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Long-term outcomes are difficult to predict after paediatric traumatic brain injury. The presence or absence of focal brain injuries often do not explain cognitive, emotional and behavioural disabilities that are common and disabling. In adults, traumatic brain injury produces progressive brain atrophy that can be accurately measured and is associated with cognitive decline. However, the effect of paediatric traumatic brain injury on brain volumes is more challenging to measure because of its interaction with normal brain development. Here we report a robust approach to the individualized estimation of brain volume following paediatric traumatic brain injury and investigate its relationship to clinical outcomes. We first used a large healthy control dataset (n > 1200, age 8–22) to describe the healthy development of white and grey matter regions through adolescence. Individual estimates of grey and white matter regional volume were then generated for a group of moderate/severe traumatic brain injury patients injured in childhood (n = 39, mean age 13.53 ± 1.76, median time since injury = 14 months, range 4–168 months) by comparing brain volumes in patients to age-matched controls. Patients were individually classified as having low or normal brain volume. Neuropsychological and neuropsychiatric outcomes were assessed using standardized testing and parent/carer assessments. Relative to head size, grey matter regions decreased in volume during normal adolescence development whereas white matter tracts increased in volume. Traumatic brain injury disrupted healthy brain development, producing reductions in both grey and white matter brain volumes after correcting for age. Of the 39 patients investigated, 11 (28%) had at least one white matter tract with reduced volume and seven (18%) at least one area of grey matter with reduced volume. Those classified as having low brain volume had slower processing speed compared to healthy controls, emotional impairments, higher levels of apathy, increased anger and learning difficulties. In contrast, the presence of focal brain injury and microbleeds were not associated with an increased risk of these clinical impairments. In summary, we show how brain volume abnormalities after paediatric traumatic brain injury can be robustly calculated from individual T1 MRI using a large normative dataset that allows the effects of healthy brain development to be controlled for. Using this approach, we show that volumetric abnormalities are common after moderate/severe traumatic brain injury in both grey and white matter regions, and are associated with higher levels of cognitive, emotional and behavioural abnormalities that are common after paediatric traumatic brain injury.

Background The role of platelets in the pathogenesis of venous thromboembolism (VTE) is receiving increasing attention; however, limited information is available on platelet function in the acute phase of the disease. Objective To characterize platelet function according to VTE phenotypes. Patients/Methods In total, 154 subjects (isolated pulmonary embolism [iPE], n = 28; isolated deep vein thrombosis [iDVT], n = 35; DVT+PE, n = 91) were included. In this study platelet function analyzer (PFA)-200, light transmission aggregometry (LTA), thrombin generation (TG) in presence (PRP) and absence (PFP) of platelets and platelet flow cytometry were investigated. LASSO regression was used to select clinical and platelet biomarkers that distinguish between VTE phenotypes. Results PFA-200 results did not differ between VTE phenotypes. LTA from DVT+PE subjects showed lowest maximum aggregation after epinephrine and adenosine diphosphate compared to iPE and iDVT. Lower % of PAC-1-positive platelets after in-vitro trigger were present in DVT+PE and iPE compared to iDVT. TG in PRP had lower peak height and velocity in DVT+PE and iPE against iDVT. The results of LASSO regression for the distinction between DVT+PE vs iDVT identified 18 variables (AUC =0.93) of which 72% were platelet biomarkers. For distinction between iPE and iDVT, 10 variables were selected (AUC = 0.96) of which 50% were platelet-related. Obesity was the only variable weakly discriminating between DVT+PE vs iPE (AUC = 0.66). Conclusion This explorative study suggests an important distinction between PE-related phenotypes and iDVT when considering clinical and platelet function data. Lower platelet-dependent TG along with reduced platelet reactivity suggest higher platelet degranulation in PE-dependent phenotypes compared to iDVT.

BACKGROUND: The gait modification strategies Trunk Lean and Medial Thrust have been shown to reduce the external knee adduction moment (EKAM) in patients with knee osteoarthritis which could contribute to reduced progression of the disease. Which strategy is most optimal differs between individuals, but the underlying mechanism that causes this remains unknown. RESEARCH QUESTION: Which gait parameters determine the optimal gait modification strategy for individual patients with knee osteoarthritis? METHODS: Forty-seven participants with symptomatic medial knee osteoarthritis underwent 3-dimensional motion analysis during comfortable gait and with two gait modification strategies: Medial Thrust and Trunk Lean. Kinematic and kinetic variables were calculated. Participants were then categorized into one of the two subgroups, based on the modification strategy that reduced the EKAM the most for them. Multiple logistic regression analysis with backward elimination was used to investigate the predictive nature of dynamic parameters obtained during comfortable walking on the optimal modification gait strategy. RESULTS: For 68.1 % of the participants, Trunk Lean was the optimal strategy in reducing the EKAM. Baseline characteristics, kinematics and kinetics did not differ significantly between subgroups during comfortable walking. Changes to frontal trunk and tibia angles correlated significantly with EKAM reduction during the Trunk Lean and Medial Thrust strategies, respectively. Regression analysis showed that MT is likely optimal when the frontal tibia angle range of motion and peak knee flexion angle in early stance during comfortable walking are high (R2Nagelkerke = 0.12). SIGNIFICANCE: Our regression model based solely on kinematic parameters from comfortable walking contained characteristics of the frontal tibia angle and knee flexion angle. As the model explains only 12.3 % of variance, clinical application does not seem feasible. Direct assessment of kinetics seems to be the most optimal strategy for selecting the most optimal gait modification strategy for individual patients with knee osteoarthritis. ispartof: GAIT & POSTURE vol:102 pages:1-9 ispartof: location:England status: published

Heart development and rhythm control are highly Tbx5 dosage-sensitive. TBX5 haploinsufficiency causes congenital conduction disorders, whereas increased expression levels of TBX5 in human heart samples has been associated with atrial fibrillation (AF). We deleted the conserved mouse orthologues of two independent AF-associated genomic regions in the Tbx5 locus, one intronic (RE(int)) and one downstream (RE(down)) of Tbx5. In both lines, we observed a modest (30%) increase of Tbx5 in the postnatal atria. To gain insight into the effects of slight dosage increase in vivo, we investigated the atrial transcriptional, epigenetic and electrophysiological properties of both lines. Increased atrial Tbx5 expression was associated with induction of genes involved in development, ion transport and conduction, with increased susceptibility to atrial arrhythmias, and increased action potential duration of atrial cardiomyocytes. We identified an AF-associated variant in the human RE(int) that increases its transcriptional activity. Expression of the AF-associated transcription factor Prrx1 was induced in Tbx5RE(int)KO cardiomyocytes. We found that some of the transcriptional and functional changes in the atria caused by increased Tbx5 expression were normalized when reducing cardiac Prrx1 expression in Tbx5RE(int)KO mice, indicating an interaction between these two AF genes. We conclude that modest increases in expression of dose-dependent transcription factors, caused by common regulatory variants, significantly impact on the cardiac gene regulatory network and disease susceptibility.

Previous research suggests that belief in free will correlates with intentionality attribution. However, whether belief in free will is also related to more basic social processes is unknown. Based on evidence that biological motion contains intentionality cues that observers spontaneously extract, we investigate whether people who believe more in free will, or in related constructs, such as dualism and determinism, would be better at picking up such cues and therefore at detecting biological agents hidden in noise, or would be more inclined to detect intentionality cues and therefore to detect biological agents even when there are none. Signal detection theory was used to measure participants' ability to detect biological motion from scrambled background noise (d ') and their response bias (c) in doing so. In two experiments, we found that belief in determinism and belief in dualism, but not belief in free will, were associated with biological motion perception. However, no causal effect was found when experimentally manipulating free will-related beliefs. In sum, our results show that biological motion perception, a low-level social process, is related to high-level beliefs about dualism and determinism.

