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Background The current childhood obesity pandemic is likely to result in an increased risk of chronic kidney disease (CKD) later in life. Correlations between obesity-related comorbidities and kidney function can be found, but it is unclear to what extent this is caused by bias due to different mathematical forms of the estimated glomerular filtration rate (eGFR) equations. The present study aimed to analyze correlations between obesity-related comorbidities and different eGFR equations and to investigate whether rescaled serum creatinine (SCr/Q) for sex and age or height might be an alternative biomarker for kidney function estimation. Methods This cross-sectional cohort study included 600 children with overweight and obesity. Mean age was 12.20 ± 3.28 years, 53.5% were female, and mean BMI z-score was 3.31 ± 0.75. All children underwent a comprehensive assessment that included anthropometrical and blood pressure measurements, laboratory examination, air displacement plethysmography, and polysomnography. Qage and Qheight polynomials were used to rescale SCr and multiple creatinine-based eGFR equations were compared. Results SCr/Q and almost all GFR estimations significantly correlated with a waist-to-hip ratio, fat mass, homeostasis model assessment for insulin resistance, and triacylglyceride, HDL cholesterol, alanine transaminase, and serum uric acid concentrations. Multiple correlations, however, were not confirmed by all equations, which suggests dependency on the mathematical form of the different eGFR equations. Conclusions Correlations between obesity-related comorbidities and creatinine-based eGFR are present in children with overweight and obesity, but depend to a large extent on the eGFR equation of choice. SCr/Q might be an alternative biomarker for assessing correlations between obesity-related comorbidities and kidney function in children with overweight and obesity. Graphical Abstract

Aims There is considerable controversy regarding optimal management of patients with paraesophageal hiatus hernia (pHH). This survey aims at identifying recommended strategies for work-up, surgical therapy, and postoperative follow-up using Delphi methodology. Methods We conducted a 2-round, 33-question, web-based Delphi survey on perioperative management (preoperative work-up, surgical procedure and follow-up) of non-revisional, elective pHH among European surgeons with expertise in upper-GI. Responses were graded on a 5-point Likert scale and analyzed using descriptive statistics. Items from the questionnaire were defined as “recommended” or “discouraged” if positive or negative concordance among participants was > 75%. Items with lower concordance levels were labelled “acceptable” (neither recommended nor discouraged). Results Seventy-two surgeons with a median (IQR) experience of 23 (14–30) years from 17 European countries participated (response rate 60%). The annual median (IQR) individual and institutional caseload was 25 (15–36) and 40 (28–60) pHH-surgeries, respectively. After Delphi round 2, “recommended” strategies were defined for preoperative work-up (endoscopy), indication for surgery (typical symptoms and/or chronic anemia), surgical dissection (hernia sac dissection and resection, preservation of the vagal nerves, crural fascia and pleura, resection of retrocardial lipoma) and reconstruction (posterior crurorrhaphy with single stitches, lower esophageal sphincter augmentation (Nissen or Toupet), and postoperative follow-up (contrast radiography). In addition, we identified “discouraged” strategies for preoperative work-up (endosonography), and surgical reconstruction (crurorrhaphy with running sutures, tension-free hiatus repair with mesh only). In contrast, many items from the questionnaire including most details of mesh augmentation (indication, material, shape, placement, and fixation technique) were “acceptable”. Conclusions This multinational European Delphi survey represents the first expert-led process to identify recommended strategies for the management of pHH. Our work may be useful in clinical practice to guide the diagnostic process, increase procedural consistency and standardization, and to foster collaborative research.

BACKGROUND: There is a lack of evidence on acute kidney injury (AKI) and new-onset chronic kidney disease (CKD) after surgery for localised renal masses (LRMs) in patients with two kidneys and preserved baseline renal function. OBJECTIVE: To evaluate the prevalence and risk of AKI and new-onset clinically significant CKD (csCKD) in patients with a single renal mass and preserved renal function after being treated with partial (PN) or radical (RN) nephrectomy. DESIGN SETTING AND PARTICIPANTS: We queried our prospectively maintained databases to identify patients with a preoperative estimated glomerular filtration rate (eGFR) of ≥60 ml/min/1.73 m2 and a normal contralateral kidney who underwent PN or RN for a single LRM (cT1-T2N0M0) between January 2015 and December 2021 at four high-volume academic institutions. INTERVENTION: PN or RN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The outcomes of this study were AKI at hospital discharge and the risk of new-onset csCKD, defined as eGFR

Amyotrophic Lateral Sclerosis (ALS) is an incurable neurodegenerative condition. Despite significant advances in pre-clinical models that enhance understanding of disease pathobiology, translation of candidate drugs to effective human therapies has been disappointing. There is increasing recognition of the need for a precision medicine approach toward drug development, as many failures in translation can be attributed in part to disease heterogeneity in humans. PRECISION-ALS is an academic industry collaboration between clinicians, Computer Scientists, Information engineers, technologists, data scientists and industry partners that will address the key clinical, computational, data science and technology associated research questions to generate a sustainable precision medicine based approach toward new drug development. Using extant and prospectively collected population based clinical data across nine European sites, PRECISION-ALS provides a General Data Protection Regulation (GDPR) compliant framework that seamlessly collects, processes and analyses research-quality multimodal and multi-sourced clinical, patient and caregiver journey, digitally acquired data through remote monitoring, imaging, neuro-electric-signaling, genomic and biomarker datasets using machine learning and artificial intelligence. PRECISION-ALS represents a first-in-kind modular transferable pan-European ICT framework for ALS that can be easily adapted to other regions that face similar precision medicine related challenges in multimodal data collection and analysis. ispartof: AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION vol:24 issue:5-6 ispartof: location:England status: Published online

What Is Known? In elderly inpatients, potential inappropriate medication (PIM) is a prominent prescription challenge. However, there is limited information available regarding PIM in patients with central nervous system (CNS) diseases in China. Objective. To evaluate and improve the rational use of drugs for the treatment of CNS diseases in elderly inpatients. Method. A retrospective, cross-sectional study was conducted among elderly inpatients (≥65 years) admitted to the Ninth People’s Hospital of Zhengzhou in China from March 2020 to March 2021. PIM was identified based on the 2019 Beers criteria at admission and discharge. The patients recruited in March 2020 were considered a baseline group, which was used as a comparison to evaluate PIM of CNS disease-related drugs in June 2020, September 2020, December 2020, and March 2021. Results. A total of 1500 patients were included in the evaluation. There was a statistically significant difference in the number of average hospitalization days, drug varieties used, and PIM detection ( p < 0.05 ), as determined by X2 test. A total of 332 cases of PIM were identified, and 226 cases were detected for the interaction with CNS disease dementia. Multifactor logistic regression analysis showed that male, length of stay ≥15 days, and >10 medication types were risk factors for the occurrence of PIM ( p < 0.05 ). After clinical supervision and training based on the High-Risk Drug Replacement Program for the Elderly, the rate of irrational medication under medical advice decreased from 34.67% in March 2020 to 14.0% ( p < 0.001 ) in March 2021. What Is New and Conclusion. There was certain rationality based on the High-Risk Drug Replacement Program for the Elderly, and the rates of selective serotonin reuptake inhibitor, 5-hydroxylamine/norepinephrine re-intake inhibitor, rotenone, quetiapine, and proton pump inhibitor use were improved. These results provide a reference for the continuous improvement of the PIM catalog for elderly patients.

Background There is evidence for a polygenic contribution to psychosis. One targetable mechanism through which polygenic variation may impact on individuals and interact with the social environment is stress sensitization, characterized by elevated reactivity to minor stressors in daily life. The current study aimed to investigate whether stress reactivity is modified by polygenic risk score for schizophrenia (PRS) in cases with enduring non-affective psychotic disorder, first-degree relatives of cases, and controls. Methods We used the experience sampling method to assess minor stressors, negative affect, positive affect and psychotic experiences in 96 cases, 79 first-degree relatives, i.e. siblings, and 73 controls at wave 3 of the Dutch Genetic Risk and Outcome of Psychosis (GROUP) study. Genome-wide data were collected at baseline to calculate PRS. Results We found that associations of momentary stress with psychotic experiences, but not with negative and positive affect, were modified by PRS and group (all pFWEv. low level of PRS. By contrast, controls with high PRS showed more intense psychotic experiences in response to stress compared to those with low PRS. Conclusions This tentatively suggests that polygenic risk may operate in different ways than previously assumed and amplify reactivity to stress in unaffected individuals but operate as a resilience factor in relatives by attenuating their stress reactivity.

