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The prediction of lane changes can reduce traffic accidents and improve traffic flow. In this paper two classifiers, Echo State Network and a recurrent neural network with Long Short Term Memory cells, were compared to predict lane changes using the input variables steering angle and indicator. The input variables were extracted from a data set which was generated from a naturalistic driving study in the urban area of Chemnitz, Germany. Both classifiers predicted left and right lane changes successfully. They achieved high true positive rates and low false positive rates. The Echo State Network predicted left and the recurrent neural network predicted right lane changes better.

Advanced glycation endproducts (AGEs) may contribute to liver carcinogenesis because of their proinflammatory and prooxidative properties. Diet is a major source of AGEs, but there is sparse human evidence on the role of AGEs intake in liver cancer etiology. We examined the association between dietary AGEs and the risk of hepatobiliary cancers in the European Prospective Investigation into Cancer and Nutrition prospective cohort (n = 450 111). Dietary intake of three AGEs, Nε‐[carboxymethyl]lysine (CML), Nε‐[1‐carboxyethyl]lysine (CEL) and Nδ‐[5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl]‐ornithine (MG‐H1), was estimated using country‐specific dietary questionnaires linked to an AGEs database. Cause‐specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations between dietary AGEs and risk of hepatocellular carcinoma (HCC), gallbladder and biliary tract cancers were estimated using multivariable Cox proportional hazard regression. After a median follow‐up time of 14.9 years, 255 cases of HCC, 100 cases of gallbladder cancer and 173 biliary tract cancers were ascertained. Higher intakes of dietary AGEs were inversely associated with the risk of HCC (per 1 SD increment, HR‐CML = 0.87, 95% CI: 0.76‐0.99, HR‐CEL = 0.84, 95% CI: 0.74‐0.96 and HR‐MH‐G1 = 0.84, 95% CI: 0.74‐0.97). In contrast, positive associations were observed with risk of gallbladder cancer (per 1 SD, HR‐CML = 1.28, 95% CI: 1.05‐1.56, HR‐CEL = 1.17; 95% CI: 0.96‐1.40, HR‐MH‐G1 = 1.27, 95% CI: 1.06‐1.54). No associations were observed for cancers of the intra and extrahepatic bile ducts. Our findings suggest that higher intakes of dietary AGEs are inversely associated with the risk of HCC and positively associated with the risk of gallbladder cancer., What's new? Advanced glycation endproducts (AGEs) are proteins or lipids with sugars added to them, and they can form in foods during cooking. They have pro‐inflammatory and pro‐oxidative properties in the body. These authors investigated whether dietary consumption of AGEs affect risk of liver cancer, using the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants filled out food questionnaires to determine AGE consumption. Higher intakes of AGEs were associated with reduced risk of hepatocellular carcinoma (HCC) and increased risk of gallbladder cancer. However, it's still not entirely clear how much AGEs in the diet contribute to circulating AGE levels.

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes., R.A.I.B. was supported by a British Academy Postdoctoral fellowship and by the Autism Research Trust. J. Seidlitz was supported by NIMH T32MH019112-29 and K08MH120564. S.R.W. was funded by UKRI Medical Research Council MC_UU_00002/2 and was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). E.T.B. was supported by an NIHR Senior Investigator award and the Wellcome Trust collaborative award for the Neuroscience in Psychiatry Network. A.F.A.-B. was supported by NIMH K08MH120564. Data were curated and analysed using a computational facility funded by an MRC research infrastructure award (MR/M009041/1) to the School of Clinical Medicine, University of Cambridge and supported by the mental health theme of the NIHR Cambridge Biomedical Research Centre.

Background Obstructive hydrocephalus in adulthood can be caused by stenosis in the aqueductal area. Chronic changes lead to a dilatation of the lateral ventricles and ballooning of infratentorial recesses. In rare cases a rupture of the floor of the third ventricle (so-called spontaneous ventriculostomy) has been described in the literature. Case presentation: We present two cases of chronic obstructive hydrocephalus due to aqueductal stenosis in adult patients. Magnetic resonance imaging included phase-contrast-imaging and revealed significant flow through the floor of the third ventricle in keeping with spontaneous ventriculostomy. In addition to other typical changes associated with chronic hydrocephalus, a distinct flattening of the tectal plate could be identified in one case. Conclusion We present two cases of spontaneous ventriculostomy in patients with chronic hydrocephalus. To our knowledge, flattening of the tectal plate has not yet been described in the literature and may be caused by continuous cerebrospinal fluid-pulsation.

Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age‐related groups

Since the addition of fluoride to drinking water in the 1940s, there have been frequent and sometimes heated discussions regarding its benefits and risks. In a recently published review, we addressed the question if current exposure levels in Europe represent a risk to human health. This review was discussed in an editorial asking why we did not calculate benchmark doses (BMD) of fluoride neurotoxicity for humans. Here, we address the question, why it is problematic to calculate BMDs based on the currently available data. Briefly, the conclusions of the available studies are not homogeneous, reporting negative as well as positive results; moreover, the positive studies lack control of confounding factors such as the influence of well-known neurotoxicants. We also discuss the limitations of several further epidemiological studies that did not meet the inclusion criteria of our review. Finally, it is important to not only focus on epidemiological studies. Rather, risk analysis should consider all available data, including epidemiological, animal, as well as in vitro studies. Despite remaining uncertainties, the totality of evidence does not support the notion that fluoride should be considered a human developmental neurotoxicant at current exposure levels in European countries.

It is unclear whether deviations in brain and behavioral development, which may underpin elevated substance use during adolescence, are predispositions for or consequences of substance use initiation. Here, we examine behavioral and neuroimaging indices at early and mid-adolescence in drug-naive youths to identify possible predisposing factors for substance use initiation and its possible consequences.Among 304 drug-naive adolescents at baseline (age 14 years) from the IMAGEN dataset, 83 stayed drug-naive, 133 used alcohol on 1 to 9 occasions, 42 on 10 to 19 occasions, 27 on 20 to 39 occasions, and 19 on40 occasions at follow-up (age 16 years). Baseline measures included brain activation during the Monetary Incentive Delay task. Data at both baseline and follow-up included measures of trait impulsivity and delay discounting.From baseline to follow-up, impulsivity decreased in the 0 and 1- to 9-occasions groups (p .004), did not change in the 10- to 19-occasions and 20- to 29-occasions groups (p.294), and uncharacteristically increased in the40-occasions group (p = .046). Furthermore, blunted medial orbitofrontal cortex activation during reward outcome at baseline significantly predicted higher alcohol use frequency at follow-up, above and beyond behavioral and clinical variables (p = .008).These results suggest that the transition from no use to frequent drinking in early to mid-adolescence may disrupt normative developmental changes in behavioral control. In addition, blunted activity of the medial orbitofrontal cortex during reward outcome may underscore a predisposition toward the development of more severe alcohol use in adolescents. This distinction is clinically important, as it informs early intervention efforts in preventing the onset of substance use disorder in adolescents.