Aims Whether and how iron deficiency (ID) impacts patients with heart failure (HF) with preserved ejection fraction (HFpEF) remain unclear. The aim of our study was to investigate the impact of ID on functional status, exercise capacity, and prognosis in HFpEF. Methods and results The study population consisted of 300 HFpEF patients. ID was defined as serum ferritin

Background: Merkel cell carcinoma (MCC) is a rare but highly aggressive neuroendocrine carcinoma of the skin with a poor prognosis. Improving the prognosis of MCC by means of targeted therapies requires further understanding of the mechanisms that drive tumor progression. In this study, we aimed to identify the genes, processes, and pathways that play the most crucial roles in determining MCC outcomes. Methods: We investigated transcriptomes generated by RNA sequencing of formalin-fixed paraffin-embedded tissue samples of 102 MCC patients and identified the genes that were upregulated among survivors and in patients who died from MCC. We subsequently cross-referenced these genes with online databases to investigate the functions and pathways they represent. We further investigated differential gene expression based on viral status in patients who died from MCC. Results: We found several novel genes associated with MCC-specific survival. Genes upregulated in patients who died from MCC were most notably associated with angiogenesis and the PI3K-Akt and MAPK pathways; their expression predominantly had no association with viral status in patients who died from MCC. Genes upregulated among survivors were largely associated with antigen presentation and immune response. Conclusion: This outcome-based discrepancy in gene expression suggests that these pathways and processes likely play crucial roles in determining MCC outcomes.

Early haemorrhage control and minimizing the time to definitive care have long been the cornerstones of therapy for patients exsanguinating from non-compressible haemorrhage (NCH) after penetrating injuries, as only basic treatment could be provided on scene. However, more recently, advanced on-scene treatments such as the transfusion of blood products, resuscitative thoracotomy (RT) and resuscitative endovascular balloon occlusion of the aorta (REBOA) have become available in a small number of pre-hospital critical care teams. Although these advanced techniques are included in the current traumatic cardiac arrest algorithm of the European Resuscitation Council (ERC), published in 2021, clear guidance on the practical application of these techniques in the pre-hospital setting is scarce. This paper provides a scoping review on how these advanced techniques can be incorporated into practice for the resuscitation of patients exsanguinating from NCH after penetrating injuries, based on available literature and the collective experience of several helicopter emergency medical services (HEMS) across Europe who have introduced these advanced resuscitation interventions into routine practice.

Background and objective The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable, and accurate prognostic markers are needed. KL-6 is a mucin-like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21-1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury. Methods Serum KL-6 and CYFRA 21-1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed-effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis. Results In both cohorts, KL-6 and CYFRA 21-1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL-6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc-ILD, serum KL-6, but not CYFRA 21-1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL-6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage. Conclusion Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.

The objective of this retrospective study was to determine the role of F-18-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. Methods: The 495 patients were treated with Lu-177- or Y-90-DOTATOC/DOTATATE PRRT between February 2002 and July 2018. All subjects received both Ga-68-DOTATOC/TATE/NOC and F-18-FDG PET/CT before treatment and were followed 3-189 mo. Kaplan-Meier analysis, log-rank testing (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). Results: One hundred ninety-nine patients (40.2%) presented with pancreatic NENs, 49 with cancer of unknown primary, and 139 with midgut NENs, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8, and in other locations in 42. F-18-FDG PET/CT was positive in 382 (77.2%) patients and negative in 113 (22.8%) before PRRT, whereas 100% were Ga-68-DOTATOC/TATE/NOC-positive. For all patients, the median PFS and OS, defined from the start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive F-18-FDG results predicted shorter PFS (18.5 mo vs. 24.1 mo; P = 0.0015) and OS (53.2 mo vs. 83.1 mo; P

Most physical and other natural systems are complex entities composed of a large number of interacting individual elements. It is a surprising fact that they often obey the so-called scaling laws relating an observable quantity with a measure of the size of the system. Here we describe the discovery of universal superlinear metabolic scaling laws in human cancers. This dependence underpins increasing tumour aggressiveness, due to evolutionary dynamics, which leads to an explosive growth as the disease progresses. We validated this dynamic using longitudinal volumetric data of different histologies from large cohorts of cancer patients. To explain our observations we put forward increasingly-complex biologically-inspired mathematical models that captured the key processes governing tumor growth. Our models predicted that the emergence of superlinear allometric scaling laws is an inherently three-dimensional phenomenon. Moreover, the scaling laws thereby identified allowed us to define a set of metabolic metrics with prognostic value, thus providing added clinical utility to the base findings. This research has been supported by the James S. McDonnell Foundation 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer (collaborative awards 220020560 and 220020450), Ministerio de Economia y Competitividad/FEDER, Spain (grant no. MTM2015-71200-R), Junta de Comunidades de Castilla-La Mancha (grant no. SBPLY/17/180501/000154). Research in the Brain Metastasis Group is supported by MINECO grant MINECO-Retos SAF2017-89643-R (M.V.), Bristol-Myers Squibb Melanoma Research Alliance Young Investigator Award 2017 (498103) (M.V.), Beug Foundation's Prize for Metastasis Research 2017 (M.V.), Fundacion Ramon Areces (CIVP19S8163) (M.V.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972) (M.V.), Fundacio La Marato de tv3 (141), Clinic and Laboratory Integration Program CRI Award 2018 (54545) (M.V.), AECC Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), La Caixa INPhINIT Fellowship (LCF/BQ/IN17/11620028) (P.G.-G.), La Caixa-Severo Ochoa International PhD Program Fellowship (LCF/BQ/SO16/52270014) (L.Z.). M.V. is a member of the European Molecular Biology Organization Young Investigators programme (4053). We would like to acknowledge J. Cervera and J. C. Penalver from the IVO Foundation (Valencia, Spain). No

Objectives: To determine the accuracy of, and agreement among, EEG and aEEG readers' estimation of maturity and a novel computational measure of functional brain age (FBA) in preterm infants. Methods: Seven experts estimated the postmenstrual ages (PMA) in a cohort of recordings from preterm infants using cloud-based review software. The FBA was calculated using a machine learning-based algorithm. Error analysis was used to determine the accuracy of PMA assessments and intraclass correlation (ICC) was used to assess agreement between experts. Results: EEG recordings from a PMA range 25 to 38 weeks were successfully interpreted. In 179 recordings from 62 infants interpreted by all human readers, there was moderate agreement between experts (aEEG ICC = 0.724; 95%CI:0.658-0.781 and EEG ICC = 0.517; 95%CI:0.311-0.664). In 149 recordings from 61 infants interpreted by all human readers and the FBA algorithm, random and systematic errors in visual interpretation of PMA were significantly higher than the computational FBA estimate. Tracking of maturation in individual infants showed stable FBA trajectories, but the trajectories of the experts' PMA estimate were more likely to be obscured by random errors. The accuracy of visual interpretation of PMA estimation was compromised by neurodevelopmental outcome for both aEEG and EEG review. Interpretation: Visual assessment of infant maturity is possible from the EEG or aEEG, with an average of human experts providing the highest accuracy. Tracking PMA of individual infants was hampered by errors in experts' estimates. FBA provided the most accurate maturity assessment and has potential as a biomarker of early outcome.