Part of the appeal of attachment language is that it feels near to our everyday experience, as terms like 'attachment', 'security' or 'disorganisation' feel readily recognisable. Yet, not one of these terms is used by academic attachment researchers in line with ordinary language. This has hindered the evidence-based use of attachment in practice, the feedback loop from practice to research and the dialogue between attachment researchers in developmental psychology and in social psychology. This paper pinpoints the difficulties arising from the existence of multiple versions of 'attachment theory' that use exactly the same terms, held by communities that assume that they are referring to the same thing and with little infrastructure to help them discover otherwise. When we talk past one another, the different communities with a stake in knowledge of attachment are obstructed from genuinely learning from one another, drawing on their respective strengths and pursuing collaborations. One factor contributing to this situation has been the use of attachment terminology with technical meanings, but often without setting out clear definitions. We here introduce a guide to attachment terminology used by the academic community, which has recently been published on the website of the Society for Emotion and Attachment Studies. The guide is meant for researchers, clinicians and everyone concerned with attachment to increase understanding of the technical meaning of important terminology used by researchers, and support the quality of discussions between researchers, and between researchers and clinicians and other publics. ispartof: JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY vol:64 issue:5 pages:839-843 ispartof: location:England status: published

OBJECTIVES: In biomedical research, spin is the overinterpretation of findings, and it is a growing concern. To date, the presence of spin has not been evaluated in prognostic model research in oncology, including studies developing and validating models for individualized risk prediction. STUDY DESIGN AND SETTING: We conducted a systematic review, searching MEDLINE and EMBASE for oncology-related studies that developed and validated a prognostic model using machine learning published between 1st January, 2019, and 5th September, 2019. We used existing spin frameworks and described areas of highly suggestive spin practices. RESULTS: We included 62 publications (including 152 developed models; 37 validated models). Reporting was inconsistent between methods and the results in 27% of studies due to additional analysis and selective reporting. Thirty-two studies (out of 36 applicable studies) reported comparisons between developed models in their discussion and predominantly used discrimination measures to support their claims (78%). Thirty-five studies (56%) used an overly strong or leading word in their title, abstract, results, discussion, or conclusion. CONCLUSION: The potential for spin needs to be considered when reading, interpreting, and using studies that developed and validated prognostic models in oncology. Researchers should carefully report their prognostic model research using words that reflect their actual results and strength of evidence. ispartof: JOURNAL OF CLINICAL EPIDEMIOLOGY vol:157 pages:120-133 ispartof: location:United States status: published

Background The impact of extent of resection (EOR), residual tumor volume (RTV), and gross-total resection (GTR) in glioblastoma subgroups is currently unknown. This study aimed to analyze their impact on patient subgroups in relation to neurological and functional outcomes. Methods Patients with tumor resection for eloquent glioblastoma between 2010 and 2020 at 4 tertiary centers were recruited from a cohort of 3919 patients. Results One thousand and forty-seven (1047) patients were included. Higher EOR and lower RTV were significantly associated with improved overall survival (OS) and progression-free survival (PFS) across all subgroups, but RTV was a stronger prognostic factor. GTR based on RTV improved median OS in the overall cohort (19.0 months, P Conclusions Maximum resection was especially beneficial in the subgroups aged

Immunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host's immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms. ispartof: ONCOIMMUNOLOGY vol:12 issue:1 ispartof: location:United States status: accepted

Owing to growing uncontrolled land-use change and urban expansion, farmers in urban fringes are struggling to sustain their livelihood. Farmers have been expressing their dissatisfaction at different times. This study analyzes the stakeholders' perspectives on the causes and outcomes of farmers' resistance to land-use change and urban expansion processes by zooming in on Bahir Dar, Ethiopia. The paper is based on focus group discussions with farmers in the neighboring villages, local agricultural extension experts, and, subsequently, key informant interviews of local government officials. Juxtaposing farmers' and local experts' positions reveals that inadequate compensations during land expropriation, lack of good governance in the urban expansion process, and inaccessibility of infrastructures are primary reasons for the farmers' struggle against urban expansion in the urban fringes. This study provides insights into the consequences of unplanned urban development challenges and may inform research and policymaking on sustainable urban development in the area and beyond.

ispartof: EXPERT REVIEW OF VACCINES vol:22 issue:1 pages:518-519 ispartof: location:England status: accepted

BACKGROUND: Training the plantar intrinsic foot muscles (PIFMs) has the potential to benefit patients with lower extremity musculoskeletal conditions as well as the aged population. Isolated foot exercises, often standard in clinical practice, are difficult to perform, whereas functional exercises are much easier to accomplish. However, it is unclear whether functional exercises are comparable to isolated foot exercises in activating the PIFMs. OBJECTIVE: This study aims to compare the activation of PIFMs between functional exercises versus isolated foot exercises. METHODS: Using surface electromyography (EMG), muscle activation of three PIFMs was measured in four functional exercises (i.e. normal/unstable toe stance, toe walking, and hopping) versus a muscle-specific isolated foot exercise in 29 younger adults, resulting in 12 comparisons. RESULTS: Functional exercises showed larger mean EMG amplitudes than the isolated foot exercises in 25% of the 12 comparisons, while there was no difference in the remaining 75%. CONCLUSION: Functional exercises provoked comparable or even more activation of the PIFMs than isolated foot exercises. Given that functional exercises are easier to perform, this finding indicates the need to further investigate the effectiveness of functional exercises in physical therapy to improve muscle function and functional task performance in populations that suffer from PIFM weakness or dysfunction. ispartof: PHYSIOTHERAPY THEORY AND PRACTICE ispartof: location:England status: Published online

OBJECTIVE: This meta-analysis assesses cognitive functioning in children with acute lymphoblastic leukemia post-treatment who were treated with either chemotherapy-only (CT-only) or in combination with radiation therapy (CTRT). METHODS: The databases Pubmed and PsychInfo were searched between 1-1-2000 and 31-12-2021. Data were analyzed using Comprehensive Meta-Analysis (version 2). RESULTS: Mean weighted intelligence after treatment was 100.2 (number of studies n = 51, 95% CI: 98.8-101.5). For CT-only, it was 100.8 (95% CI: 99.5-102.2) and for CTRT 97.8 (95% CI: 95.9-100.2). Compared to recruited healthy controls, treated children had on average lower IQ scores (n = 23, mean difference -7.8, 95% CI: -10.7 to -5.0, p

BACKGROUND: Response rates of immune checkpoint inhibitor (ICI) therapy for recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) are low. PATIENTS AND METHODS: This retrospective multicentre cohort study evaluates the predictive and prognostic value of weight loss and changes in body composition prior and during therapy. Patient, tumor, and treatment characteristics of 98 patients were retrieved, including neutrophil and platelet-lymphocyte-ratio (NLR and PLR). Programmed death-ligand 1 (PD-L1) expression was determined on residual material. Cachexia was defined according to Fearon et al. (2011). Skeletal muscle (SM), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT) were evaluated on computed tomography scans at the third lumbar vertebrae level. Univariable and multivariable regression analyses were performed for 6 months progression free survival (PFS6m) and overall survival (OS). RESULTS: Significant early weight loss (>2%) during the first 6 weeks of therapy was shown in 34 patients (35%). This patient subgroup had a significantly higher NLR and PLR at baseline. NLR and PLR were inversely correlated with SM and VAT index. Independent predictors of PFS6m were lower World Health Organization performance status (HR 0.16 [0.04-0.54] p = 0.003), higher baseline SAT index (HR 1.045 [1.02-1.08] p = 0.003), and weight loss 2% early weight loss remained a predictor of OS, independent of PD-L1 expression (HR 2.09 [1.11-3.92] p = 0.02, HR 2.18 [1.13-4.21] p = 0.02). CONCLUSION: We conclude that the combination of cachexia at baseline and weight loss during ICI therapy is associated with worse OS in R/M HNSCC patients, independent of PD-L1 expression. ispartof: CANCER MEDICINE vol:12 issue:7 pages:7699-7712 ispartof: location:United States status: published