©The European Society of Cardiology 2020. Article reuse guidelines : sagepub.com/journals-permissions, Secondary prevention through comprehensive cardiac rehabilitation has been recognized as the most cost-effective intervention to ensure favourable outcomes across a wide spectrum of cardiovascular disease, reducing cardiovascular mortality, morbidity and disability, and to increase quality of life. The delivery of a comprehensive and ‘modern’ cardiac rehabilitation programme is mandatory both in the residential and the out-patient setting to ensure expected outcomes. The present position paper aims to update the practical recommendations on the core components and goals of cardiac rehabilitation intervention in different cardiovascular conditions, in order to assist the whole cardiac rehabilitation staff in the design and development of the programmes, and to support healthcare providers, insurers, policy makers and patients in the recognition of the positive nature of cardiac rehabilitation. Starting from the previous position paper published in 2010, this updated document maintains a disease-oriented approach, presenting both well-established and more controversial aspects. Particularly for implementation of the exercise programme, advances in different training modalities were added and new challenging populations were considered. A general table applicable to all cardiovascular conditions and specific tables for each clinical condition have been created for routine practice.

Chronic inflammation, marked by C-reactive protein, has been associated with changes in methylation, but the causal relationship is unclear. Here, the authors perform a Epigenome-wide association meta-analysis for C-reactive protein levels and find that these methylation changes are likely the consequence of inflammation and could contribute to disease.We performed a multi-ethnic Epigenome Wide Association study on 22,774 individuals to describe the DNA methylation signature of chronic low-grade inflammation as measured by C-Reactive protein (CRP). We find 1,511 independent differentially methylated loci associated with CRP. These CpG sites show correlation structures across chromosomes, and are primarily situated in euchromatin, depleted in CpG islands. These genomic loci are predominantly situated in transcription factor binding sites and genomic enhancer regions. Mendelian randomization analysis suggests altered CpG methylation is a consequence of increased blood CRP levels. Mediation analysis reveals obesity and smoking as important underlying driving factors for changed CpG methylation. Finally, we find that an activated CpG signature significantly increases the risk for cardiometabolic diseases and COPD.

Purpose We assessed and compared clinical effects and safety endpoints of three methods of transarterial chemoembolization (TACE), conventional (cTACE), with drug-eluting beads (DEB-TACE), and with degradable starch microspheres (DSM-TACE), used in patients with hepatocellular carcinoma (HCC) in the bridging to liver transplant (LT) and the palliative setting. Methods In our center, 148 patients with HCC underwent 492 completed TACE procedures between 2008 and 2017 (158 for bridging to LT; 334 for palliative treatment) which we analyzed retrospectively. Of these procedures, 348 were DEB-TACE, 60 cTACE, and 84 DSM-TACE. Results The cTACE procedure revealed a significantly longer period of hospitalization (p = 0.02), increased occurrence of nausea (p = 0.025), and rise in alanine transaminase (ALT) levels (p = 0.001), especially in the palliative setting. In the bridging to LT cohort, these clinical endpoints did not reach statistical significance. Conclusions The clinical safety of different TACE methods for HCC in both the palliative and the bridging to LT setting was equivalent. In the palliative setting, the cTACE procedure revealed an increased risk for adverse clinical effects such as nausea, elevation of ALT, and a prolonged period of hospitalization what might either be related to the systemic effects of the chemotherapeutic agent or to the differences in both collectives. Thus, further studies must be conducted on a larger number of TACE procedures to effectively explore the clinical side effects of the various TACE variants.

In October of 2017 and 2019, Sonoma County California endured historic wildfires and subsequent community trauma. The Sonoma Wildfire Mental Health Collaborative was created to (a) democratize access to evidence-based mental health resources and services for personal recovery and long-term community resilience building, and to (b) measure the reach and efficacy of the strategies employed in order to create a knowledge base to inform disaster response in other communities. Offerings included a mind-body yoga program and training in Skills for Psychological Recovery (SPR) for counselors who wished to provide services to individuals impacted by the wildfires. An evaluation of the mental health strategies employed revealed that (a) the mind-body program was well-received, with a high degree of satisfaction and self-reported benefit among individuals who attended trauma-informed yoga classes and (b) counselors found SPR to be a practical, flexible short-term intervention for individuals in the aftermath of the wildfires and expressed moderate to high levels of intent to use it in practice. Importantly, the evaluation of the 2017 wildfire mental health response was compromised by the Kincade Fire in 2019, in which prolonged mandatory evacuations and power outages impacted response rates. The origin story is shared for how a community collaborative was built. Lessons learned are discussed and recommendations summarized so as to contribute to the science and practice of disaster mental health outreach. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, it may be useful to develop classification models that are explicitly generalizable to unseen sites and populations. This problem was explored in a mega‐analysis of previously published datasets from 2,034 AD and comparison participants spanning 27 sites curated by the ENIGMA Addiction Working Group. Data were grouped into a training set used for internal validation including 1,652 participants (692 AD, 24 sites), and a test set used for external validation with 382 participants (146 AD, 3 sites). An exploratory data analysis was first conducted, followed by an evolutionary search based feature selection to site generalizable and high performing subsets of brain measurements. Exploratory data analysis revealed that inclusion of case‐ and control‐only sites led to the inadvertent learning of site‐effects. Cross validation methods that do not properly account for site can drastically overestimate results. Evolutionary‐based feature selection leveraging leave‐one‐site‐out cross‐validation, to combat unintentional learning, identified cortical thickness in the left superior frontal gyrus and right lateral orbitofrontal cortex, cortical surface area in the right transverse temporal gyrus, and left putamen volume as final features. Ridge regression restricted to these features yielded a test‐set area under the receiver operating characteristic curve of 0.768. These findings evaluate strategies for handling multi‐site data with varied underlying class distributions and identify potential biomarkers for individuals with current AD., To identify neuroimaging biomarkers of alcohol dependence (AD) from structural magnetic resonance imaging, we developed classifiers on data collected from multiple sites. Exploratory data analysis revealed that inclusion of case‐ and control‐only sites led to the inadvertent learning of site‐effects. Evolutionary‐based feature selection leveraging leave‐one‐site‐out cross‐validation, to combat unintentional learning, yielded a test‐set area under the receiver operating characteristic curve of 0.768.