Background The choice of treatment in laryngeal cancer is mainly based on tumor stage, post-treatment morbidity and quality of life. Biological tumor markers might also be of potential clinical relevance.Objective of the review The aim was to systematically review the value of published biological tumor markers to predict local control in laryngeal cancer patients treated with definitive radiotherapy.Type of Review Systematic review.Search strategy PubMed, Embase, Cochrane Library.Evaluation Method A literature search was performed using multiple terms for laryngeal cancer, radiotherapy, biological markers, detection methods and local control or survival. Studies regarding the relation between biological tumor markers and local control or survival in laryngeal cancer patients primarily treated with radiotherapy were included. Markers were clustered on biological function. Quality of all studies was assessed. Study selection, data extraction and quality assessment was performed by two independent reviewers.Results A total of 52 studies out of 618 manuscripts, concerning 118 markers, were included. EGFR and P53 showed consistent evidence for not being predictive of local control after primary radiotherapy, whereas proliferation markers (ie high Ki-67 expression) showed some, but no consistent, evidence for being predictive of better local control. Other clusters of markers (markers involved in angiogenesis and hypoxia, apoptosis markers, cell cycle, COX-2 and DNA characteristics) showed no consistent evidence towards being predictors of local control after primary radiotherapy.Conclusions Cell proliferation could be of potential interest for predicting local control after primary radiotherapy in laryngeal cancer patients, whereas EGFR and p53 are not predictive in contrast to some previous analyses. Large diversity in research methods is found between studies, which results in contradictory outcomes. Future studies need to be more standardised and well described according to the REMARK criteria in order to have better insight into which biomarkers can be used as predictors of local control after primary radiotherapy.

Background The choice of treatment in laryngeal cancer is mainly based on tumor stage, post-treatment morbidity and quality of life. Biological tumor markers might also be of potential clinical relevance. Objective of the review The aim was to systematically review the value of published biological tumor markers to predict local control in laryngeal cancer patients treated with definitive radiotherapy. Type of review Systematic review. Search strategy PubMed, Embase, Cochrane Library. Evaluation method A literature search was performed using multiple terms for laryngeal cancer, radiotherapy, biological markers, detection methods and local control or survival. Studies regarding the relation between biological tumor markers and local control or survival in laryngeal cancer patients primarily treated with radiotherapy were included. Markers were clustered on biological function. Quality of all studies was assessed. Study selection, data extraction and quality assessment was performed by two independent reviewers. Results A total of 52 studies out of 618 manuscripts, concerning 118 markers, were included. EGFR and P53 showed consistent evidence for not being predictive of local control after primary radiotherapy, whereas proliferation markers (ie high Ki-67 expression) showed some, but no consistent, evidence for being predictive of better local control. Other clusters of markers (markers involved in angiogenesis and hypoxia, apoptosis markers, cell cycle, COX-2 and DNA characteristics) showed no consistent evidence towards being predictors of local control after primary radiotherapy. Conclusions Cell proliferation could be of potential interest for predicting local control after primary radiotherapy in laryngeal cancer patients, whereas EGFR and p53 are not predictive in contrast to some previous analyses. Large diversity in research methods is found between studies, which results in contradictory outcomes. Future studies need to be more standardised and well described according to the REMARK criteria in order to have better insight into which biomarkers can be used as predictors of local control after primary radiotherapy.

We investigated the transcriptomic landscape of the murine myocardium along the course of natural aging and in three distinct mouse models of premature aging with established aging-related cardiac dysfunction. Genome-wide total RNA-seq was performed and the expression patterns of protein-coding genes and non-coding RNAs were compared between hearts from naturally aging mice, mice with cardiac-specific deficiency of a component of the DNA repair machinery, mice with reduced mitochondrial antioxidant capacity and mice with reduced telomere length. Our results demonstrate that no dramatic changes are evident in the transcriptomes of naturally senescent murine hearts until two years of age, in contrast to the transcriptome of accelerated aged mice. Additionally, these mice displayed model-specific alterations of the expression levels of protein-coding and non-coding genes with hardly any overlap with age-related signatures. Our data demonstrate very limited similarities between the transcriptomes of all our murine aging models and question their reliability to study human cardiovascular senescence.

Signe Bollerup,1 Frederik Engsig,1 Sofie Hallager,1 Amanda Mocroft,2,3 Birgit T Roege,4 Peer B Christensen,5,6 Alex L Laursen,7 Henrik Krarup,8,9 Mette R Clausen,10 Peter Thielsen,11 Lone G Madsen,12,13 Lars Noerregaard,14 Toke S Barfod,15 Ulla Balslev,16 Britta Tarp,17 Jesper B Hansen,9 Lone H Mygind,18 Jan Gerstoft,13,19 Nina Weis1,13 1Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark; 2Centre for Clinical Research, Epidemiology, Modelling and Evaluation (CREME), Institute for Global Health, UCL, London, England; 3Centre of Excellence for Health, Immunity and Infections (CHIP) and PERSIMUNE, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 4Department of Internal Medicine, Kolding Hospital, Kolding, Denmark; 5Department of Infectious Diseases, Odense University Hospital, Odense, Denmark; 6Clinical Institute, University of Southern Denmark, Odense, Denmark; 7Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark; 8Department of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark; 9Department of Medical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark; 10Department of Medical Gastroenterology and Hepatology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 11Department of Gastroenterology, Herlev Hospital, Herlev, Denmark; 12Department of Medical Gastroenterology, Zealand University Hospital, Koege, Denmark; 13Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 14Department of Lung- and Infectious Diseases, North Zealand Hospital, Hilleroed, Denmark; 15Department of Internal Medicine and Infectious Diseases, Zealand University Hospital, Roskilde, Denmark; 16Department of Infectious Diseases, Herlev Hospital, Herlev, Denmark; 17Diagnostic Centre, University Research Clinic for Innovative Patient Pathways, Silkeborg Regional Hospital, Silkeborg, Denmark; 18Department of Infectious Diseases, Aalborg University Hospital, Aalborg, Denmark; 19Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, DenmarkCorrespondence: Nina Weis, Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark, Tel: +45 38623514, Email Nina.Weis@regionh.dkPurpose: We aimed to determine incidence of hepatocellular carcinoma (HCC) and decompensated liver cirrhosis in persons with chronic hepatitis B virus (HBV) infection in Denmark stratified by disease phase, liver cirrhosis, and treatment status at baseline. Additionally, we aimed to assess the prognostic value of the PAGE-B HCC risk score in a mainly non-cirrhotic population.Patients and Methods: In this register-based cohort study, we included all individuals over the age of 18, with chronic HBV infection first registered between 2002 and 2016 in at least one of three nationwide registers. The study population was followed until HCC, decompensated liver cirrhosis, death, emigration, or December 31, 2017, which ever came first.Results: Among 6016 individuals included in the study, 10 individuals with and 23 without baseline liver cirrhosis developed HCC during a median follow up of 7.3 years (range 0.0– 15.5). This corresponded to five-year cumulative incidences of 7.1% (95% confidence interval (CI) 2.0– 12.3) and 0.2% (95% CI 0.1– 0.4) in persons with and without baseline liver cirrhosis. The five-year cumulative incidence of decompensated liver cirrhosis was 0.7% (95% CI 0.5– 1.0). Among 2038 evaluated for liver events stratified by disease phase, incidence of HCC was low in all who were non-cirrhotic and untreated for HBV at baseline. PAGE-B score was evaluated in 1529 persons. The 5-year cumulative incidence of HCC was 0, 0.8 (95% CI 0.5– 1.8), and 8.7 (95% CI 1.0– 16.4) in persons scoring < 10, 10– 17 and > 17, respectively (c-statistic 0.91 (95% CI 0.84– 0.98)).Conclusion: We found low incidence of HCC and decompensated liver cirrhosis in persons with chronic HBV infection in Denmark. Moreover, the PAGE-B score showed good accuracy for five-year risk of developing HCC in the population with chronic HBV infection in Denmark.Keywords: hepatitis B virus, viral hepatitis, Scandinavia, morbidity, nationwide

Emerging evidence indicates a major impact for the tumor microenvironment (TME) and immune escape in the pathogenesis and clinical course of classical Hodgkin lymphoma (cHL). We used gene expression profiling (n = 88), CIBERSORT, and multiplex immunohistochemistry (n = 131) to characterize the immunoprofile of cHL TME and correlated the findings with survival. Gene expression analysis divided tumors into subgroups with T cell-inflamed and -noninflamed TME. Several macrophage-related genes were upregulated in samples with the non–T cell-inflamed TME, and based on the immune cell proportions, the samples clustered according to the content of T cells and macrophages. A cluster with high proportions of checkpoint protein (programmed cell death protein 1, PD-1 ligands, indoleamine 2,3 dioxygenase 1, lymphocyte-activation gene 3, and T-cell immunoglobulin and mucin domain containing protein 3) positive immune cells translated to unfavorable overall survival (OS) (5-year OS 76% vs 96%; P = .010) and remained an independent prognostic factor for OS in multivariable analysis (HR, 4.34; 95% CI, 1.05-17.91; P = .043). cHL samples with high proportions of checkpoint proteins overexpressed genes coding for cytolytic factors, proposing paradoxically that they were immunologically active. This checkpoint molecule gene signature translated to inferior survival in a validation cohort of 290 diagnostic cHL samples (P < .001) and in an expansion cohort of 84 cHL relapse samples (P = .048). Our findings demonstrate the impact of T cell- and macrophage-mediated checkpoint system on the survival of patients with cHL.