Background Drug eluting stents (DES) are associated with a 2% to 4% annual rate of target lesion failure through 5-to-10-year follow-up. The presence of a metallic protheses is a trigger for neo-atherosclerosis and very late stent thrombosis. A "leave nothing behind" strategy using Drug Coated Balloons has been suggested; however, paclitaxel coated balloons are only recommended in selected indications. Recently a novel sirolimus eluting balloon, the SELUTION SLR TM 014 PTCA balloon (SEB) (M.A. MedAlliance SA, Nyon, Switzerland) has been developed.Hypothesis A strategy of percutaneous coronary intervention (PCI) with SEB and provisional DES is non-inferior to a strategy of systematic DES on target vessel failure (TVF) at one and five years. If non-inferiority is met at 5 years, superiority will be tested.Design SELUTION DeNovo is a multi-center international open-label randomized trial. Subjects meeting eligibility criteria are randomized 1:1 to treatment of all lesions with either SEB and provisional DES or systematic DES. Major inclusion criteria are PCI indicated for >= 1 lesion considered suitable for treatment by either SEB or DES and clinical presentation with chronic coronary syndrome, unstable angina or non-ST segment elevation myocardial infarction (NSTEMI). There is no limitation in the number of lesions to be treated. Target lesions diameters are between 2 and 5 mm. Major exclusion criteria are lesions in the left main artery, chronic total occlusions, ST segment elevation myocardial infarction and unstable non-ST segment elevation myocardial infarction. Three thousand three hundred twenty six patients will be included in 50 sites in Europe and Asia. TVF rates and their components will be determined at 30 days, 6 months and annually up to 5 years post-intervention. Among secondary endpoints, bleeding events, cost-effectiveness data and net clinical benefits will be assessed.Summary SELUTION DeNovo trial is an open-label, multi-center international randomized trial comparing a strategy of PCI with SEB and provisional DES to a strategy of PCI with systematic DES on TVF at one and five years. Non-inferiority will be tested at one and five years. If non-inferiority is met at five years, superiority will be tested. (Am Heart J 2023;258:77-84.) The SELUTION DeNovo trial is funded by MedAlliance CardioVascular SA, Rue de Rive 5, 1260 Nyon, Switzerland.

The geochemical signature in alluvial soils is a witness of human activities that took place in a river catchment. Sampling of alluvial soils at depth, in combination with information on sedimentological history and age of samples, may even allow to reconstruct the pollution history of the river basin. In the present study, data on alluvial soils contaminated by a major pollution source were analyzed, with special attention for these soils as an archive for information on the pollution history of a river/river catchment, and on the postdepositional downward migration of metal(loid)s in the alluvial soils. Besides the lateral variation of soil properties and metal(loid) concentrations in the alluvial soils, the vertical distribution of metal(loid)s in soil profiles, as well as the evolution of soil composition in relation to the distance from the river, was addressed. The postdepositional mobilization of Cd was evaluated in a fine-scale sampled alluvial soil core, by comparing data from 137Cs dating with data about the Cd emissions through time and by using leaching tests to calculate the downward migration of Cd. A substantial amount of Cd could leach from superficial to deeper soil layers. Therefore, the low-resolution (cm-scale) sampling of the alluvial soil was not reliable to reconstruct the pollution history of the river catchment, because the elevated chloride-concentrations in the river water increased the downward leaching of Cd through the formation of chloro-complexes. Moreover, the variability in flooding and sedimentation regimes along the river resulted in a heterogeneous composition of the alluvial soils, allowing very large differences in metal(loid) concentrations in places only a few meters apart.

INTRODUCTION: Worldwide, polypharmacy and medication appropriateness-related outcomes (MARO) are growing public health concerns associated with potentially inappropriate prescribing, adverse health effects, and avoidable costs to health systems. Continuity of care (COC) is a cornerstone of high-quality care that has been shown to improve patient-relevant outcomes. However, the relationship between COC and polypharmacy/MARO has not been systematically explored. OBJECTIVE: The aim of this systematic review was to investigate the operationalization of COC, polypharmacy, and MARO as well as the relationship between COC and polypharmacy/MARO. METHODS: We performed a systematic literature search in PubMed, Embase, and CINAHL. Quantitative observational studies investigating the associations between COC and polypharmacy and/or COC and MARO by applying multivariate regression analysis techniques were eligible. Qualitative or experimental studies were not included. Information on the definition and operationalization of COC, polypharmacy, and MARO and reported associations was extracted. COC measures were assigned to the relational, informational, or management dimension of COC and further classified as objective standard, objective non-standard, or subjective. Risk of bias was assessed by using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. RESULTS: Twenty-seven studies were included. Overall, substantial differences existed in terms of the COC dimensions and related COC measures. Relational COC was investigated in each study, while informational and management COC were only covered among three studies. The most frequent type of COC measure was objective non-standard (n = 16), followed by objective standard (n = 11) and subjective measures (n = 3). The majority of studies indicated that COC is strongly associated with both polypharmacy and MARO, such as potentially inappropriate medication (PIM), potentially inappropriate drug combination (PIDC), drug-drug interaction (DDI), adverse drug events (ADE), unnecessary drug use, duplicated medication, and overdose. More than half of the included studies (n = 15) had a low risk of bias, while five studies had an intermediate and seven studies a high risk of bias. CONCLUSIONS: Differences regarding the methodological quality of included studies as well as the heterogeneity in terms of the operationalization and measurement of COC, polypharmacy, and MARO need to be considered when interpreting the results. Yet, our findings suggest that optimizing COC may be helpful in reducing polypharmacy and MARO. Therefore, COC should be acknowledged as an important risk factor for polypharmacy and MARO, and the importance of COC should be considered when designing future interventions targeting these outcomes. ispartof: DRUGS & AGING vol:40 issue:6 pages:473-497 ispartof: location:New Zealand status: published

Aims To investigate whether the elevation in postprandial concentrations of the gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY) accounts for the beneficial changes in food preferences, sweet taste function and eating behaviour after Roux-en-Y gastric bypass (RYGB). Materials and methods This was a secondary analysis of a randomized single-blind study in which we infused GLP-1, OXM, PYY (GOP) or 0.9% saline subcutaneously for 4 weeks in 24 subjects with obesity and prediabetes/diabetes, to replicate their peak postprandial concentrations, as measured at 1 month in a matched RYGB cohort (ClinicalTrials.gov NCT01945840). A 4-day food diary and validated eating behaviour questionnaires were completed. Sweet taste detection was measured using the method of constant stimuli. Correct sucrose identification (corrected hit rates) was recorded, and sweet taste detection thresholds (EC50s: half maximum effective concencration values) were derived from concentration curves. The intensity and consummatory reward value of sweet taste were assessed using the generalized Labelled Magnitude Scale. Results Mean daily energy intake was reduced by 27% with GOP but no significant changes in food preferences were observed, whereas a reduction in fat and increase in protein intake were seen post-RYGB. There was no change in corrected hit rates or detection thresholds for sucrose detection following GOP infusion. Additionally, GOP did not alter the intensity or consummatory reward value of sweet taste. A significant reduction in restraint eating, comparable to the RYGB group was observed with GOP. Conclusion The elevation in plasma GOP concentrations after RYGB is unlikely to mediate changes in food preferences and sweet taste function after surgery but may promote restraint eating.

Background: A growing body of empirical research shows that suicidal behaviors are prevalent in childhood. Yet, few studies have examined risk factors related to suicidal ideation (SI) among children aged 12 and younger. Aims: The current study addresses this gap. Method: A questionnaire was filled out by 1,350 Flemish primary caregivers (94.7% mothers) of 9-year-old children (50.4% boys, Mage = 9.45). Their responses were analyzed using logistic regression and independent samples t tests. Results: The presence of passive SI was reported in 10.5% of the children. A psychiatric, developmental, or behavioral condition (or multiple conditions), a learning disorder, impulsivity, aggression, and experiencing multiple stressful family life events were discovered as potential risk factors of passive SI in childhood. Limitations: The cross-sectional nature of this study meant that causality could not be inferred. In addition, it was based on reports of primary caregivers, rather than on reports from the children themselves. Conclusion: These new empirical findings can be used for the development of prevention programs and be taken into account in risk assessments of SI in clinical practice. Confirmation of our findings in a longitudinal child-reported study is needed. ispartof: CRISIS-THE JOURNAL OF CRISIS INTERVENTION AND SUICIDE PREVENTION vol:44 issue:2 ispartof: location:Canada status: published

An anal fissure is a painful tear of the sensitive anoderm, distally from the dentate line. It is a prevalent disorder and impairs quality of life dramatically. Typical or primary fissures are associated with constipation and mostly located at the posterior midline. About 1% of fissures are atypical in appearance and are generally secondary in nature. These secondary fissures should arouse attention and require further exploration for underlying conditions, such as Crohn's disease, malignancy, trauma or venereal infections. The aim of this manuscript is to provide a comprehensive review on the clinical aspects, evaluation and treatment of secondary anal fissures. (Acta gastroenterol. belg., 2023, 86, 58-67).