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The prevalence of homologous recombination–DNA damage response (HR-DDR) genetic alterations is of therapeutic interest in gastroesophageal cancers. This study is a comprehensive assessment of HR-DDR mutation prevalence across gastroesophageal adenocarcinomas and squamous cell carcinomas. Here we investigate the association of HR-DDR mutations with known predictors for immune-checkpoint inhibition [deficiency in mismatch-repair (dMMRP), tumor mutational burden (TMB), and programmed death ligand 1 (PD-L1)]. We confirmed HR-DDR mutations are present in a subset of gastroesophageal adenocarcinomas (23%) and gastroesophageal squamous cell carcinomas (20%). Biomarker expression of dMMRP (18% vs. 1%) and TMB-high with a cutoff of ≥10 mt/MB (27% vs. 9%) was significantly more prevalent in the DDR-mutated cohort compared with the non-DDR-mutated cohort. Mean combined positive score for PD-L1 in the total adenocarcinoma cohort was significantly higher in the DDR-mutated cohort compared with the non–DDR-mutated cohort (10.1 vs. 5.8). We demonstrated that alterations in ARID1A, BRCA2, PTEN, and ATM are correlated with dMMRP, TMB-high, and increased PD-L1 expression in gastroesophageal adenocarcinomas. Our findings show that a subset of gastroesophageal tumors harbor HR-DDR mutations correlated with established immune biomarkers. By better understanding the relationship between HR-DDR mutations and immune biomarkers, we may be able to develop better immunotherapy combination strategies to target these tumors.

Summary Background With the experience-based hypothesis of low donor site morbidity (DSM) for free flaps from the distal femur, this cohort study aimed to evaluate the DSM according to objective and reproducible criteria. Methods One hundred and fifty-six patients who had a flap harvest from either the medial or lateral femoral condyle region between 2005 and 2017 were included. A retrospective chart review was performed for all patients. In total, 97 patients were available for a follow-up examination. Outcomes were assessed according to objective (Knee Society Score; Larson Knee Score; OAK Score; 0–100 points), patient-reported (IKDC Score; KOOS Score; 0–100 points), and radiologic criteria (Kellgren and Lawrence Score; MRI Osteoarthritis Knee Score). Results The median follow-up time was 1,529 days (range: 248–4,810). The mean Knee Society Score (94.8 ± 10.1), Larson Knee Score (94.5 ± 10.1), and OAK Score (95.5 ± 6.6) showed nearly unimpaired knee function. The overall patient-reported DSM was low (IKDC Score: 86.7 ± 17.4; KOOS Score: 89.3 ± 17.1). Osteochondral (OC) flaps had a significantly higher DSM, regardless of the donor site. Bone flaps did not show any relevant radiologic morbidity in the Kellgren and Lawrence Score. Besides the procedure-associated cartilage lesions at the OC donor sites, MRI Osteoarthritis Knee Score did not show any significant presence of further knee pathologies in the bilateral MRI Scans. The obvious cartilage lesions did not have a relevant impact on the knee function of most patients. Conclusion The DSM for bone and soft-tissue flaps from the femoral condyle region is negligible. OC flaps are associated with a significantly higher DSM, although a clinically relevant impact on knee function was not evident in the majority of patients.

Background Transperineal magnetic resonance imaging–transrectal ultrasound fusion guided biopsy (MFGB) is an increasingly popular technique due to increasing rates of biopsy-related infections. However, its widespread implementation has been hampered by the supposed necessity of epidural or general anesthesia. Objective To demonstrate the technique, feasibility, and results of transperineal MFGB under local anesthesia, in an ambulatory setting without the administration of prophylactic antibiotics. Design, setting, and participants This single-center study enrolled consecutive biopsy-naive men with a clinical suspicion of prostate cancer into a prospective database between November 2015 and November 2020. Men with Prostate Imaging Reporting and Data System (PI-RADS) version 2 scores 3–5 underwent transperineal MFGB. Surgical procedure Transperineal MFGB was performed in an ambulatory setting under local anesthesia by a single operator. Measurements Procedure-associated adverse events were recorded. Patient discomfort during both the local anesthesia and the biopsy procedure was determined using a visual analogic scale (0–10). Detection rates of grade group (GG) ≥2 prostate cancer and the proportion of men with GG 1 cancer were assessed. Results and limitations A total of 1097 eligible men underwent transperineal MFGB. The complication rate was 0.73% (8/1097); complications comprised five (0.46%) urinary tract infections including one hospitalization and three (0.27%) urinary retentions. In 735 men, the median pain scores were 2 (interquartile range [IQR] 2–3) for the local anesthesia procedure and 1 (IQR 0-2) for the biopsy. Prostate cancer was detected in 84% (926/1097) of men; 66% (723/1097) had GG ≥2 and 19% (203/1097) GG 1. Conclusions Transperineal MFGB can safely be performed as an outpatient procedure under local anesthesia in an ambulatory setting. The detection rate of clinically significant prostate cancer is high, and biopsy is well tolerated. Although no antibiotic prophylaxis was used, the rate of infectious complications is practicably negligible. Patient summary This article shows how tissue samples (biopsies) can accurately be obtained from suspicious regions seen on prostate magnetic resonance imaging via needles inserted in the perineum (skin between the scrotum and the anus) in men with suspected prostate cancer. This technique appears to be very well tolerated under local anesthesia and has a lower risk of infection without antibiotic prophylaxis than the more common biopsy route through the rectum, with antibiotics.

Local recurrence after epidermoid cyst surgery is a frequently reported complication, but intraventricular spread after surgery has not yet been described in literature. We present the case of a 61-year-old male patient with steadily progressive headaches after surgical excision of an epidermoid cyst in the right cerebellopontine angle about two months ago. The MRI showed multiple intraventricular FLAIR-hyperintensities with diffusion restriction, suggestive of scattered remnants of the epidermoid cyst. We recommend early postoperative MRI-scans after cranial epidermoid surgery, which should be carefully inspected not only for local remnants but also rare complications like intraventricular spread.

International audience; Assessment of visual encryption of video and image content requires a reliable estimation of content recognizability and low quality. As pointed out in the literature, current methods are insufficient and research into this topic, as well as into the relation between low quality and recognizability, is still lacking. This lack of research is primarily due to a lack of data. To improve on the status-quo we have taken a recognizability database and performed a subjective quality evaluation on a subset of the images. This gives us a new database with both subjective recognizability and quality information and allows to delve into the relation between low quality and recognizability. We analyze the relationship between quality and recognizability as well as the predictive quality of state of the art visual quality indices. We show that the visual quality indices are poor indicators for the estimation of recognizability. Furthermore, we show that they must be a poor fit because of the disparity between two distinct perceptual tasks: quality and recognizability.

The study investigates collaborative learning of small groups via text-based computer-mediated communication. We analyzed how two approaches to pre-structure communication influence participation, individual knowledge transfer, the convergence of participation and the convergence of knowledge among peers. We varied the factor scripted cooperation and the factor scaffolding in a 2x2-design. 105 university students of Educational Psychology participated. Results show that scripted cooperation was most and scaffolding least beneficial to individual transfer, knowledge convergence and participation in comparison to open discourse.

We present a shared workspace application for co-constructive tasks with functions for tracking, analyzing and feeding back parameters of collaboration to group members. The interdisciplinary approach is based on an integrative methodology for analyzing collaboration behavior and explicit surveyed data of group members' attitudes. In an exploratory study, we examined the influence of the feedback function, with the long term perspective of enriching collaboration processes in real communities of learners.