Dapagliflozin reduces kidney failure risk in patients with CKD but can result in a reversible acute reduction in eGFR upon treatment initiation. Determinants of this eGFR reduction and its associations with efficacy and safety outcomes are unknown.The DAPA-CKD trial randomized 4304 adults with CKD and albuminuria to once-daily dapagliflozin 10 mg or placebo, added to standard care. We prespecified an analysis comparing the effects of dapagliflozin among patients who experienced relative reductions in eGFR (gt;10% orgt;0%-10%) or an increase in eGFR from baseline to 2 weeks and assessed long-term efficacy and safety thereafter.A total of 4157 (96.6%) patients had eGFR data available at baseline and at 2 weeks. In the dapagliflozin and placebo groups, 1026 (49.4%) and 494 (23.7%), respectively, experienced an acute reduction in eGFRgt;10%. Among patients receiving dapagliflozin, those with an acute reduction in eGFRgt;10% experienced a long-term eGFR decline of -1.58 ml/min per 1.73 msup2/supper year compared with -2.44 and -2.48 ml/min per 1.73 msup2/supper year among those experiencing a less pronounced reduction or increase in eGFR, respectively (iP/i-interaction=0.05). In the placebo group, long-term eGFR decline was -3.27, -3.84, and -3.77 ml/min per 1.73 msup2/supper year for acute eGFR reduction subgroups ofgt;10%,gt;0%-10%, or increase in eGFR (iP/i-interaction=0.48). Rates of serious adverse events and adverse events of special interest in patients randomized to dapagliflozin were unrelated to the acute eGFR change.Among patients with CKD and albuminuria treated with dapagliflozin, an acute reduction in eGFR (from baseline to 2 weeks) is not associated with higher rates of CKD progression.bClinical Trial registration number:/bA Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease (Dapa-CKD) NCT03036150.

Abstract Early haemorrhage control and minimizing the time to definitive care have long been the cornerstones of therapy for patients exsanguinating from non-compressible haemorrhage (NCH) after penetrating injuries, as only basic treatment could be provided on scene. However, more recently, advanced on-scene treatments such as the transfusion of blood products, resuscitative thoracotomy (RT) and resuscitative endovascular balloon occlusion of the aorta (REBOA) have become available in a small number of pre-hospital critical care teams. Although these advanced techniques are included in the current traumatic cardiac arrest algorithm of the European Resuscitation Council (ERC), published in 2021, clear guidance on the practical application of these techniques in the pre-hospital setting is scarce. This paper provides a scoping review on how these advanced techniques can be incorporated into practice for the resuscitation of patients exsanguinating from NCH after penetrating injuries, based on available literature and the collective experience of several helicopter emergency medical services (HEMS) across Europe who have introduced these advanced resuscitation interventions into routine practice. Graphical Abstract

This dataset comprises 1,040,752 measurements, collated from 9,544 sampling locations in 46 countries and representing 10,635 species. The data was collated from 115 existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database was assembled as part of the PREDICTS project - Projecting Responses of Ecological Diversity In Changing Terrestrial Systems; https://www.nhm.ac.uk/our-science/our-work/biodiversity/predicts.html This release is an addition to the data presented with The 2016 release of the PREDICTS database (available on the NHM Data Portal: https://data.nhm.ac.uk/dataset/the-2016-release-of-the-predicts-database).

BackgroundThere is no effective prognostic signature that could predict the prognosis of nasopharyngeal carcinoma (NPC).MethodsWe constructed a prognostic signature based on five microRNAs using random forest and Least Absolute Shrinkage And Selection Operator (LASSO) algorithm on the GSE32960 cohort (N = 213). We verified its prognostic value using three independent external validation cohorts (GSE36682, N = 62; GSE70970, N = 246; and TCGA-HNSC, N = 523). Through principal component analysis, receiver operating characteristic curve analysis, and C-index calculation, we confirmed the predictive accuracy of this prognostic signature.ResultsWe calculated the risk score based on the LASSO algorithm and divided the patients into high- and low-risk groups according to the calculated optimal cutoff value. The patients in the high-risk group tended to have a worse prognosis outcome and chemotherapy response. The time-dependent receiver operating characteristic curve showed that the 1-year overall survival rate of the five-microRNA signature had an area under the curve of more than 0.83. A functional annotation analysis of the five-microRNA signature showed that the patients in the high-risk group were usually accompanied by activation of DNA repair and MYC-target pathways, while the patients in the low-risk group had higher immune-related pathway signals.ConclusionsWe constructed a five-microRNA prognostic signature, which could accurately predict the prognosis of nasopharyngeal carcinoma, and constructed a nomogram that could conveniently predict the overall survival of patients.

Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT). Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research. Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years). Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.

Low heart rate variability (HRV) is related to health problems that are known reasons for sick-leave or early retirement. A 1-minute-protocol could allow large scale HRV measurement for screening of health problems and, potentially, sustained employability. Our objectives were to explore the association of HRV with measures of health. Cross-sectional design with 877 Dutch employees assessed during a Workers’ Health Assessment. Personal and job characteristics, workability, psychological and mental problems, and lifestyle were measured with questionnaires. Biometry was measured (BMI, waist circumference, blood pressure, glucose, cholesterol). HRV was assessed with a 1-minute paced deep-breathing protocol and expressed as mean heart rate range (MHRR). A low MHRR indicates a higher health risk. Groups were classified age adjusted for HRV and compared. Spearman correlations between raw MHRR and the other measures were calculated. Significant univariable correlations (p < 0.05) were entered in a linear regression model to explore the multivariable association with MHRR. Age, years of employment, BMI and waist circumference differed significantly between HRV groups. Significant correlations were found between MHRR and age, workability, BMI, waist circumference, cholesterol, systolic and diastolic blood-pressure and reported physical activity and alcohol consumption. In the multivariable analyses 21.1% of variance was explained: a low HRV correlates with aging, higher BMI and higher levels of reported physically activity. HRV was significantly associated with age, measures of obesity (BMI, waist circumference), and with reported physical activity, which provides a first glance of the utility of a 1-minute paced deep-breathing HRV protocol as part of a comprehensive preventive Workers’ Health Assessment.Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat ivecommons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate redit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

The majority of patients with newly diagnosed chronic myeloid leukemia (CML) will enjoy a life expectancy equivalent to that of unaffected individuals, but will remain on life-long treatment with a concomitant requirement for on-going hospital interactions for molecular monitoring and drug dispensing. In order to determine more accurately the frequency of monitoring required, we performed a ‘real-life’ retrospective single-center cohort study of 450 patients with CML in at least major molecular remission (MR3) to analyze the risk of loss of MR3 [defined as at least 2 consecutive real-time quantitative polymerase chain reaction (RT-qPCR) results >0.1% International Scale (IS)]. Patients who achieved sustained MR4 (sMR4, BCR-ABL1 RT-qPCR