ispartof: AMERICAN JOURNAL OF MEDICAL GENETICS PART A status: Published online

BACKGROUND: Gastroparesis and functional dyspepsia are disorders characterized by upper gastrointestinal symptoms and multifaceted etiologies. One of the main therapeutic approaches is accelerating gastric emptying (GE) by means of prokinetic agents. Their efficacy has been demonstrated, although the association between symptom improvement and acceleration of emptying is less clear. Meta-analyses have found contradictory results. Differences in applied methodology and included trials might drive these contradictions. OBJECTIVE: To provide a transparent meta-analysis update to elucidate the association between symptom improvement and acceleration of GE due to gastroprokinetic agents available for long-term use in patients with gastroparesis. DESIGN: Two approaches from earlier meta-analyses were executed and compared. One analyzed the relative changes on active treatment versus baseline, the other compared the change from baseline on active treatment versus the change from baseline on placebo. Papers that reported sufficient numerical data for both analyses were selected. Both analyses included the same trials. RESULTS: Overall, both approaches yield the same positive direction of association between symptom improvement and acceleration of emptying (0.291 (-0.391, 0.972), p = 0.4 and 0.453 (0.123, 0.782), p = 0.007 for the active-only and placebo-controlled analysis respectively). The association between symptom improvement and GE acceleration for studies using optimal GE tests was either 0.028 (p > 0.9) or 0.463 (p = 0.007), and for sub-optimal GE tests was either 0.370 (p = 0.4) or 0.052 (p > 0.9) depending on the used meta-analysis methodology. CONCLUSIONS: The applied methodology for GE testing, and the meta-analysis substantially impacts the conclusion. When considering the clinically relevant outcome of improvement from baseline, symptoms and emptying improve with prokinetics, but no correlation is found between both aspects. When the change over placebo is considered, limiting the analysis to scientifically more rigorous study approaches, changes in emptying rate and symptom improvement are positively associated. ispartof: UNITED EUROPEAN GASTROENTEROLOGY JOURNAL vol:11 issue:2 ispartof: location:England status: Published online

Understanding how we can age healthily is a challenge at the heart of biogerontological interest. Whereas myriad genes are known to affect the lifespan of model organisms, effects of such interventions on healthspan-the period of life where an animal is considered healthy, rather than merely alive-are less clear. To understand relationships between life- and healthspan, in recent years several platforms were developed with the purpose of assessing both readouts simultaneously. We here relied on one such platform, the WorMotel, to study effects of adulthood-restricted knock-down of 130 Caenorhabditis elegans genes on the locomotive health of the animals along their lifespans. We found that knock-down of six genes affected healthspan while lifespan remained unchanged. For two of these, F26A3.4 and chn-1, knock-down resulted in an improvement of healthspan. In follow-up experiments we showed that knockdown of F26A3.4 indeed improves locomotive health and muscle structure at old age. ispartof: Biogerontology vol:24 issue:2 ispartof: location:Netherlands status: Published online

Social insects display extreme phenotypic differences between sexes and castes even though the underlying genome can be almost identical. Epigenetic processes have been proposed as a possible mechanism for mediating these phenotypic differences. Using whole genome bisulfite sequencing of queens, males, and reproductive female workers we have characterised the sex- and caste-specific methylome of the bumblebee Bombus terrestris. We have identified a potential role for DNA methylation in histone modification processes which may influence sex and caste phenotypic differences. We also find differentially methylated genes generally show low levels of DNA methylation which may suggest a separate function for lowly methylated genes in mediating transcriptional plasticity, unlike highly methylated genes which are usually involved in housekeeping functions. We also examined the relationship between the underlying genome and the methylome using whole genome re-sequencing of the same queens and males. We find DNA methylation is enriched at zero-fold degenerate sites. We suggest DNA methylation may be acting as a targeted mutagen at these sites, providing substrate for selection via non-synonymous changes in the underlying genome. However, we did not see any relationship between DNA methylation and rates of positive selection in our samples. In order to fully assess a possible role for DNA methylation in adaptive processes a specifically designed study using natural population data is needed. ispartof: HEREDITY vol:130 issue:4 pages:188-195 ispartof: location:England status: published

Aims Multinomial logistic regression models allow one to predict the risk of a categorical outcome with > 2 categories. When developing such a model, researchers should ensure the number of participants ([Formula: see text]) is appropriate relative to the number of events ([Formula: see text]) and the number of predictor parameters ([Formula: see text]) for each category k. We propose three criteria to determine the minimum n required in light of existing criteria developed for binary outcomes. Proposed criteria The first criterion aims to minimise the model overfitting. The second aims to minimise the difference between the observed and adjusted [Formula: see text] Nagelkerke. The third criterion aims to ensure the overall risk is estimated precisely. For criterion (i), we show the sample size must be based on the anticipated Cox-snell [Formula: see text] of distinct ‘one-to-one’ logistic regression models corresponding to the sub-models of the multinomial logistic regression, rather than on the overall Cox-snell [Formula: see text] of the multinomial logistic regression. Evaluation of criteria We tested the performance of the proposed criteria (i) through a simulation study and found that it resulted in the desired level of overfitting. Criterion (ii) and (iii) were natural extensions from previously proposed criteria for binary outcomes and did not require evaluation through simulation. Summary We illustrated how to implement the sample size criteria through a worked example considering the development of a multinomial risk prediction model for tumour type when presented with an ovarian mass. Code is provided for the simulation and worked example. We will embed our proposed criteria within the pmsampsize R library and Stata modules.

BACKGROUND: While prior Micra trials demonstrated a high implant success rate and favorable safety and efficacy results, changes in implant populations and safety over time is not well studied. The objective of this analysis was to report the performance of Micra in European and Middle Eastern patients and compare to the Micra Investigational Device Exemption (IDE) and Micra Post Approval Registry (PAR) studies. METHODS: The prospective, single-arm Micra Acute Performance European and Middle Eastern (MAP EMEA) registry was designed to further study the performance of Micra in patients from EMEA. The primary endpoint was to characterize acute (30-day) major complications. Electrical performance was analyzed. The major complication rate through 12 months was compared with the IDE and PAR studies. RESULTS: The MAP EMEA cohort (n = 928 patients) had an implant success rate of 99.9% and were followed for an average of 9.7 ± 6.5 months. Compared to prior studies, MAP EMEA patients were more likely to have undergone dialysis and have a condition which precluded the use of a transvenous pacemaker (p

BACKGROUND Several GnRH antagonist protocols are currently used during COS in the context of ART treatments; however, questions remain regarding whether these protocols are comparable in terms of efficacy and safety. OBJECTIVE AND RATIONALE A systematic review followed by a pairwise and network meta-analyses were performed. The systematic review and pairwise meta-analysis of direct comparative data according to the PRISMA guidelines evaluated the effectiveness of different GnRH antagonist protocols (fixed Day 5/6 versus flexible, ganirelix versus cetrorelix, with or without hormonal pretreatment) on the probability of live birth and ongoing pregnancy after COS during ART treatment. A frequentist network meta-analysis combining direct and indirect comparisons (using the long GnRH agonist protocol as the comparator) was also performed to enhance the precision of the estimates. SEARCH METHODS The systematic literature search was performed using Embase (Ovid), MEDLINE (Ovid), Cochrane Central Register of Trials (CENTRAL), SCOPUS and Web of Science (WOS), from inception until 23 November 2021. The search terms comprised three different MeSH terms that should be present in the identified studies: GnRH antagonist; assisted reproduction treatment; randomized controlled trial (RCT). Only studies published in English were included. OUTCOMES The search strategy resulted in 6738 individual publications, of which 102 were included in the systematic review (corresponding to 75 unique studies) and 73 were included in the meta-analysis. Most studies were of low quality. One study compared a flexible protocol with a fixed Day 5 protocol and the remaining RCTs with a fixed Day 6 protocol. There was a lack of data regarding live birth when comparing the flexible and fixed GnRH antagonist protocols or cetrorelix and ganirelix. No significant difference in live birth rate was observed between the different pretreatment regimens versus no pretreatment or between the different pretreatment protocols. A flexible GnRH antagonist protocol resulted in a significantly lower OPR compared with a fixed Day 5/6 protocol (relative risk (RR) 0.76, 95% CI 0.62 to 0.94, I2 = 0%; 6 RCTs; n = 907 participants; low certainty evidence). There were insufficient data for a comparison of cetrorelix and ganirelix for OPR. OCP pretreatment was associated with a lower OPR compared with no pretreatment intervention (RR 0.79, 95% CI 0.69 to 0.92; I2 = 0%; 5 RCTs, n = 1318 participants; low certainty evidence). Furthermore, in the network meta-analysis, a fixed protocol with OCP resulted in a significantly lower OPR than a fixed protocol with no pretreatment (RR 0.84, 95% CI 0.71 to 0.99; moderate quality evidence). The surface under the cumulative ranking (SUCRA) scores suggested that the fixed protocol with no pretreatment is the antagonist protocol most likely (84%) to result in the highest OPR. There was insufficient evidence of a difference between fixed/flexible or OCP pretreatment/no pretreatment interventions regarding other outcomes, such as ovarian hyperstimulation syndrome and miscarriage rates. WIDER IMPLICATIONS Available evidence, mostly of low quality and certainty, suggests that different antagonist protocols should not be considered as equivalent for clinical decision-making. More trials are required to assess the comparative effectiveness of ganirelix versus cetrorelix, the effect of different pretreatment interventions (e.g. progestins or oestradiol) or the effect of different criteria for initiation of the antagonist in the flexible protocol. Furthermore, more studies are required examining the optimal GnRH antagonist protocol in women with high or low response to ovarian stimulation.