Funder: MUG (within the PhD program Molecular Medicine), Funder: Austrian Society of Internal Medicine (Joseph-Skoda Award), Austrian Science Fund (grant P32783), Austrian Society of Hematology and Medical Oncology (Clinical Research Grant) and MEFOgraz, Funder: Austrian Science Fund (grant P 31430-458 B26) and Leukämiehilfe Steiermark, Funder: Austrian Society of Internal Medicine (Joseph-Skoda Award)and Leukämiehilfe Steiermark

Idiopathic inflammatory myopathy (IIM) can present with dysphagia as a leading or only symptom. In such cases, diagnostic evaluation may be difficult, especially if serological and electromyographical findings are unsuspicious. In this observational study we propose and evaluate a diagnostic algorithm to identify IIM as a cause of unexplained dysphagia.Over a period of 4 years, patients with unexplained dysphagia were offered diagnostic evaluation according to a specific algorithm: The pattern of dysphagia was characterized by instrumental assessment (swallowing endoscopy, videofluoroscopy, high-resolution manometry). Patients with an IIM-compatible dysphagia pattern were subjected to further IIM-focused diagnostic procedures, including whole-body muscle magnetic resonance imaging, electromyography, creatine kinase blood level, IIM antibody panel and, as a final diagnostic step, muscle biopsy. Muscle biopsies were taken from affected muscles. In cases where no other muscles showed abnormalities, the cricopharyngeal muscle was targeted.Seventy-two patients presented with IIM-compatible dysphagia as a leading or only symptom. As a result of the specific diagnostic approach, 19 of these patients were diagnosed with IIM according to the European League Against Rheumatism (EULAR) criteria. Eighteen patients received immunomodulatory therapy as a result of the diagnosis. Of 10 patients with follow-up swallowing examination, dysphagia improved in three patients after therapy, while it remained at least stable in six patients.Idiopathic inflammatory myopathy constitutes a potentially treatable etiology in patients with unexplained dysphagia. The diagnostic algorithm presented in this study helps to identify patients with an IIM-compatible dysphagia pattern and to assign those patients for further IIM-focused diagnostic and therapeutic procedures.

Gray-zone lymphoma (GZL) reflects an aggressive B-cell neoplasm with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL). The International Prognostic Index (IPI) and its derivatives (R-IPI, NCCN-IPI, and the Hasenclever IPS) have been established for DLBCL or cHL while the most suitable scoring system for GZL remains undetermined. In an exploratory multi-centric cohort of GZL (n = 61), we performed a comparative analysis of prognostic indices with regard to model fit and mutual concordance. The calculation of the corrected Akaike's information criterion (cAIC) and Harrel's concordance index (c-index) for each scoring system identified the NCCN-IPI to harbor the most convincing prognostic capabilities regarding both overall survival (OS) and progression-free survival (PFS) compared to its enhanced derivatives. The current results affirm the clinical utility of the NCCN-IPI and suggest its preferential use in clinical practice in GZL-patients.

ZusammenfassungMehr als 20% der Patienten mit idiopathischem Parkinson-Syndrom (IPS) entwickeln Psychosen. Am häufigsten sind visuelle Halluzinationen. Bei der Entwicklung der Psychosen scheinen die Pathogenese der Parkinson-Erkrankung sowie ihre Dauer ebenso eine Rolle zu spielen wie modulierende Effekte der dopaminergen Therapie. Beim Therapiemanagement steht neben allgemeinen Maßnahmen zunächst die Anpassung der dopaminergen Therapie im Vordergrund. Dies kann zu einer Gratwanderung werden zwischen Besserung der Halluzinationen und Verschlechterung der Motorik. Bei unzureichendem Erfolg kann eine antipsychotische Therapie notwendig werden – dabei ist die Auswahl auf sehr wenige Antipsychotika beschränkt, um nicht ernsthafte motorische Verschlechterungen zu riskieren. In der vorliegenden Arbeit wurden basierend auf dem aktuellen Stand der Literatur sowie empirischen Experten-basierten Erfahrungen aus dem klinischen Alltag relevante Aspekte zu Halluzinationen bei IPS-Patienten in der Praxis zusammengefasst und Empfehlungen zum Therapiemanagement erarbeitet.

ObjectivesTo assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response.MethodsWe enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response.ResultsSamples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC.ConclusionsPatients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy.

BACKGROUND Treatment of patients with type 1 diabetes requires experience and a specific infrastructure. Therefore, center size might influence outcome in diabetes treatment. OBJECTIVE To analyze the influence of center size on the quality of diabetes treatment in children and adolescents in Germany and Austria. PATIENTS AND METHODS In 2009 and 2018, we analyzed metabolic control, acute complications, and rates of recommended screening tests in the DPV cohort. Diabetes centers were classified according to the number of patients from "XS" to "XL" (

Heart failure (HF) will be one of the biggest medical challenges in the coming years, with increasing prevalence in an aging society. It is associated with a poor prognosis and impaired quality of life-despite steadily improving medical therapy which has resulted in a steady decrease in mortality and an increase in quality of life. In medically refractory patients with impaired left ventricular (LV) function, left bundle branch block and wide QRS complex (≥130 ms) cardiac resynchronization therapy (CRT) in addition to medical therapy has become the gold standard. Additionally, other therapeutic modalities such as vagal stimulation are being clinically tested but as yet have no general therapeutic recommendation. Overall, CRT patients represent only one-third of all HF patients and about 25% are "non-responders" who do not benefit from CRT.In HF patients with an LVEF between 25 and 45% and a QRS duration

Reinduction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second-line standard of care for transplant-eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high-dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant-eligible patients aged 18–60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase-I-part) was administered on day 0–13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end-point of computed tomography (CT)-based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT-based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end-point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy.

Objective: Hypotonic fluids are commonly used in pediatric oncology despite evidence that these fluids can lead to hospital-acquired hyponatremia. This practice is most likely due to lack of data evaluating risks and benefits of isotonic fluids in pediatric oncology. To address this issue, our study investigates the effects of exchanging hypotonic fluids with isotonic fluids in a large pediatric oncology unit. Study Design: Prevalence of laboratory disorders before and after the change to balanced, isotonic fluids for all patients are compared in this retrospective analysis. Disturbances in electrolyte levels, fluid-, acid-base balance and kidney function were examined. Results: The rate of hyponatremia was reduced using isotonic fluids. There were no hypernatremic events. Volume overload might increase the use of furosemide when using isotonic fluids. Potassium and bivalent cation levels increased. The risk of acidosis is greatly reduced, whereas alkalosis was more frequent due to furosemide use. The rate of acute kidney injury did not increase. Conclusion: Using isotonic fluids for hyper-hydration in pediatric oncology lead to a modest reduction of hospital-acquired hyponatremia without causing hypernatremia, but the effects on fluid balance need further investigation. The additional intake of bivalent cations and buffering anions in balanced fluids has measurable effects.