Background: Stroke is the second leading cause of death worldwide with heterogeneous characteristics. The subtypes of stroke are due to different pathophysiological regulations and causes. This study aimed to investigate the correlation of serum levels of apolipoprotein B 48, interleukin-1 beta and Homocysteine with BMI in patients with ischemic stroke (IS). Methods: Over one hundred controls (120) and an equal number of IS patients, including 31 women and 89 men, were recruited to participate in the case-control study conducted at Imam Reza Hospital (Tabriz, Iran) from February 2019 to March 2020. We measured serum levels of apolipoprotein B 48, interleukin-1 beta, and Homocysteine. Receiver operating characteristic analysis (ROC) was performed to evaluate the diagnostic value of these indices in patients and control groups. Results: The mean serum levels of apolipoprotein B 48, interleukin-1 beta, and Homocysteine, were significantly increased in the experimental group compared to the control group with a p-value of 0.001. The ROC curve analysis showed that the area under the curve for apo B48, IL-1 beta, hs-CRP, and Homocysteine serum levels were 0.94, 0.98, 0.99, and 1, respectively. Conclusions: The results of our current study show that the determination of serum levels of apolipoprotein B 48, interleukin-1 beta, and Homocysteine can potentially be used to monitor and diagnose IS patients. However, there was no statistically significant correlation between serum levels of apolipoprotein B 48, interleukin 1 beta and Homocysteine and BMI in the patient group. However, there was a statistically significant inverse correlation between serum levels of high-sensitivity C-reactive protein (hs-CRP) and BMI in the patient group., Research Vice-Chancellor of Tabriz University of medical sciences, Tabriz, IRAN [25992], The present study was supported by grants from the Research Vice-Chancellor of Tabriz University of medical sciences, Tabriz, IRAN grant no. 25992.

Background Inflammation scores based on general inflammation markers as leucocyte count or C-reactive protein have been evaluated as prognostic markers of inferior survival in several cancers. In small cell lung cancer (SCLC), however, inflammation scores are less studied. In the present study, we set out to perform a systematic review and meta-analysis investigating reported associations between inflammation scores and overall survival (OS) in SCLC. Methods A literature search was performed in PubMed, Embase, Scopus, and Web of Science following the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) guidelines. Of the identified publications, only studies in English containing original data evaluating inflammation scores as a prognostic factor in SCLC patients were included. Hazard ratios (HRs) for OS were pooled in a random-effects model. Results In total, 33 articles were included evaluating eight different inflammation scores in 7762 SCLC patients. Seven of the identified scores were based on leucocyte count. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) ratio were the most frequently evaluated scores (NLR: n = 23; PLR: n = 22). For NLR, a meta-analysis including 16 studies demonstrated that patients with a high NLR had a significantly shorter OS compared to patients with a low NLR (pooled HR = 1.39 (95% CI, 1.23–1.56)). For PLR, an association with survival could not be confirmed in a meta-analysis performed based on eight studies (pooled HR = 1.20 (95% CI, 0.96–1.51)). Conclusions This review identifies that inflammation scores based on general inflammation markers have some potential as prognostic biomarkers in SCLC. The meta-analyses indicated that NLR is associated with inferior OS, whereas an association between PLR and OS could not be confirmed. Thus, NLR could be a useful biomarker of OS in SCLC patients. Systematic review registration The protocol for the study was submitted to the PROSPERO database (registration number CRD42020188553).

Background: Carotid endarterectomy (CEA) has been associated with both postoperative cognitive dysfunction (POCD) and improvement (POCI). However, the prognostic significance of postoperative cognitive changes related to CEA is largely unknown. The aim of this study was to examine the associations between postoperative cognitive changes after CEA and long-term survival.Methods: We studied 43 patients 1 day before CEA as well as 4 days and 3 months after surgery with an extensive neuropsychological test array, and followed them for up to 14 years. POCD and POCI relative to baseline were determined with the reliable change index derived from 17 healthy controls. Associations between POCD/POCI and mortality within the patient group were studied with Cox regression analyses adjusted for confounders.Results: POCD in any functional domain was evident in 28% of patients 4 days after surgery and in 33% of patients 3 months after surgery. POCI was shown in 23% of patients at 4 days and in 44% of patients at 3 months. POCD at 3 months was associated with higher long-term mortality (hazard ratio 5.0, 95% CI 1.8–13.9, p = 0.002) compared with patients with no cognitive decline.Conclusions: Our findings suggest that POCD in a stable phase, 3 months after CEA predicts premature death. Evaluation of postoperative cognitive changes is essential, and POCD in a stable phase after CEA should prompt scrutiny of underlying factors and better adherence to therapies to prevent recurrences and to promote early intervention in imminent deterioration.

The site-level data frame and code to reproduce models in Burton et al. Land use and soil characteristics affect soil organisms differently from above-ground assemblages. Human activities, particularly land-use change and habitat degradation, are driving major changes in biodiversity worldwide. However, studies of such effects have overwhelmingly focused on above-ground taxa: the effects on soil biodiversity are less well known, despite the importance of soil organisms in developing soil structure, nutrient cycling and water drainage. Modelling data collated as part of the Projecting Responses of Ecological Diversity in Changing Terrestrial Systems (PREDICTS) project, we compared how the abundance of soil-dwelling and above-ground organisms responded to land-use and soil properties. We found that land use affects overall abundance differently in soil and above-ground assemblages. Abundance of soil organisms was markedly lower in cropland and plantation habitats than in primary vegetation and pasture. Soil properties influenced the overall abundance of soil biota in ways that differed among land uses, suggesting they shape both abundance and its response to land use. Soil properties also influenced the response of above-ground assemblages, but in ways that differed from their influence on soil assemblages. Our results caution against assuming that models or indicators derived from above-ground data can apply to soil assemblages, and highlight the potential value of incorporating soil properties into models of both soil and above-ground biodiversity.

Author Correction: https://doi.org/10.1038/s41598-021-98620-6. The original version of this Article contained errors: The spelling of the author Monica Neri was incorrectly given as Neri Monica; Additionally, Affiliation 39 was incorrectly given as ‘National Institute of Health, Lisbon, Portugal’, the correct affiliation is listed below: National Institute of Health Doutor Ricardo Jorge, Porto, Portugal. The original Article has been corrected. [Abstract] The comet assay or single cell gel electrophoresis, is the most common method used to measure strand breaks and a variety of other DNA lesions in human populations. To estimate the risk of overall mortality, mortality by cause, and cancer incidence associated to DNA damage, a cohort of 2,403 healthy individuals (25,978 person-years) screened in 16 laboratories using the comet assay between 1996 and 2016 was followed-up. Kaplan–Meier analysis indicated a worse overall survival in the medium and high tertile of DNA damage (p

Background: Women are less likely to receive cardiac resynchronization therapy, yet, they are more responsive to the therapy and respond at shorter QRS duration. The present study hypothesized that a relatively larger left ventricular (LV) electrical dyssynchrony in smaller hearts contributes to the better cardiac resynchronization therapy response in women. For this, the vectorcardiography-derived QRS area is used, since it allows for a more detailed quantification of electrical dyssynchrony compared with conventional electrocardiographic markers. Methods: Data from a multicenter registry of 725 cardiac resynchronization therapy patients (median follow-up, 4.2 years [interquartile range, 2.7–6.1]) were analyzed. Baseline electrical dyssynchrony was evaluated using the QRS area and the corrected QRS area for heart size using the LV end-diastolic volume (QRSarea/LVEDV). Impact of the QRSarea/LVEDV ratio on the association between sex and LV reverse remodeling (LV end-systolic volume change) and sex and the composite outcome of all-cause mortality, LV assist device implantation, or heart transplantation was assessed. Results: At baseline, women (n=228) displayed larger electrical dyssynchrony than men (QRS area, 132±55 versus 123±58 μVs; P =0.043), which was even more pronounced for the QRSarea/LVEDV ratio (0.76±0.46 versus 0.57±0.34 μVs/mL; P P =0.003) and a lower occurrence of the composite outcome (hazard ratio, 0.59 [0.42–0.85]; P =0.004). A part of the female advantage regarding reverse remodeling was attributed to the larger QRSarea/LVEDV ratio in women (25-fold change in β from 0.12 to 0.09). The larger QRSarea/LVEDV ratio did not contribute to the better survival observed in women. In both volumetric responders and nonresponders, female sex remained strongly associated with a lower risk of the composite outcome (adjusted hazard ratio, 0.59 [0.36–0.97]; P =0.036; and 0.55 [0.33–0.90]; P =0.018, respectively). Conclusions: Greater electrical dyssynchrony in smaller hearts contributes, in part, to more reverse remodeling observed in women after cardiac resynchronization therapy, but this does not explain their better long-term outcomes.