THEMIS is a double-blind, randomized trial of 19,220 patients with diabetes mellitus and stable coronary artery disease (CAD) comparing ticagrelor to placebo, in addition to aspirin. The present study aimed to describe the proportion of patients eligible and reasons for ineligibility for THEMIS within a population of patients with diabetes and CAD included in the Reduction of Atherothrombosis for Continued Health (REACH) registry. The THEMIS eligibility criteria were applied to REACH patients. THEMIS included patients ≥50 years with type 2 diabetes and stable CAD as determined by either a history of previous percutaneous coronary intervention, coronary artery bypass grafting, or documentation of angiographic stenosis of ≥50% of at least one coronary artery. Patients with prior myocardial infarction or stroke were excluded. In REACH, 10,156 patients had stable CAD and diabetes. Of these, 6515 (64.1%) patients had at least one exclusion criteria. From the remaining population, 784 patients did not meet inclusion criteria (7.7%) mainly due to absence of aspirin treatment (7.2%), yielding a 'THEMIS-eligible population' of 2857 patients (28.1% of patients with diabetes and stable CAD). The main reasons for exclusion were a history of myocardial infarction (53.1%), use of oral anticoagulation (14.5%), or history of stroke (12.9%). Among the 4208 patients with diabetes and a previous PCI, 1196 patients (28.4%) were eligible for inclusion in the THEMIS-PCI substudy. In a population of patients with diabetes and stable coronary artery disease, a sizeable proportion appear to be 'THEMIS eligible.' http://www. gov identifier: NCT01991795. The THEMIS trial was funded by AstraZeneca. The REACH registry was sponsored by Sanofi, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan) and is endorsed by the World Heart Federation. Sí

Poly (ADP-ribose) polymerase inhibitors (PARPis) have demonstrated clinical activity in patients with BRCA1 and/or BRCA2 mutated breast, ovarian, prostate, and pancreatic cancers. Notably, BRCA mutations are associated with defects in the homologous recombination repair (HRR) pathway. This homologous recombination deficiency (HRD) phenotype can also be observed as genomic instability in tumour cells. Accordingly, PARPi sensitivity has been observed in various tumours with HRD, independent of BRCA mutations. Currently, four PARPis are approved by regulatory agencies for the treatment of cancer across multiple tumour types. Most indications are specific to tumours with a confirmed BRCA mutation, mutations in other HRR-related genes, HRD evidenced by genomic instability, or evidence of platinum sensitivity. Regulatory agencies have also approved companion and complementary diagnostics to facilitate patient selection for each PARPi indication. This review aims to summarise the biological basis, clinical validation, and clinical relevance of the available diagnostic methods and assays to assess HRD. ispartof: EUROPEAN JOURNAL OF CANCER vol:179 pages:136-146 ispartof: location:England status: published

ispartof: CENTRAL EUROPEAN JOURNAL OF PUBLIC HEALTH vol:30 issue:4 pages:207-212 status: published

ObjectivesAnetumab ravtansine is an antibody-drug conjugate consisting of a fully human anti-mesothelin monoclonal antibody conjugated to cytotoxic maytansinoid tubulin inhibitor DM4. Mesothelin is highly expressed in ovarian cancer. This phase Ib study determines the safety, pharmacokinetics, and anti-tumor activity of anetumab ravtansine and pegylated liposomal doxorubicin in mesothelin-expressing platinum-resistant ovarian cancer.MethodsAnetumab ravtansine (5.5 or 6.5 mg/kg) and pegylated liposomal doxorubicin (30 mg/m2) were administered intravenously every 3 weeks to 65 patients with platinum-resistant epithelial ovarian cancer. Mesothelin expression was assessed by central immunohistochemistry. Adverse events, tumor response (RECIST 1.1), and progression-free survival were determined. Biomarker samples were assessed by ELISA and next-generation sequencing.ResultsIn dose escalation, nine patients received anetumab ravtansine across two doses (5.5 or 6.5 mg/kg). The maximum tolerated dose of anetumab ravtansine was 6.5 mg/kg every 3 weeks and no dose-limiting toxicities were observed. In dose expansion, 56 patients were treated at the maximum tolerated dose. The most common treatment-emergent adverse events of any grade were nausea (47.7%), decreased appetite (43.1%), fatigue (38.5%), diarrhea (32.3%), and corneal disorder (29.2%). In all treated patients the objective response rate was 27.7% (95% CI 17.3% to 40.2%), including one complete (1.5%) and 17 partial responses (26.2%), with median duration of response of 7.6 (95% CI 3.3 to 10.2) months and median progression-free survival of 5.0 (95% CI 3.2 to 6.0) months. In an exploratory analysis of a sub-set of patients (n=19) with high mesothelin expression who received ≤3 prior lines of systemic therapy, the objective response rate was 42.1% (95% CI 20.3% to 66.5%) with a median duration of response of 8.3 (95% CI 4.1 to 12.0) months and median progression-free survival of 8.5 (95% CI 4.0 to 11.4) months.ConclusionsAnetumab ravtansine and pegylated liposomal doxorubicin showed tolerability and promising clinical activity. These results established the dose schedule and the mesothelin-positive target population of this combination for a phase III study in platinum-resistant ovarian cancer.Trial registration numberNCT02751918.

This study investigates the pilot-scale ozone treatment of reverse osmosis concentrate (ROC), originating from variable tank truck cleaning wastewater. The influence of ozonation on short- and long-term biodegradation potential was examined through respirometry and Zahn-Wellens, respectively. Ecotoxicity was also examined for several concentrate batches and ozonation steps. Chemical oxidation through ozone had a beneficial effect on chemical oxygen demand removal, with a removal efficiency up to 56%. Formation of short-term biochemical oxygen demand (BODst) was induced for several, but not all batches, showing the potential of subsequent biological treatment of ozonated ROC. An increase in the inherent biodegradability through Zahn-Wellens was observed for all tested samples after ozonation, rising to a maximum of 68% after 3 hours of ozonation, highlighting the importance of sludge adaptation. Ecotoxicity, tested with Artemia franciscana and the saltwater algae P. tricornutum, showed initial decreases in algae inhibition after short ozonation periods. An increase in algae inhibition was, however, seen after prolonged ozonation for all tested ROC samples, pointing to the formation of ecotoxic by-products. Artemia showed no significant toxicity effects. When applying biological treatment through Zahn-Wellens, a decrease in ecotoxicity was observed for several samples, likely through biological oxidation of the produced degradation products. ispartof: WATER SCIENCE AND TECHNOLOGY vol:87 issue:1 pages:1-12 ispartof: location:England status: published

The prenatal environment may program health and disease susceptibility via epigenetic mechanisms. We evaluated associations of maternal trimester-specific intake of micronutrients with global DNA methylation (%5mC) and 5-hydroxymethylation (%5hmC) at birth in cord blood and tested for persistence into childhood. We quantified global %5mC and %5hmC in cord blood cells (n= 434) and in leukocytes collected in early (n= 108) and mid-childhood (n= 390) from children in Project Viva, a pre-birth cohort from Boston, MA. Validated food frequency questionnaires estimated maternal first- and second-trimester intakes of vitamin B2, vitamin B6, vitamin B12, folate, betaine, choline, methionine, iron, and zinc. Mean (SD) cord blood %5mC and %5hmC was 5.62% (2.04) and 0.25% (0.15), respectively. Each μg increase in first-trimester B12intake was associated with 0.002 lower %5hmC in cord blood (95% CI: −0.005, −0.0003), and this association persisted in early childhood (β= −0.007; 95% CI: −0.01, −0.001) but not mid-childhood. Second-trimester iron (mg) was associated with 0.01 lower %5mC (95% CI: −0.02, −0.002) and 0.001 lower %5hmC (95% CI: −0.01, −0.00001) in cord blood only. Increased second-trimester zinc (mg) intake was associated with 0.003 greater %5hmC in early childhood (β= 0.003; 95% CI: 0.0004, 0.006). Second-trimester folate was positively associated with %5hmC in early childhood only (β= 0.08, 95% CI: 0.003, 0.16). Associations did not survive multiple testing adjustment; future replication is needed. Trimester-specific nutrients may impact various sensitive windows of epigenetic programming some with lasting effects in childhood. Further research is needed to understand the role of gene-specific epigenetic changes and how global DNA methylation measures relate to child health.

Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by mutations of the transcription factor 4 (Tcf4) gene. Individuals with PTHS often suffer from severe abdominal bloating and constipation. In this short communication, we discuss two individuals with PTHS who died unexpectedly due to gastrointestinal complications. We aim to increase awareness among healthcare professionals who care for individuals with PTHS, to ensure adequate screening and management of gastrointestinal symptoms in this population. Moreover, we discuss how fatal gastrointestinal complications may be related to PTHS and provide an overview of the literature.

OBJECTIVE: To establish a generally accepted Danish definition of dysphagia to enhance collaboration across sectors and professions. METHODS: The study was initiated by a multi-professional group of experienced researchers and board members of the Danish Society for Dysphagia. We used a modified Delphi methodology to achieve consensus among experienced health care professionals from different professions and contexts. The initial stage consisted of a literature search leading to the draft of different definitions followed by two Delphi rounds between professionals and a stakeholder consultation round. RESULTS: We conducted two Delphi rounds until one definition was clearly preferred. A total of 194 participants responded in round one, and 279 in round two. Both rounds had a broad representation of sectors and geography and most participants had worked with dysphagia for more than four years. CONCLUSION: The preferred definition was 'Dysphagia is a functional impairment that either prevents or limits the intake of food and fluids, and which makes swallowing unsafe, inefficient, uncomfortable or affects quality of life'. The definition was widely accepted among different health professional groups, patients and across sectors. ispartof: SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY vol:58 issue:6 pages:583-588 ispartof: location:England status: accepted

Background Early reports on the pandemic nature of coronavirus disease 2019 (COVID-19) directed the nephrology community to develop infection prevention and control (IPC) guidance. We aimed to make an inventory of strategies that dialysis centres followed to prevent infection with COVID-19 in the first pandemic wave. Methods We analyzed IPC measures taken by hemodialysis centres treating patients presenting with COVID-19 between 1 March 2020 and 31 July 2020 and that completed the European Renal Association COVID-19 Database centre questionnaire. Additionally, we made an inventory of guidelines published in European countries to prevent spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in dialysis centres. Results Data from 73 dialysis units located in and bordering Europe were analyzed. All participating centres implemented IPC measures to mitigate the impact of SARS-CoV-2 during the first pandemic wave. Measures mentioned most often included triage with questions before entering the dialysis ward, measuring body temperature, hand disinfection, masking for all patients and staff, and personal protective equipment for staff members. These measures were also recommended in most of the 14 guidelines that were identified in the inventory of national guidelines and were also scored as being among the most important measures by the authors of this paper. Heterogeneity existed between centres and national guidelines regarding the minimal distance between dialysis chairs and recommendations regarding isolation and cohorting. Conclusions Although variation existed, measures to prevent transmission of SARS-CoV-2 were relatively similar across centres and national guidelines. Further research is needed to assess causal relationships between measures taken and spread of SARS-CoV-2.

Objective As preservation of cognitive functioning increasingly becomes important in the light of ameliorated survival after intracranial tumor treatments, identification of eloquent brain areas would enable optimization of these treatments. Methods This cohort study enrolled adult intracranial tumor patients who received neuropsychological assessments pre-irradiation, estimating processing speed, verbal fluency and memory. Anatomical magnetic resonance imaging scans were used for multivariate voxel-wise lesion-symptom predictions of the test scores (corrected for age, gender, educational level, histological subtype, surgery, and tumor volume). Potential effects of histological and molecular subtype and corresponding WHO grades on the risk of cognitive impairment were investigated using Chi square tests. P-values were adjusted for multiple comparisons (p Results A cohort of 179 intracranial tumor patients was included [aged 19–85 years, median age (SD) = 58.46 (14.62), 50% females]. In this cohort, test-specific impairment was detected in 20–30% of patients. Higher WHO grade was associated with lower processing speed, cognitive flexibility and delayed memory in gliomas, while no acute surgery-effects were found. No grading, nor surgery effects were found in meningiomas. The voxel-wise analyses showed that tumor locations in left temporal areas and right temporo-parietal areas were related to verbal memory and processing speed, respectively. Interpretation Patients with intracranial tumors affecting the left temporal areas and right temporo-parietal areas might specifically be vulnerable for lower verbal memory and processing speed. These specific patients at-risk might benefit from early-stage interventions. Furthermore, based on future validation studies, imaging-informed surgical and radiotherapy planning could further be improved.

Background: It is uncertain if medical masks offer similar protection against COVID-19 compared with N95 respirators. Objective: To determine whether medical masks are noninferior to N95 respirators to prevent COVID-19 in health care workers providing routine care. Design: Multicenter, randomized, noninferiority trial. (ClinicalTrials.gov: NCT04296643). Setting: 29 health care facilities in Canada, Israel, Pakistan, and Egypt from 4 May 2020 to 29 March 2022. Participants: 1009 health care workers who provided direct care to patients with suspected or confirmed COVID-19. Intervention: Use of medical masks versus fit-tested N95 respirators for 10 weeks, plus universal masking, which was the policy implemented at each site. Measurements: The primary outcome was confirmed COVID-19 on reverse transcriptase polymerase chain reaction (RT-PCR) test. Results: In the intention-to-treat analysis, RT-PCR–confirmed COVID-19 occurred in 52 of 497 (10.46%) participants in the medical mask group versus 47 of 507 (9.27%) in the N95 respirator group (hazard ratio [HR], 1.14 [95% CI, 0.77 to 1.69]). An unplanned subgroup analysis by country found that in the medical mask group versus the N95 respirator group RT-PCR–confirmed COVID-19 occurred in 8 of 131 (6.11%) versus 3 of 135 (2.22%) in Canada (HR, 2.83 [CI, 0.75 to 10.72]), 6 of 17 (35.29%) versus 4 of 17 (23.53%) in Israel (HR, 1.54 [CI, 0.43 to 5.49]), 3 of 92 (3.26%) versus 2 of 94 (2.13%) in Pakistan (HR, 1.50 [CI, 0.25 to 8.98]), and 35 of 257 (13.62%) versus 38 of 261 (14.56%) in Egypt (HR, 0.95 [CI, 0.60 to 1.50]). There were 47 (10.8%) adverse events related to the intervention reported in the medical mask group and 59 (13.6%) in the N95 respirator group. Limitation: Potential acquisition of SARS-CoV-2 through household and community exposure, heterogeneity between countries, uncertainty in the estimates of effect, differences in self-reported adherence, differences in baseline antibodies, and between-country differences in circulating variants and vaccination. Conclusion: Among health care workers who provided routine care to patients with COVID-19, the overall estimates rule out a doubling in hazard of RT-PCR–confirmed COVID-19 for medical masks when compared with HRs of RT-PCR–confirmed COVID-19 for N95 respirators. The subgroup results varied by country, and the overall estimates may not be applicable to individual countries because of treatment effect heterogeneity. Primary Funding Source: Canadian Institutes of Health Research, World Health Organization, and Juravinski Research Institute.

Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment. There is practice variation in management due to differences in guidelines and their usage and adherence. We aimed to assess whether management in febrile children below 3 months attending European Emergency Departments (EDs) was according to the guidelines for fever. This study is part of the MOFICHE study, which is an observational multicenter study including routine data of febrile children (0–18 years) attending twelve EDs in eight European countries. In febrile children below 3 months (excluding bronchiolitis), we analyzed actual management compared to the guidelines for fever. Ten EDs applied the (adapted) NICE guideline, and two EDs applied local guidelines. Management included diagnostic tests, antibiotic treatment, and admission. We included 913 children with a median age of 1.7 months (IQR 1.0–2.3). Management per ED varied as follows: use of diagnostic tests 14–83%, antibiotic treatment 23–54%, admission 34–86%. Adherence to the guideline was 43% (374/868) for blood cultures, 29% (144/491) for lumbar punctures, 55% (270/492) for antibiotic prescriptions, and 67% (573/859) for admission. Full adherence to these four management components occurred in 15% (132/868, range 0–38%), partial adherence occurred in 56% (484/868, range 35–77%).Conclusion: There is large practice variation in management. The guideline adherence was limited, but highest for admission which implies a cautious approach. Future studies should focus on guideline revision including new biomarkers in order to optimize management in young febrile children. What is Known:• Febrile children below 3 months have a higher risk of serious bacterial infections, which often leads to extensive diagnostics and treatment.• There is practice variation in management of young febrile children due to differences in guidelines and their usage and adherence. What is New:• Full guideline adherence is limited, whereas partial guideline adherence is moderate in febrile children below 3 months across Europe.• Guideline revision including new biomarkers is needed to improve management in young febrile children.