Gynecological sonography is the central and most frequently used technical examination method used by gynecologists. Its focus is on the clarification of masses of the uterus and the adnexa, fertility diagnosis, clarification of bleeding disorders and chronic and acute pelvic problems, pelvic floor and incontinence diagnosis as well as the differential diagnosis of disturbed early pregnancy. The indication for diagnostic and therapeutic interventions, preoperative planning and postoperative controls are largely based on the findings of gynecological sonography. These examinations are particularly dependent on the experience of the examiner.Based on the proven multi-stage concept of obstetric diagnostics, gynecological sonography should primarily be performed by an experienced and specialized examiner in patients for whom the initial gynecological examinations have not yet led to a sufficient assessment of the findings. So that the expert status required for this has an objective basis, the Gynecology and Obstetrics Section of DEGUM in cooperation with ÖGUM and SGUM implemented the option of acquiring DEGUM Level II for gynecological sonography. The effectiveness of the care in the multi-level concept depends on the quality of the ultrasound examination at level I. Quality requirements for the basic examination and the differentiation between the basic and further examination have therefore already been defined by DEGUM/ÖGUM. The present work is intended to set out quality requirements for gynecological sonography of DEGUM level II and for the correspondingly certified gynecologists.Common pathologies from gynecological sonography and requirements for imaging and documentation are described.Die gynäkologische Sonografie ist das zentrale und am häufigsten angewandte apparative Untersuchungsverfahren der Frauenärzt*innen. Ihre Schwerpunkte sind die Abklärung von Raumforderungen des Uterus und der Adnexen, die Fertilitätsdiagnostik, Abklärung von Blutungsstörungen und chronischen wie akuten Unterbauchbeschwerden, die Beckenboden- und Inkontinenzdiagnostik sowie die Differentialdiagnostik der gestörten Frühschwangerschaft. Die Indikation zu diagnostischen und therapeutischen Interventionen, die präoperative Planung und die postoperativen Kontrollen beruhen maßgeblich auf Befunden der gynäkologischen Sonografie. Diese Untersuchungen sind im besonderen Maße von der Erfahrung des Untersuchers abhängig.In Anlehnung an das bewährte Mehrstufenkonzept der geburtshilflichen Diagnostik sollte daher bei Patientinnen, in denen die frauenärztlichen Erstuntersuchungen noch nicht zu einer ausreichenden Einschätzung der Befunde führen, primär eine gynäkologische Sonografie durch einen erfahrenen und spezialisierten Untersucher erfolgen. Damit der hierfür erforderliche Expertenstatus eine objektivierbare Grundlage bekommt, wurde von der Sektion Gynäkologie und Geburtshilfe der DEGUM in Kooperation mit der ÖGUM und SGUM die Möglichkeit des Erwerbs der DEGUM-Stufe II für die gynäkologische Sonografie implementiert. Die Effektivität der Versorgung im Mehrstufenkonzept lebt aber von der Qualität der Ultraschalluntersuchung auf Stufe I. Qualitätsanforderungen für die Basisunteruntersuchung und die Differenzierung zwischen Basis- und weiterführender Untersuchung wurden daher bereits von der DEGUM/ÖGUM definiert. Die vorliegende Arbeit soll Qualitätsanforderungen an eine gynäkologische Sonografie der DEGUM-Stufe II und an die entsprechend zertifizierten Frauenärztinnen und Frauenärzte darlegen.Häufige Pathologien aus der gynäkologischen Sonografie und Anforderungen an die Bildgebung und Dokumentation werden beschrieben.

Exhaled aerosol particles play an important role in the transmission of SARS-CoV‑2, particularly when many people gather indoors. This article summarises the knowledge on virus transmission in schools and practical measures to reduce aerosol-driven infections. A central preventive measure is to enhance room and building ventilation, i.e. the exchange of possibly contaminated indoor air with ambient air. Besides the concentrations of possibly infectious particles, ventilation reduces carbon dioxide concentrations, humidity and other chemical substances in indoor air as well. Irrespective of ventilation, face masks (surgical or FFP2) represent a vital part of hygiene measures. Fixed or mobile air purifiers can support these measures particularly when rooms providing only poor ventilation must be utilized. The article reflects the state of knowledge in October 2021 of the various techniques that have been shown as useful for the prevention of indirect infections. New variants of SARS-CoV‑2, the progress of the vaccination campaign in children and adolescents, and the increase in general immunity might require a re-evaluation of the prevention strategies described. The COVID-19 pandemic has revealed common deficits in room and building ventilation, not least in schools. Apart from short-term measures for the prevention of airborne infectious diseases, a long-term strategy seems advisable to alleviate the deficits encountered in schools with respect to room and building ventilation. In view of a permanent improvement of indoor air and prevention against airborne infections the fitting of schools with fixed ventilation systems - preferably including heat and moisture recovery - appears to be a sustainable social investment.Aller Kenntnis nach spielen die mit der Atmung ausgeschiedenen Aerosolpartikel eine wichtige Rolle bei der Verbreitung des 2019 erstmalig aufgetretenen Coronavirus SARS-CoV‑2, insbesondere im Rahmen menschlicher Zusammenkünfte in Innenräumen. Diese Arbeit fasst die für den Schulbetrieb relevanten Sachverhalte und Maßnahmen zur Verminderung von Infektionen über den Aerosolpfad zusammen. Eine wichtige Maßnahme ist die Verstärkung der Raumlüftung, d. h. der Austausch möglicherweise kontaminierter Innenraumluft mit Außenluft. Neben der Verminderung der Konzentration infektiöser Aerosole ist Lüftung unabdingbar zur Abfuhr des in Klassenräumen erzeugten Kohlendioxids, der Luftfeuchte und anderer chemischer Stoffe in der Innenraumluft. Unabhängig von Lüftung erweist sich das Tragen von Mund-Nasen-Masken (medizinische Masken bzw. filtrierende Halbmasken) als wirksame Maßnahme. Eine für virushaltige Partikel wirksame Luftreinigung durch feste bzw. mobile Anlagen kann die genannten Maßnahmen unterstützen bzw. in Fällen aushelfen, wenn Räume trotz schlechter Lüftungsmöglichkeit genutzt werden müssen. Der Artikel gibt den Stand des Wissens im Oktober 2021 über verschiedene technische Schutzmaßnahmen wieder, die sich seit Beginn der Pandemie als sinnvoll erwiesen haben, wobei der Fokus auf der Reduzierung von indirekten Infektionen liegt. Neu hinzukommende Varianten von SARS-CoV‑2, der Fortschritt der Impfkampagne bei Kindern und Jugendlichen sowie die Zunahme der allgemeinen Immunität werden möglicherweise eine Neubewertung der Maßnahmen erfordern. Neben kurzfristigen und schnell wirksamen Maßnahmen zum Infektionsschutz erscheint es auch geboten, die in Deutschland existierenden Defizite bei Raum- und Gebäudelüftung an Schulen durch eine langfristige Strategie zu beheben. Im Sinne einer dauerhaften Verbesserung der Innenraumluft und der Prävention gegen künftige luftübertragene Infektionskrankheiten erscheint die zunehmende Ausstattung von Schulen mit fest installierten Lüftungsanlagen bzw. raumlufttechnischen Anlagen – mit Option auf Wärme- und Feuchterückgewinnung – als nachhaltige gesellschaftliche Investition.