ObjectivesTo investigate the utility of spectral computed tomography (CT) parameters for the prediction of the preoperative Masaoka-Koga stage of thymic epithelial tumors (TETs).Materials and MethodsFifty-four patients with TETs, aged from 37 to 73 years old, an average age of 55.56 ± 9.79 years, were included in the study.According to the Masaoka-Koga staging method, there were 19 cases of stage I, 15 cases of stage II, 8 cases of stage III, and 12 cases of stage IV disease. All patients underwent dual-phase enhanced energy spectral CT scans. Regions of interest (ROIs) were defined in sections of the lesion with homogeneous density, the thoracic aorta at the same level as the lesion, the outer fat layer of the lesion, and the anterior chest wall fat layer. The single-energy CT value at 40-140 keV, iodine concentration, and energy spectrum curve of all lesion and thoracic aorta were obtained. The energy spectrum CT parameters of the lesions, extracapsular fat of the lesions, and anterior chest wall fat in stage I and stage II were obtained. The energy spectrum CT parameters of the lesions, enlarged lymph nodes and intravascular emboli in the 3 groups were obtained. The slope of the energy spectrum curve and the normalized iodine concentration were calculated.ResultsIn stage I lesions, there was a statistically significant difference between the slope of the energy spectrum curve for the lesion and those of the fat outside the lesion and the anterior chest wall in the arteriovenous phase (P0.05). The energy spectrum curve of the tumor parenchyma was consistent with that of the enlarged lymph nodes and intravascular emboli. The two radiologists have strong consistency in evaluating TETs Masaoka-Koga staging, The Kappa coefficient is 0.873,(95%CI:0.768-0.978).ConclusionSpectral CT parameters, especially the energy spectrum curve and slope, are valuable for preoperative TET and can be used in preoperative staging prediction.

Background Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response. Methods Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29–1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25–18) months. Results After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event. Conclusions This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance. This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.

Previous studies demonstrated that memory accuracy is affected by the availability of the individual's cognitive resources. A predominant role in complex cognition has been postulated for executive functions (EF). The aim of the present study was to verify if there are differences in remembering a crime with respect to the individual's EF availability (i.e., Shifting, Inhibition, and Updating). We showed participants a video of a violent crime. Next, they were requested to imagine to be an eyewitness of the crime and report a testimony as detailed as possible. A subsequent memory test was run after ten days. EF resources were assessed in a third session through three neuropsychological tasks. Findings showed that high EF individuals reported more correct details and fewer memory distortions (i.e., omissions and commissions) than low EF individuals. Our results underline that individual EF resources are implicated in the recalling of an event. ispartof: CONSCIOUSNESS AND COGNITION vol:84 ispartof: location:United States status: published

Background Emerging evidence indicates that an elevated C-reactive protein-to-albumin ratio (CAR) may be associated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Further evidence showing that this ratio has significant prognostic value could contribute to current prediction models and clinical decision-making. Methods Data were analysed of consecutive patients who underwent curative pancreatic resection between 2013 and 2018 and were histologically diagnosed with PDAC. We investigated the relation between the ultimate preoperative CAR and overall survival. Results A total of 163 patients were analysed. Median overall survival was 18 months (IQR 9–36). Multivariate analysis demonstrated that a higher CAR (HR 1.745, P = 0.004), a higher age (HR 1.062, P P = 0.001), poor differentiation grade (HR 2.812, P P P = 0.003). Conclusion We demonstrated that an ultimate preoperative elevated CAR is an independent indicator of decreased overall survival after resection for PDAC. The preoperative CAR may be of additional value to the current prediction models.

Contains fulltext : 218355.pdf (Publisher’s version ) (Open Access) Different inputs from a multisensory object or event are often integrated into a coherent and unitary percept, despite differences in sensory formats, neural pathways, and processing times of the involved modalities. Presumably, multisensory integration occurs if the cross-modal inputs are presented within a certain window of temporal integration where inputs are perceived as being simultaneous. Here, we examine the role of ongoing neuronal alpha (i.e. 10-Hz) oscillations in multimodal synchrony perception. While EEG was measured, participants performed a simultaneity judgement task with visual stimuli preceding auditory ones. At stimulus onset asynchronies (SOA’s) of 160–200 ms, simultaneity judgements were around 50%. For trials with these SOA’s, occipital alpha power was smaller preceding correct judgements, and the individual alpha frequency was correlated with the size of the temporal window of integration. In addition, simultaneity judgements were modulated as a function of oscillatory phase at 12.5 Hz, but the latter effect was only marginally significant. These results support the notion that oscillatory neuronal activity in the alpha frequency range, which has been taken to shape perceptual cycles, is instrumental in multisensory perception. 8 p.

Anhedonia reflects a dysfunction in the reward system, which can be manifested in an inability to enjoy pleasurable situations (i.e., lack of positive emotions), but also by a lack of motivation to engage in pleasurable activities (i.e., lack of motivation). Little is known about the interrelations between positive emotions and motivation in daily life, and whether these associations are altered in anhedonic individuals. In the present study, we used a network approach to explore the reciprocal, lagged associations between positive emotions and motivation in anhedonic individuals (N = 66) and controls (N = 68). Participants (aged between 18 and 24 years) filled out momentary assessments of affect 3 times per day for 30 consecutive days. Our results showed that (a) anhedonic individuals and controls had similar moment-to-moment transfer of positive emotions; (b) in the anhedonic network feeling cheerful was the node with the highest outstrength, both within this group and compared with the control group; (c) feeling relaxed had the highest outstrength in the control network, and (d) anhedonic individuals had stronger pathways from positive emotions to motivation than controls. Taken together, our findings suggest that low levels of positive emotions lead to decreased motivation in the anhedonic group, which could instigate a negative spiral of low pleasure and low motivation. On a more positive note, we showed that cheerfulness had the highest outstrength in the network of anhedonic participants. Hence, interventions may focus on increasing cheerfulness in anhedonic individuals, as this will likely have the greatest impact on other positive emotions and motivations. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

BACKGROUND: Approximately 20–40% of patients diagnosed with breast cancer will experience a recurrence up to 20 years after their original diagnosis. 17?-hydroxysteroid dehydrogenase 1 and 2 (HSD17B1 and HSD17B2, respectively) regulate intratumoral concentrations of oestradiol, which promotes growth and proliferation of hormone dependent tumours. Breast carcinomas with increased HSD17B1, without a corresponding increase in HSD17B2, expression may become resistant to tamoxifen therapy by producing locally higher concentrations of oestradiol, which compete with tamoxifen and its metabolites for binding to the oestrogen receptor (ER). MATERIALS AND METHODS: In this population-based case-control study, we included women diagnosed with stage I–III breast cancer between 1985 and 2001, aged 35–69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with ER positive disease who were treated with tamoxifen for at least 1 year (ER+TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER negative disease, not treated with tamoxifen, who survived at least 1 year (ER?/TAM?). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, stage, and county or residence. Expression of HSD17B1 and HSD17B2 were measured by immunohistochemistry on tissue microarrays. We fit logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating the HSD17B1:HSD17B2 ratio (>1 vs. ?1)—and each enzyme’s independent expression—with recurrence. RESULTS: We found no association between the HSD17B1:HSD17B2 ratio and breast cancer recurrence in either ER/TAM stratum (ER+/TAM+: OR=1.03, 95% CI: 0.78, 1.40; ER?/TAM?: OR=1.02, 95% CI: 0.77, 1.19). Associations for expression of each individual enzyme were also near null. CONCLUSION: The ratio of HSD17B1 expression to HSD17B2 expression was not associated with breast cancer recurrence in this study.

