used as dissimilarity measure to compare mass- and intensity-based features from the observed and theoretical isotope distributions. Results: The relative abundance of the second and the third aggregated isotopic variants (as compared to the monoisotopic one) and the mass difference between the second and third aggregated isotopic variants are the most important features to predict the number of S-atoms. Conclusions: The mass and intensity accuracies of the observed aggregated isotopic variants are insufficient to accurately predict the number of atoms. However, using a limited set of predictions for a peptide, rather than predicting a single number of S-atoms, has a reasonably high prediction accuracy.

Contains fulltext : 235296.pdf (Publisher’s version ) (Open Access) BACKGROUND: In premenopausal women, treatment with direct oral factor Xa inhibitors is associated with an increased risk of heavy menstrual bleeding (HMB) compared with vitamin K antagonists (VKA). Treatment with the direct oral thrombin inhibitor dabigatran appears to be associated with a reduced risk of HMB compared with VKA. These findings come from small observational studies or post hoc analyses of trials in which HMB was not a primary outcome. Use of tranexamic acid during the menstrual period may be effective in patients with HMB, but prospective data regarding efficacy and safety in patients on anticoagulant treatment are lacking. RATIONALE AND DESIGN: A direct comparison of a factor Xa inhibitor and a thrombin inhibitor with HMB as primary outcome, as well as an evaluation of the effects of adding tranexamic acid in women with anticoagulant-associated HMB is highly relevant for clinical practice. The MEDEA study is a randomized, open-label, pragmatic clinical trial to evaluate management strategies in premenopausal women with HMB associated with factor Xa inhibitor therapy. OUTCOMES: Women using factor Xa inhibitors with proven HMB, as assessed by a pictorial blood loss assessment chart (PBAC) score of >150, will be randomized to one of three study arms: (i) switch to dabigatran; (ii) continue factor Xa inhibitor with addition of tranexamic acid during the menstrual period; or (iii) continue factor Xa inhibitor without intervention. The primary outcome is the difference in PBAC score before and after randomization. Here, we present the rationale and highlight several unique features in the design of the study.