Background: Patients with peripheral artery disease (PAD) fall under the category of a very high cardiovascular risk. Although consequent lipid-lowering therapy (LLT) is advised, only sparse data on attained target level in PAD exists. Objectives: We aimed to analyse contemporary guideline recommendations for LLT in symptomatic PAD patients. Methods: A monocentric, prospective, observational study involving 200 symptomatic PAD patients was conducted. Guideline target level attainment and LLT were analysed between 2017 and 2019. Results: Overall, 78.5% of the patients were on statin therapy, mainly of high intensity, with atorvastatin in 50% and rosuvastatin in 33% of the cases. The average statin dosage adjusted for simvastatin was 55 mg/d. Low density lipoprotein-cholesterol (LDL-C) was Conclusion: It appears that there are more awareness and improvement of previously documented undertreatment of LDL-C levels in symptomatic PAD patients. Although statin treatment is initiated in the majority of patients, our findings call for a continuously intensified LLT in symptomatic PAD patients.

Background Depending on the classification system used, 5–40% of manic subjects present with concomitant depressive symptoms. This post-hoc analysis evaluates the hypothesis that (hypo)manic subjects have a higher burden of depression than non-(hypo)manic subjects. Methods Data from 806 Bipolar I or II participants of the Stanley Foundation Bipolar Network (SFBN) were analyzed, comprising 17,937 visits. A split data approach was used to separate evaluation and verification in independent samples. For verification of our hypotheses, we compared mean IDS-C scores ratings of non-manic, hypomanic and manic patients. Data were stored on an SQL-server and extracted using standard SQL functions. Linear correlation coefficients and pivotal tables were used to characterize patient groups. Results Mean age of participants was 40 ± 12 years (range 18–81). 460 patients (57.1%) were female and 624 were diagnosed as having bipolar I disorder (77.4%) and 182 with bipolar II (22.6%). Data of 17,937 visits were available for analyses, split into odd and even patient numbers and stratified into three groups by YMRS-scores: not manic Conclusion Subjects with a higher manic symptom load are also significantly more likely to experience a higher number of depressive symptoms. Mania and depression are not opposing poles of bipolarity but complement each other.

In 2015, 193 member states of the United Nations (UN) signed the 2030 Agenda, entitled “Transforming Our World: The 2030 Agenda for Sustainable Development,”. The planned implementation by 2030, leaves only a decade to realize the 17 Sustainable Development Goals (SDG). Municipalities and cities constitute important stakeholders, who are obliged under SDG 11, to find ways to develop realistic solutions. Implementation and strategic planning require, among other things, new instruments to digitally model various sustainable development scenarios. Currently, however, it is still unclear what has to be modelled and how. What is clear is that sustainability and digitalization have to come together to deliver results. Several key challenges need to be overcome. First, is the heterogeneity of existing data and documents used in the built environment. Future solutions will depend on a combination of Building Information Modelling (BIM) and Geographic Information System (GIS). Second, is the merging of different existing data on an adequate level of abstraction which allows practical use of GIS and BIM data in a common model. Third, is the development of functioning, cost-effective workflows that will enable broad applications which adequately simulate specific sustainability aspects using spatial and temporal scenarios. This paper shows how these challenges can be systematically addressed in practice. It demonstrates which aspects of sustainability can be made visible and comprehensible for all stakeholders using only one single BIM- and GIS based data model. The proposed workflow could thus be considered as the basis for planning the next generation of smart and sustainable cities.

Genetic design automation methods for combinational circuits often rely on standard algorithms from electronic design automation in their circuit synthesis and technology mapping. However, those algorithms are domain-specific and are hence often not directly suitable for the biological context. In this work we identify aspects of those algorithms that require domain-adaptation. We first demonstrate that enumerating structural variants for a given Boolean specification allows us to find better performing circuits and that stochastic gate assignment methods need to be properly adjusted in order to find the best assignment. Second, we present a general circuit scoring scheme that accounts for the limited accuracy of biological device models including the variability across cells and show that circuits selected according to this score exhibit higher robustness with respect to parametric variations. If gate characteristics in a library are just given in terms of intervals, we provide means to efficiently propagate signals through such a circuit and compute corresponding scores. We demonstrate the novel design approach using the Cello gate library and 33 logic functions that were synthesized and implemented in vivo recently (1). We show that an average 1.3-fold and a peak 6.5-fold performance increase can be achieved by simply considering structural variants and that an average 1.8-fold and a peak 30-fold gain in the novel robustness score can be obtained when selecting circuits according to it.Graphical TOC Entry

Space Situational Awareness (SSA) is key to ensure Space Safety and Sustainability. In order to better understand the challenges of an increasingly congested space environment and to cope with those challenges, Airbus Defence and Space acknowledges the need to develop new sensors and enhanced data processing capabilities. This paper presents how the Special Perturbations Orbit determination and Orbit analysis toolkit (SPOOK), a group of software tools developed at Airbus Defence and Space, serves as a research platform and can be used to cover a range of SSA tasks.