Exposure to Stressful Life Events (SLEs) has been linked to psychosis. However, the combined effect of SLEs and familial risk on subclinical psychotic symptoms over time remains unknown. The objective of the present study was to investigate the effect of SLEs on the level of subclinical psychotic symptoms in individuals with and without familial vulnerability for psychosis. Data were collected from siblings of individuals diagnosed with psychotic disorder and healthy controls at baseline (N = 293) and three years later at follow-up (N = 928). We assessed self-reported and observer-rated subclinical positive, negative, and depressive psychotic symptoms. Participants reported the number of SLEs in the preceding 6 months. A multilevel multivariate regression analysis revealed a positive association between the retrospectively assessed number of SLEs and symptom levels, regardless of vulnerability status (p

BACKGROUND: FMRI resting state networks (RSNs) are used to characterize brain disorders. They also show extensive heterogeneity across patients. Identifying systematic differences between RSNs in patients, i.e. discovering neurofunctional subtypes, may further increase our understanding of disease heterogeneity. Currently, no methodology is available to estimate neurofunctional subtypes and their associated RSNs simultaneously. NEW METHOD: We present an unsupervised learning method for fMRI data, called Clusterwise Independent Component Analysis (C-ICA). This enables the clustering of patients into neurofunctional subtypes based on differences in shared ICA-derived RSNs. The parameters are estimated simultaneously, which leads to an improved estimation of subtypes and their associated RSNs. RESULTS: In five simulation studies, the C-ICA model is successfully validated using both artificially and realistically simulated data (N = 30-40). The successful performance of the C-ICA model is also illustrated on an empirical data set consisting of Alzheimer's disease patients and elderly control subjects (N = 250). C-ICA is able to uncover a meaningful clustering that partially matches (balanced accuracy = .72) the diagnostic labels and identifies differences in RSNs between the Alzheimer and control cluster. COMPARISON WITH OTHER METHODS: Both in the simulation study and the empirical application, C-ICA yields better results compared to competing clustering methods (i.e., a two step clustering procedure based on single subject ICA's and a Group ICA plus dual regression variant thereof) that do not simultaneously estimate a clustering and associated RSNs. Indeed, the overall mean adjusted Rand Index, a measure for cluster recovery, equals 0.65 for C-ICA and ranges from 0.27 to 0.46 for competing methods. CONCLUSIONS: The successful performance of C-ICA indicates that it is a promising method to extract neurofunctional subtypes from multi-subject resting state-fMRI data. This method can be applied on fMRI scans of patient groups to study (neurofunctional) subtypes, which may eventually further increase understanding of disease heterogeneity. ispartof: JOURNAL OF NEUROSCIENCE METHODS vol:382 ispartof: location:Netherlands status: published

Background The promotion of healthy lifestyles has high priority on the global public health agenda. Evidence on the real-world (cost-)effectiveness of policies addressing nutrition and physical activity is needed. To estimate short-term policy impacts, quasi-experimental methods using observational data are useful, while simulation models can estimate long-term impacts. We review the methods, challenges and potential synergies of both approaches for the evaluation of nutrition and physical activity policies. Methods We performed an integrative review applying purposive literature sampling techniques to synthesize original articles, systematic reviews and lessons learned from public international workshops conducted within the European Union Policy Evaluation Network. Results We highlight data requirements for policy evaluations, discuss the distinct assumptions of instrumental variable, difference-in-difference, and regression discontinuity designs and describe the necessary robustness and falsification analyses to test them. Further, we summarize the specific assumptions of comparative risk assessment and Markov state-transition simulation models, including their extension to microsimulation. We describe the advantages and limitations of these modelling approaches and discuss future directions, such as the adequate consideration of heterogeneous policy responses. Finally, we highlight how quasi-experimental and simulation modelling methods can be integrated into an evidence cycle for policy evaluation. Conclusions Assumptions of quasi-experimental and simulation modelling methods in policy evaluations should be credible, rigorously tested and transparently communicated. Both approaches can be applied synergistically within a coherent framework to compare policy implementation scenarios and improve the estimation of nutrition and physical activity policy impacts, including their distribution across population sub-groups.

Most invasive fungal infections are opportunistic in nature but the epidemiology is constantly changing, with new risk groups being identified. Neutropenia is a classical risk factor for fungal infections, while critically ill patients in the ICU are now increasingly at risk of yeast and mould infections. Factors to be considered when choosing antifungal treatment include the emergence of rarer fungal pathogens, the risk of resistance to azoles and echinocandins and the possibility of drug-drug interactions. Liposomal amphotericin B has retained its place in the therapeutic armamentarium based on its clinical profile: a broad spectrum of antifungal activity with a low risk of resistance, predictable pharmacokinetics with a rapid accumulation at the infection site (including biofilms), a low potential for drug-drug interactions and a low risk of acute and chronic treatment-limiting toxicities versus other formulations of amphotericin B. It is a suitable choice for the first-line empirical or pre-emptive treatment of suspected fungal infections in neutropenic haematology patients and is an excellent alternative for patients with documented fungal disease who can no longer tolerate or continue their first-line azole or echinocandin therapy, both in the haematology setting and in the ICU. Moreover, it is the first-line drug of choice for the treatment of invasive mucormycosis. Finally, liposomal amphotericin B is one of the few antifungal agents approved for use in children of all ages over 1 month and is included in paediatric-specific guidelines for the management of fungal disease. ispartof: JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY vol:77 issue:Suppl_2 pages:11-20 ispartof: location:England status: published

Funder: CIBERNED, Funder: Canadian Institutes of Health Research; doi: http://dx.doi.org/10.13039/501100000024, Funder: Lemaire Family Foundation, Funder: Swedish Frontotemporal Dementia Initiative, Funder: Italian Ministry of Health, Funder: Weston Brain Institute; doi: http://dx.doi.org/10.13039/100012479, Funder: Mady Browaaeys Fund, Funder: Miriam Marks Brain Research UK, Funder: Bluefield Project, OBJECTIVE: To investigate the optimal method of adding motor features to a clinical rating scale for frontotemporal dementia (FTD). METHODS: Eight hundred and thirty-two participants from the international multicentre Genetic FTD Initiative (GENFI) study were recruited: 522 mutation carriers (with C9orf72, GRN and MAPT mutations) and 310 mutation-negative controls. A standardised clinical questionnaire was used to assess eight motor symptoms (dysarthria, dysphagia, tremor, slowness, weakness, gait disorder, falls and functional difficulties using hands). Frequency and severity of each motor symptom was assessed, and a principal component analysis (PCA) was performed to identify how the different motor symptoms loaded together. Finally, addition of a motor component to the CDR® plus NACC FTLD was investigated (CDR® plus NACC FTLD-M). RESULTS: 24.3% of mutation carriers had motor symptoms (31.7% C9orf72, 18.8% GRN, 19.3% MAPT) compared to 6.8% of controls. Slowness and gait disorder were the commonest in all genetic groups while tremor and falls were the least frequent. Symptom severity scores were similar to equivalent physical motor examination scores. PCA revealed that all motor symptoms loaded together so a single additional motor component was added to the CDR® plus NACC FTLD to form the CDR® plus NACC FTLD-M. Individual global scores were more severe with the CDR® plus NACC FTLD-M, and no patients with a clinically diagnosed motor disorder (ALS/FTD-ALS or parkinsonism) were classified anymore as asymptomatic (unlike the CDR® plus NACC FTLD alone). CONCLUSIONS: Motor features are present in mutation carriers at all disease stages across all three genetic groups. Inclusion of motor symptoms in a rating scale that can be used in future clinical trials will not only ensure a more accurate severity measure is recorded but that a wider spectrum of FTD phenotypes can be included in the same trial.

Background Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017–1.109 and OR = 2.438, 95%CI 1.023–5.813, respectively). Conclusions Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

The effects of synthetic fertilizer and nutrient leaching are causing serious problems impacting soil function and its fertility. Mitigation of nutrient leaching and use of chemical fertilizer is crucial as fertile land adds up sustainability to climate changes. Biochar produced from agricultural bio-waste and municipal solid waste has been used for crop production and when applied in combination with organic nutrients may support mitigation of nutrient loss and adverse effects of chemical fertilizers. Different types of biochar and their application for soil enhancement have been observed, pine needle and sewage sludge derived low-temperature biochar along with compost, organic fertilizer in the form of manure and microalgal biomass may interact with soil chemistry and plant growth to impact nutrient loss and compensate the hazardous effect of chemical fertilizer, but it has not been investigated yet. This present study elaborates application of sewage sludge and pine needle biochar produced at 400 °C in an application rate of 5 % w/w and 10 t h-1 in combination with compost, manure and microalgal biomasses of Closteriopsis acicularis (BM1) and Tetradesmus nygaardi (BM2) on the growth of Chickpea (Cicer arietinum) and Fenugreek (Trigonella foenum-graecum) crop assessed in a pot experiment over a two crop (Chickpea - Fenugreek) cycle in Pakistan. Results depict that the pine needle biochar with additives has increased plant height by 104.1 ± 2.76 cm and fresh biomass by 49.9 ± 1.02 g, buffered the soil pH to 6.5 for optimum growth of crops and enhance carbon retention by 36 %. This study highlights the valorization of sewage sludge and pine needle into biochar and the effect of biochar augmentation, its impact on soil nutrients and plant biomass enhancement. The greener approach also mitigates and helps in the sustainable management of solid wastes.