An impaired immune response could play a role in the acquisition of secondary infections in critically ill children. Human leukocyte antigen-DR expression on monocytes (mHLA-DR) has been proposed as marker to detect immunosuppression, but its potential to predict secondary infections in critically ill children is unclear. We aimed to assess the association between mHLA-DR expression at several timepoints and the change of mHLA-DR expression over time with the acquisition of secondary infections in critically ill children. In this prospective observational study, children Conclusions: Our results confirm that infectious critically ill children have significantly lower mHLA-DR expression than controls. mHLA-DR expression was not associated with the acquisition of secondary infections. What is Known:• An impaired immune response, estimated by mHLA-DR expression, could play an essential role in the acquisition of secondary infections in critically ill children.• In critically ill children, large studies on the association of mHLA-DR expression with secondary infections are scarce. What is New:• Our study confirms that critically ill children have lower mHLA-DR expression than healthy controls.• mHLA-DR expression and change in mHLA-DR was not associated with the acquisition of secondary infection.

The appropriate definition and scaling of the magnitude of EEG oscillations is an underdeveloped area. The aim of this study was to optimize the analysis of resting EEG alpha magnitude, focusing on alpha peak frequency and non-linear transformation of alpha power. A family of non-linear transforms, Box-Cox transforms, were applied to find the transform that (a) maximized a non-disputed effect: the increase in alpha magnitude when the eyes are closed (Berger effect), and (b) made the distribution of alpha magnitude closest to normal across epochs-within each participant, or across participants. The transformations were done either at the single epoch level, or at the epoch-average level. Alpha peak frequency showed large individual differences, yet good correspondence between various ways to estimate it in two minutes of eyes-closed and two minutes of eyes-open resting EEG data. Both alpha magnitude and the Berger effect were larger for individual alpha than for a generic (8-12 Hz) alpha band. The log transform on single epochs (a) maximized the t-value of the contrast between the eyes-open and eyes-closed condition when tested within each participant, and (b) rendered near-normally distributed alpha power across epochs and participants, thereby making further transformation of epoch-averages superfluous. The results suggest that the log-normal distribution is a fundamental property of variations in alpha power across time in the order of seconds. Moreover, effects on alpha power appear to be multiplicative rather than additive. These findings support the use of the log transform on single epochs to achieve appropriate scaling of alpha magnitude. This article is protected by copyright. All rights reserved.

Purpose Patients are referred to exercise-based cardiac rehabilitation (ECR) to increase exercise capacity and health-related quality of life (HRQOL) and thereby reduce risk of morbidity and mortality. The purpose of this study was to examine the correlation between exercise capacity and HRQOL. Furthermore, this study examined whether improvements in HRQOL were directly related to improvements in exercise capacity. Methods The study included 277 patients participating in ECR. HRQOL was assessed using the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), and exercise capacity was measured as peak oxygen uptake ((Equation is included in full-text article.)O2peak) and oxygen uptake ((Equation is included in full-text article.)O2) at the ventilatory threshold (VTh). Patients were examined before and after completion of an 8-wk ECR program. Results Analyses at baseline showed a significant correlation between (Equation is included in full-text article.)O2peak and VTh and physical functioning (PF), role limitations because of physical problems (RP), general health perceptions (GH), vitality (VT), and physical component summary (PCS) on the SF-36; PF was the only dimension showing a moderate correlation (>0.40 Spearman ρ) with (Equation is included in full-text article.)O2peak. The follow-up analyses demonstrated a significant correlation between changes in (Equation is included in full-text article.)O2peak and changes in PF, RP, VT, and MH. Changes in (Equation is included in full-text article.)O2 peak explained 4% of the changes in the PF and VT scores. Conclusion The correlations between exercise capacity and HRQOL were weak and varied considerably among patients. The ECR program improved both exercise capacity and HRQOL, but it was not necessarily the same patients who improved both parameters. Therefore, it is recommended to use separate objective measures and patient-reported outcomes when evaluating the effect of ECR.

Background: Stopping nucleos(t)ide analogues (NA) after hepatitis B e antigen (HBeAg) seroconversion is associated with high relapse rates in Asian patients, but data in Caucasian cohorts are scarce. Clinical course, outcomes and immunological aspects of chronic hepatitis B infections differ substantially between distinct ethnicities. Aim: The aim of this study was to determine relapse rates, factors predicting relapse and clinical outcomes after nucleos(t)ide analogue cessation in a large, predominantly Caucasian cohort of chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroconversion. Methods: This is a nationwide observational cohort study including HBeAg positive, mono-infected chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroconversion from 18 centres in Belgium. Results: A total of 98 patients with nucleo(s)tide analogue-induced HBeAg seroconversion were included in the study. Of the 62 patients who stopped treatment after a median consolidation treatment of 8 months, 30 relapsed. Higher gamma-glutamyl transferase levels at both treatment initiation (HR 1.004; P = 0.001 per unit increment) and HBeAg seroconversion (HR 1.006; P = 0.013 per unit increment) were associated with an increased risk of clinically significant relapse in a multivariate Cox regression model. Treatment cessation led to liver-related death in 2 patients, of whom one showed a severe flare. Of the patients who continued treatment after HBeAg seroconversion, none relapsed or developed severe hepatic outcomes. Conclusion: Treatment withdrawal in Caucasian chronic hepatitis B patients after nucleos(t)ide analogue-induced HBeAg seroconversion results in viral relapses in more than half of patients with potential fatal outcomes. These real-world data further lend support to preferentially continue NA treatment after HBeAg seroconversion until HBsAg loss. Foundation Against Cancer Belgium, Grant/Award Number: 2014-087

Background. In patients treated for early-stage squamous cell vulvar carcinoma local recurrence is reported in up to 40% after ten years. Knowledge on prognostic factors related to local recurrences should be helpful to select high risk patients and/or to develop strategies to prevent local recurrences.Objective. This systematic review aims to evaluate the current knowledge on the incidence of local recurrences in vulvar carcinoma related to clinicopathologic and cell biologic variables.Data sources. Relevant studies were identified by an extensive online electronic search in July 2017.Study eligibility criteria Studies reporting prognostic factors specific for local recurrences of vulvar carcinoma were included. Study appraisal and synthesis methods. Two review authors independently performed data selection, extraction and assessment of study quality. The risk difference was calculated for each prognostic factor when described in two or more studies.Results. Twenty-two studies were included; most of all were retrospective and mainly reported pathologic prognostic factors. Our review indicates an estimated annual local recurrence rate of 4% without plateauing. The prognostic relevance for local recurrence of vulvar carcinoma of all analyzed variables remains equivocal, including pathologic tumor free margin distanceConclusions. Current quality of data on prognostic factors for local recurrences in vulvar carcinoma patients does not allow evidence-based clinical decision making. Further research on prognostic factors, applying state of the art methodology is needed to identify high-risk patients and to develop alternative primary and secondary prevention strategies. (C) 2017 Elsevier Inc. All rights reserved.