We thank all EPIC participants and staff for their contribution to the study. We also thank staff from the EPIC-CVD coordinating centres for sample preparation and data handling. This research has been conducted using the UK Biobank Resource (application number 29916). Data on coronary artery disease have been contributed by CARDIoGRAMplusC4D investigators and have been downloaded from www.CARDIOGRAMPLUSC4D.ORG.I Sluijswas supported by a personal Dr. Dekker postdoctoral grant (2015T019) from the Netherlands Heart Foundation. NGF and FI acknowledge core Medical Research Council Epidemiology Unit support (MC_UU_12015/5) and NGF acknowledges NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). The InterAct project was funded by the EU FP6 programme (grant number LSHM_CT_2006_037197) and provided the biomarker data in the sub-cohort that was used in the current study. These analyses were supported by Cancer Research UK (C8221/A19170). The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) PI13/00061 (EPIC-Granada) and PI13/01162 (EPIC-Murcia), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, ISCIII Health Research Funds RD12/0036/0018 (cofounded by FEDER funds/European Regional Development Fund ERDF) (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vasterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C570/A16491 and C8221/A19170 for EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk, MR/M012190/1 to EPIC-Oxford) (UK). EPIC-CVD has been supported by the European Commission Framework Programme 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (MR/L003120/1), the British Heart Foundation (RG13/13/30194 and RG/18/13/33946) and the National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust). The MEGASTROKE project received funding from sources specified at http://www.megastroke.org/acknowledgments.html. L.E.T.V.analysed the data and drafted the manuscript. L. E. T. V., I. S. and Y. T. vdS. had access to all data for this study. L. E. T. V., I. S., Y. T. vdS., S. B., N. G. F., H. F., F. I., T. K. N., F. R., E. W., K. A., C. D., A. P. C., M. B. S., T. Y. N. T. and A. S. B. contributed to study conception, design and interpretation of data. All authors contributed to critical revision of the manuscript and approval of version to be published., Higher milk intake has been associated with a lower stroke risk, but not with risk of CHD. Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29 328 participants (4611 stroke; 9828 CHD) of the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD (eight European countries) and European Prospective Investigation into Cancer and Nutrition-Netherlands (EPIC-NL) case-cohort studies. rs4988235, a lactase persistence (LP) SNP which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777 024 participants (50 804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483 966 participants (61 612 cases) from CARDIoGRAM, UK Biobank, EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (beta = 13 center dot 7 g/d; 95 % CI 8 center dot 4, 19 center dot 1) and EPIC-NL (36 center dot 8 g/d; 95 % CI 20 center dot 0, 53 center dot 5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/d 1 center dot 05; 95 % CI 0 center dot 94, 1 center dot 16) or CHD (1 center dot 02; 95 % CI 0 center dot 96, 1 center dot 08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (OR 1 center dot 02; 95 % CI 0 center dot 99, 1 center dot 05) or CHD (OR 0 center dot 99; 95 % CI 0 center dot 95, 1 center dot 03). Current Mendelian randomisation analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk., Netherlands Heart Foundation 2015T019, UK Research & Innovation (UKRI) Medical Research Council UK (MRC), European Commission MC_UU_12015/5, NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme IS-BRC-1215-20014, European Commission LSHM_CT_2006_037197, Cancer Research UK C8221/A19170, European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Deutsche Krebshilfe German Cancer Research Center (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Deutsche Krebshilfe Deutsches Krebsforschungszentrum (Germany), Fondazione AIRC per la ricerca sul cancro Consiglio Nazionale delle Ricerche (CNR), Netherlands Government Netherlands Government, World Cancer Research Fund International (WCRF), Netherlands Government, Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia Regional Government of Asturias (Spain) Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain), ISCIII Health Research Funds (FEDER funds/European Regional Development Fund ERDF) (Spain) RD12/0036/0018, Swedish Cancer Society Swedish Research Council County Council of Skane (Sweden) County Council of Vasterbotten (Sweden), European Commission Framework Programme 7 HEALTH-F2-2012-279233 European Research Council (ERC) European Commission 268834, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/L003120/1 British Heart Foundation RG13/13/30194 RG/18/13/33946 National Institute for Health Research (Cambridge Biomedical Research Centre at the Cambridge University Hospitals NHS Foundation Trust) UK Research & Innovation (UKRI) Medical Research Council UK (MRC) 1000143 MR/M012190/1 Cancer Research UK C8221/A19170 14136 C570/A16491

Objective Irritable mood, a common and impairing symptom in psychopathology, has been proposed to underlie the developmental link between oppositional problems in youth and depression in adulthood. We examined the neural correlates of adolescent irritability in IMAGEN, a sample of 2,024 14-year-old adolescents from 5 European countries. Method The Development and Well-Being Assessment (DAWBA) was used to assess attention-deficit/hyperactivity disorder, major depressive disorder, oppositional defiant disorder, and generalized anxiety disorder. Three items from the DAWBA, selected as close matches to the Affective Reactivity Index, were used to assess irritability. Structural magnetic resonance imaging was examined using whole-brain voxel-based morphometry analysis, and functional magnetic resonance imaging was examined during a stop signal task of inhibitory control. Imaging data were included in structural equation models to examine the direct and indirect associations between irritable mood and comorbid DSM diagnoses. Results Whole-brain voxelwise analysis showed that adolescent irritable mood was associated with less gray matter volume and less neural activation underlying inhibitory control in frontal and temporal cortical areas (cluster-correction at p Conclusion This study identifies adolescent irritability as an independent construct and points to a neurobiological correlate to irritability that is an important contributing feature to many psychopathological disorders.

Numerical simulation approaches have been widely applied to study mining induced subsidence, and they are potential methods to study the flooding induced uplift for abandoned mines. This paper gives an overview about different numerical approaches to simulate uplift induced by flooding abandoned underground mines, including three different hydraulic conditions, considering both unconfined and confined water conditions. Four basic simulation schemes using 1-dimensional rock column models verified by analytical solutions demonstrate these procedures. The results reveal that flooding induced uplift is mainly related to the pore pressure in the mine goaf. The parameter study documents that height and stiffness of the mine goaf have the strongest influence on maximum surface uplift.

The digital transformation offers new opportunities for organizations to expand their existing service portfolio in order to achieve competitive advantages. A popular way to create new customer value is the offer of analytics-based services (ABS)—services that apply analytical methods to data to empower customers to make better decisions and to solve complex problems. However, research still lacks to provide a profound conceptualization of this novel service type. Similarly, actionable insights on how to purposefully establish ABS in the market to enrich the service portfolio remain scarce. We perform a cluster analysis of 105 ABS and triangulate it with a revelatory case study to identify four generic ABS archetypes and to unveil their specific service objectives and characteristics. We also isolate essential factors that shape decision-making regarding the choice of adequate archetypes and subsequent transitions between them. The detailed characterization of different ABS types contributes to a more profound theorizing process on ABS as well as provides a systematization for strategic opportunities to enrich service portfolios in practice.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA quantities, measured by reverse transcription quantitative PCR (RT-qPCR), have been proposed to stratify clinical risk or determine analytical performance targets. We investigated reproducibility and how setting diagnostic cutoffs altered the clinical sensitivity of coronavirus disease 2019 (COVID-19) testing. Methods Quantitative SARS-CoV-2 RNA distributions [quantification cycle (Cq) and copies/mL] from more than 6000 patients from 3 clinical laboratories in United Kingdom, Belgium, and the Republic of Korea were analyzed. Impact of Cq cutoffs on clinical sensitivity was assessed. The June/July 2020 INSTAND external quality assessment scheme SARS-CoV-2 materials were used to estimate laboratory reported copies/mL and to estimate the variation in copies/mL for a given Cq. Results When the WHO-suggested Cq cutoff of 25 was applied, the clinical sensitivity dropped to about 16%. Clinical sensitivity also dropped to about 27% when a simulated limit of detection of 106 copies/mL was applied. The interlaboratory variation for a given Cq value was >1000 fold in copies/mL (99% CI). Conclusion While RT-qPCR has been instrumental in the response to COVID-19, we recommend Cq (cycle threshold or crossing point) values not be used to set clinical cutoffs or diagnostic performance targets due to poor interlaboratory reproducibility; calibrated copy-based units (used elsewhere in virology) offer more reproducible alternatives. We also report a phenomenon where diagnostic performance may change relative to the effective reproduction number. Our findings indicate that the disparities between patient populations across time are an important consideration when evaluating or deploying diagnostic tests. This is especially relevant to the emergency situation of an evolving pandemic.