Amyloid-beta 42 (Aβ42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer’s disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for Aβ42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple Aβ42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume. This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Programme, Neurodegenerative Disease Research (JPND). Amsterdam dementia Cohort (ADC): Research of the Alzheimer center Amsterdam is part of the neurodegeneration research program of Amsterdam Neuroscience. The Alzheimer Center Amsterdam is supported by Stichting Alzheimer Nederland and Stichting VUmc fonds. The clinical database structure was developed with funding from Stichting Dioraphte. Genotyping of the Dutch case-control samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). Part of the work described in this study was carried out in the context of the Parelsnoer Institute (PSI). PSI was part of and funded by the Dutch Federation of University Medical Centers and has received initial funding from the Dutch Government (from 2007-2011). Since 2020, this work was carried out in the context of Parelsnoer clinical biobanks at Health-RI (https://www.health-ri.nl/initiatives/parelsnoer).Part of the genotyping included in this work was funded by the JPND EADB grant (German Federal Ministry of Education and Research (BMBF) grant: 01ED1619A). Alfredo Ramirez is also supported by the German Research Foundation (DFG) grants Nr: RA 1971/6-1, RA1971/7-1, and RA 1971/8-1. We would like to thank patients and controls who participated in this project. The Genome Research @ Fundacio ACE project (GR@ACE) is supported by Grifols SA, Fundacion bancaria 'La Caixa', Fundacio ACE, and CIBERNED. A.R. and M.B. receive support from the European Union/EFPIA Innovative Medicines Initiative Joint undertaking ADAPTED and MOPEAD projects (grant numbers 115975 and 115985, respectively). M.B. and A.R. are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240 and PI19/01301. Accion Estrategica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)-Subdireccion General de Evaluacion and the Fondo Europeo de Desarrollo Regional (FEDER-'Una manera de hacer Europa'). The position held by I.dR. is funded by grant. FI20/00215. PFIS Contratos Predoctorales de Formacion en Investigacion en Salud. We would like to thank UCL Genomics, London, UK, for performing the genotyping analyses of the samples within the Gothenburg H70 Birth Cohort Studies and Clinical AD Sweden. The recruitment and clinical characterization of research participants at Washington University were supported by NIH P30AG066444, and P01AG003991. This work was supported by access to equipment made possible by the Hope Center for Neurological Disorders, the Neurogenomics and Informatics Center (NGI: https://neurogenom ics.wustl.edu/)and the Departments of Neurology and Psychiatry at Washington University School of Medicine. Research at the Belgian EADB site is funded in part by the Alzheimer Research Foundation (SAO-FRA), The Research Foundation Flanders (FWO), and the University of Antwerp Research Fund. FK is supported by a BOF DOCPRO fellowship of the University of Antwerp Research Fund. The work of Valdecilla was supported by grants from the Instituto de Salud Carlos III (Fondo de Investigacion Sanitario, PI08/0139, PI12/02288, PI16/01652, and PI20/01011), the JPND (DEMTEST PI11/03028), the CIBERNED, and the Siemens Healthineers. We thank the Valdecilla Biobank (PT17/0015/0019), integrated into the Spanish Biobank Network, for their support and collaboration in sample collection and management. Our heartfelt thanks to the participants of the Valdecilla Cohort for their generosity. The work of ADGEN was supported by EU Joint Programme-Neurodegenerative Disease Research (301220) and the Academy of Finland (338182). The DELCODE study (Study-ID:BN012) was supported and conducted by the German Center for Neurodegenerative Diseases (DZNE). The data samples were provided by the DELCODE study group. Details and participating sites can be found at www.dzne.de/en/research/studies/clinical-studies/delco de. The German Dementia Competence Network (KND) is funded by the German Federal Ministry of Education and Research (BMBF) grants Number: 01G10102, 01GI0420, 01GI0422, 01GI0423, 01GI0429, 01GI0431, 01GI0433, 04GI0434, 01GI0711. WF, SvdL, HHolstege, CT and PhS are recipients of ABOARD, which is a public-private partnership receiving funding from ZonMW (#73305095007) and HealthHolland, Topsector Life Sciences & Health (PPP-allowance; #LSHM20106). More than 30 partners participate in ABOARD (www.aboard-project.nl).ABOARD also receives funding from de Hersenstichting, Edwin Bouw Fonds and Gieskes-Strijbisfonds. IEJ was partially supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). AZ was supported by the Swedish Alzheimer Foundation (AF-939988, AF-930582, AF-646061, AF-741361), and the Dementia Foundation (2020-04-13, 2021-0417). ISk was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALFagreement (ALF 716681), the Swedish Research Council (no 11267, 825-2012-5041, 2013-8717, 2015-02830, 2017-00639, 2019-01096), Swedish Research Council for Health, Working Life and Welfare (no 2001-2646, 2001-2835, 2001-2849, 2003-0234, 2004-0150, 20050762, 2006-0020, 2008-1229, 2008-1210, 2012-1138, 2004-0145, 2006-0596, 2008-1111, 2010-0870, 2013-1202, 2013-2300, 20132496), Swedish Brain Power, Hjarnfonden, Sweden (FO2016-0214, FO2018-0214, FO2019-0163), the Alzheimer's Association Zenith Award (ZEN-01-3151), the Alzheimer's Association Stephanie B. Overstreet Scholars (IIRG-00-2159), the Alzheimer's Association (IIRG-03-6168, IIRG-09-131338) and the Bank of Sweden Tercentenary Foundation. SK was supported by the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-81392, ALF GBG-771071), the Swedish Alzheimer Foundation (AF-842471, AF-737641, AF-939825), and the Swedish Research Council (2019-02075). MW was supported by the Swedish Research Council 2016-01590. DP was supported by BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (grant no. 024.004.012), and a European Research Council advanced grant (Grant No, ERC-2018-AdG GWAS2FUNC 834057. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (2018-02532), the European Research Council (681712), Swedish State Support for Clinical Research (ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (2018092016862), the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. KB was supported by the Swedish Research Council (#2017-00915), the Alzheimer Drug Discovery Foundation (ADDF), USA (#RDAPB201809-2016615), the Swedish Alzheimer Foundation (#AF-742881), Hjarnfonden, Sweden (#FO2017-0243), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the National Institute of Health (NIH), USA, (grant #1R01AG06839801), and the Alzheimer's Association 2021 Zenith Award (ZEN-21848495). CC receives support from the National Institutes of Health (R01AG044546, R01AG064877, RF1AG053303, R01AG058501, U01AG058922, RF1AG058501, R01AG064614), and the Chuck Zuckerberg Initiative (CZI).

BACKGROUND: Somatostatin receptor-2 (SSTR2) is expressed on cell surface of neuroendocrine neoplasias; its presence is exploited for the delivery of peptide receptor radionuclide therapy (PRRT). Patients with no or low expression of SSTR2 are not candidates for PRRT. SSTR2 promotor undergoes epigenetic modification, known to regulate gene expression. We investigated whether the demethylation agent, guadecitabine, could enhance the expression of SSTR2 in NET models, using radioligand uptake/PET imaging as a biomarker of epigenetic modification. METHODS: The effects of guadecitabine on the transcriptional, translational, and functional regulation of SSTR2 both in vitro and in vivo using low (QGP-1) and high (BON-1) methylated neuroendocrine neoplasia models was characterised. Promotor region methylation profiling of clinical samples (n = 61) was undertaken. Safety of combination guadecitabine and PRRT was assessed in vivo. RESULTS: Pyrosequencing of cell lines illustrated differential methylation indices - BON: 1 94%, QGP: 1 21%. Following guadecitabine treatment, a dose-dependent increase in SSTR2 in BON-1 at a transcriptional, translational, and functional levels using the SSTR2-directed radioligand, 18F-FET-βAG-TOCA ([18F]-FETO) (150% increase [18F]-FETO uptake, p

In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing. ispartof: IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS vol:26 issue:11 pages:5282-5286 ispartof: location:United States status: published