Antiapoptotic Bcl-2 family members have recently (re)emerged as key drug targets in cancer, with a tissue- and tumor-specific activity profile of available BH3 mimetics. In multiple myeloma, MCL-1 has been described as a major gatekeeper of apoptosis. This discovery has led to the rapid establishment of clinical trials evaluating the impact of various MCL-1 inhibitors. However, our understanding about the clinical impact and optimal use of MCL-1 inhibitors is still limited. We therefore explored mechanisms of acquired MCL-1 inhibitor resistance and optimization strategies in myeloma. Our findings indicated heterogeneous paths to resistance involving baseline Bcl-2 family alterations of proapoptotic (BAK, BAX, and BIM) and antiapoptotic (Bcl-2 and MCL-1) proteins. These manifestations depend on the BH3 profile of parental cells that guide the enhanced formation of Bcl-2:BIM and/or the dynamic (ie, treatment-induced) formation of Bcl-xL:BIM and Bcl-xL:BAK complexes. Accordingly, an unbiased high-throughput drug-screening approach (n = 528) indicated alternative BH3 mimetics as top combination partners for MCL-1 inhibitors in sensitive and resistant cells (Bcl-xL>Bcl-2 inhibition), whereas established drug classes were mainly antagonistic (eg, antimitotic agents). We also revealed reduced activity of MCL-1 inhibitors in the presence of stromal support as a drug-class effect that was overcome by concurrent Bcl-xL or Bcl-2 inhibition. Finally, we demonstrated heterogeneous Bcl-2 family deregulation and MCL-1 inhibitor cross-resistance in carfilzomib-resistant cells, a phenomenon linked to the MDR1-driven drug efflux of MCL-1 inhibitors. The implications of our findings for clinical practice emphasize the need for patient-adapted treatment protocols, with the tracking of tumor- and/or clone-specific adaptations in response to MCL-1 inhibition.

Objectives To compare the diagnostic value of ultrashort echo time (UTE) magnetic resonance imaging (MRI) for the lung versus the gold standard computed tomography (CT) and two T1-weighted MRI sequences in children. Methods Twenty-three patients with proven oncologic disease (14 male, 9 female; mean age 9.0 + / − 5.4 years) received 35 low-dose CT and MRI examinations of the lung. The MRI protocol (1.5-T) included the following post-contrast sequences: two-dimensional (2D) incoherent gradient echo (GRE; acquisition with breath-hold), 3D volume interpolated GRE (breath-hold), and 3D high-resolution radial UTE sequences (performed during free-breathing). Images were evaluated by considering image quality as well as distinct diagnosis of pulmonary nodules and parenchymal areal opacities with consideration of sizes and characterisations. Results The UTE technique showed significantly higher overall image quality, better sharpness, and fewer artefacts than both other sequences. On CT, 110 pulmonary nodules with a mean diameter of 4.9 + / − 2.9 mm were detected. UTE imaging resulted in a significantly higher detection rate compared to both other sequences (p p Conclusion The UTE technique for lung MRI is favourable in children with generally high diagnostic performance compared to standard T1-weighted sequences as well as CT. Key Points • Due to the possible acquisition during free-breathing of the patients, the UTE MRI sequence for the lung is favourable in children. • The UTE technique reaches higher overall image quality, better sharpness, and lower artefacts, but not higher contrast compared to standard post-contrast T1-weighted sequences. • In comparison to the gold standard chest CT, the detection rate of small pulmonary nodules small nodules ≤ 4 mm and subtle parenchymal areal opacities is higher with the UTE imaging than standard T1-weighted sequences.

Aims Cardiac involvement in COVID-19 is associated with adverse outcome. However, it is unclear whether cell-specific consequences are associated with cardiac SARS-CoV-2 infection. Therefore, we investigated heart tissue utilizing in situ hybridization, immunohistochemistry, and RNA-sequencing in consecutive autopsy cases to quantify virus load and characterize cardiac involvement in COVID-19. Methods and results In this study, 95 SARS-CoV-2-positive autopsy cases were included. A relevant SARS-CoV-2 virus load in the cardiac tissue was detected in 41/95 deceased (43%). Massive analysis of cDNA ends (MACE)-RNA-sequencing was performed to identify molecular pathomechanisms caused by the infection of the heart. A signature matrix was generated based on the single-cell dataset ‘Heart Cell Atlas’ and used for digital cytometry on the MACE-RNA-sequencing data. Thus, immune cell fractions were estimated and revealed no difference in immune cell numbers in cases with and without cardiac infection. This result was confirmed by quantitative immunohistological diagnosis. MACE-RNA-sequencing revealed 19 differentially expressed genes (DEGs) with a q-value, Graphical Abstract

Despite the acknowledged injustice and widespread existence of parachute research studies conducted in low- or middle-income countries by researchers from institutions in high-income countries, there is currently no pragmatic guidance for how academic journals should evaluate manuscript submissions and challenge this practice. We assembled a multidisciplinary group of editors and researchers with expertise in international health research to develop this consensus statement. We reviewed relevant existing literature and held three workshops to present research data and holistically discuss the concept of equitable authorship and the role of academic journals in the context of international health research partnerships. We subsequently developed statements to guide prospective authors and journal editors as to how they should address this issue. We recommend that for manuscripts that report research conducted in low- or middle-income countries by collaborations including partners from one or more high-income countries, authors should submit accompanying structured reflexivity statements. We provide specific questions that these statements should address and suggest that journals should transparently publish reflexivity statements with accepted manuscripts. We also provide guidance to journal editors about how they should assess the structured statements when making decisions on whether to accept or reject submitted manuscripts. We urge journals across disciplines to adopt these recommendations to accelerate the changes needed to halt the practice of parachute research.

BackgroundThe incidence of young-onset colorectal cancer (yoCRC) is increasing. It is unknown if there are survival differences between young and older patients with metastatic colorectal cancer (mCRC).MethodsWe studied the association of age with survival in 2326 mCRC patients enrolled in the Cancer and Leukemia Group B and SWOG 80405 trial, a multicenter, randomized trial of first-line chemotherapy plus biologics. The primary and secondary outcomes of this study were overall survival (OS) and progression-free survival (PFS), respectively, which were assessed by Kaplan-Meier method and compared among younger vs older patients with the log-rank test. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated based on Cox proportional hazards modeling, adjusting for known prognostic variables. All statistical tests were 2-sided.ResultsOf 2326 eligible subjects, 514 (22.1%) were younger than age 50 years at study entry (yoCRC cohort). The median age of yoCRC patients was 44.3 vs 62.5 years in patients aged 50 years and older. There was no statistically significant difference in OS between yoCRC vs older-onset patients (median = 27.07 vs 26.12 months; adjusted HR = 0.98, 95% CI = 0.88 to 1.10; P = .78). The median PFS was also similar in yoCRC vs older patients (10.87 vs 10.55 months) with an adjusted hazard ratio of 1.02 (95% CI = 0.92 to 1.13; P = .67). Patients younger than age 35 years had the shortest OS with median OS of 21.95 vs 26.12 months in older-onset patients with an adjusted hazard ratio of 1.08 (95% CI = 0.81 to 1.44; Ptrend = .93).ConclusionIn this large study of mCRC patients, there were no statistically significant differences in survival between patients with yoCRC and CRC patients aged 50 years and older.