CPNE3, a member of a Ca2+‐dependent phospholipid‐binding protein family, was identified as a ligand of ERBB2 and has a more general role in carcinogenesis. Here, we identified the prognostic significance of CPNE3 expression in acute myeloid leukemia (AML) patients based on two datasets. In the first microarray dataset (n = 272), compared to low CPNE3 expression (CPNE3 low), high CPNE3 expression (CPNE3 high) was associated with adverse overall survival (OS, P < 0.001) and event‐free survival (EFS, P < 0.001). In the second independent group of AML patients (TCGA dataset, n = 179), CPNE3 high was also associated with adverse OS and EFS (OS, P = 0.01; EFS, P = 0.036). Notably, among CPNE3 high patients, those received allogenic hematopoietic cell transplantation (HCT) had longer OS and EFS than those with chemotherapy alone (allogeneic HCT, n = 40 vs chemotherapy, n = 46), but treatment modules played an insignificant role in the survival of CPNE3 low patients (allogeneic HCT, n = 32 vs chemotherapy, n = 54). These results indicated that CPNE3 high is an independent, adverse prognostic factor in AML and might guide treatment decisions towards allogeneic HCT. To understand its inherent mechanisms, we investigated genome‐wide gene/microRNA expression signatures and cell signaling pathways associated with CPNE3 expression. In conclusion, CPNE3 high is an adverse prognostic biomarker for AML. Its effect may be attributed to the distinctive genome‐wide gene/microRNA expression and related cell signaling pathways.

Introduction There is growing evidence that mental disorders behave like complex dynamic systems. Complex dynamic systems theory states that a slower recovery from small perturbations indicates a loss of resilience of a system. This study is the first to test whether the speed of recovery of affect states from small daily life perturbations predicts changes in psychopathological symptoms over 1 year in a group of adolescents at increased risk for mental disorders. Methods We used data from 157 adolescents from the TWINSSCAN study. Course of psychopathology was operationalized as the 1-year change in the Symptom Checklist-90 sum score. Two groups were defined: one with stable and one with increasing symptom levels. Time-series data on momentary daily affect and daily unpleasant events were collected 10 times a day for 6 days at baseline. We modeled the time-lagged effect of daily unpleasant events on negative and positive affect after each unpleasant event experienced, to examine at which time point the impact of the events is no longer detectable. Results There was a significant difference between groups in the effect of unpleasant events on negative affect 90 min after the events were reported. Stratified by group, in the Increase group, the effect of unpleasant events on both negative (B = 0.05, p B = − 0. 08, p Conclusion Findings cautiously suggest that adolescents who develop more symptoms in the following year may display a slower affect recovery from daily perturbations at baseline. This supports the notion that mental health may behave according to the laws of a complex dynamic system. Future research needs to examine whether these dynamic indicators of system resilience may prove valuable for personalized risk assessment in this field.

Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, where the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. In order to study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival over five years (long-term survivals [LTS]) and compared the findings with 84 tumors from a reference group with average survival (RG). We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n = 34,90%) and a tubulopapillary growth pattern (n = 30,70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n = 49,61%) and solid growth pattern (n = 59,70%) were more frequent in RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (p

Introduction Viral remission after analytical treatment interruption (ATI), termed post-treatment control, has been described in a small proportion of HIV-positive patients. This phenomenon has been separately associated to both low levels of HIV-1 proviral DNA as well as cell-associated RNA. We investigated whether the combination of both parameters could help predict delayed viral rebound after treatment interruption (TI). Methods We conducted an open single-arm ATI study in four Belgian HIV reference centres from January 2016 to July 2018. Eligible participants were adults who had fewer than 50 HIV-1 RNA copies/mL for more than two years, more than 500 CD4 cells/mu L for more than three months, and were in general good health. Consenting participants who had fewer than 66 copies total HIV-1 DNA (t-DNA) and fewer than 10 copies cell-associated HIV-1 unspliced RNA (US-RNA) per million peripheral blood mononuclear cells (PBMCs), interrupted therapy and were monitored closely. Antiretroviral therapy (ART) was resumed after two consecutive viral loads exceeding 1000 copies or one exceeding 10,000 copies/mL. The primary outcome was the proportion of participants with fewer than 50 HIV-1 RNA copies/mL 48 weeks after TI. Secondary outcomes were time to viral rebound, the frequency of serious adverse events (AEs) and evolution of t-DNA and US-RNA after TI. Results All 16 consenting participants who interrupted therapy experienced rapid viral rebound two to eight weeks after TI. No serious AEs were observed. Levels of t-DNA and US-RNA increased after TI but returned to pre-ATI levels after treatment restart. None of the studied demographic, clinical and biological parameters were predictive of time of viral rebound. Conclusions The combination of low levels of t-DNA and US-RNA in PBMCs, corresponding respectively to a small and transcriptionally silent viral reservoir, is not predictive of viral remission after TI in patients on ART.

Most physical and other natural systems are complex entities composed of a large number of interacting individual elements. It is a surprising fact that they often obey the so-called scaling laws relating an observable quantity with a measure of the size of the system. Here we describe the discovery of universal superlinear metabolic scaling laws in human cancers. This dependence underpins increasing tumour aggressiveness, due to evolutionary dynamics, which leads to an explosive growth as the disease progresses. We validated this dynamic using longitudinal volumetric data of different histologies from large cohorts of cancer patients. To explain our observations we put forward increasingly-complex biologically-inspired mathematical models that captured the key processes governing tumor growth. Our models predicted that the emergence of superlinear allometric scaling laws is an inherently three-dimensional phenomenon. Moreover, the scaling laws thereby identified allowed us to define a set of metabolic metrics with prognostic value, thus providing added clinical utility to the base findings. This research has been supported by the James S. McDonnell Foundation 21st Century Science Initiative in Mathematical and Complex Systems Approaches for Brain Cancer (collaborative awards 220020560 and 220020450), Ministerio de Economia y Competitividad/FEDER, Spain (grant no. MTM2015-71200-R), Junta de Comunidades de Castilla-La Mancha (grant no. SBPLY/17/180501/000154). Research in the Brain Metastasis Group is supported by MINECO grant MINECO-Retos SAF2017-89643-R (M.V.), Bristol-Myers Squibb Melanoma Research Alliance Young Investigator Award 2017 (498103) (M.V.), Beug Foundation's Prize for Metastasis Research 2017 (M.V.), Fundacion Ramon Areces (CIVP19S8163) (M.V.), Worldwide Cancer Research (19-0177) (M.V.), H2020-FETOPEN (828972) (M.V.), Fundacio La Marato de tv3 (141), Clinic and Laboratory Integration Program CRI Award 2018 (54545) (M.V.), AECC Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), La Caixa INPhINIT Fellowship (LCF/BQ/IN17/11620028) (P.G.-G.), La Caixa-Severo Ochoa International PhD Program Fellowship (LCF/BQ/SO16/52270014) (L.Z.). M.V. is a member of the European Molecular Biology Organization Young Investigators programme (4053). We would like to acknowledge J. Cervera and J. C. Penalver from the IVO Foundation (Valencia, Spain). No

Supplemental Digital Content is available in the text., Background: Long QT syndromes (LQTS) arise from many genetic and nongenetic causes with certain characteristic ECG features preceding polymorphic ventricular tachyarrhythmias (PVTs). However, how the many molecular causes result in these characteristic ECG patterns and how these patterns are mechanistically linked to the spontaneous initiation of PVT remain poorly understood. Methods: Anatomic human ventricle and simplified tissue models were used to investigate the mechanisms of spontaneous initiation of PVT in LQTS. Results: Spontaneous initiation of PVT was elicited by gradually ramping up ICa,L to simulate the initial phase of a sympathetic surge or by changing the heart rate, reproducing the different genotype-dependent clinical ECG features. In LQTS type 2 (LQT2) and LQTS type 3 (LQT3), T-wave alternans was observed followed by premature ventricular complexes (PVCs). Compensatory pauses occurred resulting in short-long-short sequences. As ICa,L increased further, PVT episodes occurred, always preceded by a short-long-short sequence. However, in LQTS type 1 (LQT1), once a PVC occurred, it always immediately led to an episode of PVT. Arrhythmias in LQT2 and LQT3 were bradycardia dependent, whereas those in LQT1 were not. In all 3 genotypes, PVCs always originated spontaneously from the steep repolarization gradient region and manifested on ECG as R-on-T. We call this mechanism R-from-T, to distinguish it from the classic explanation of R-on-T arrhythmogenesis in which an exogenous PVC coincidentally encounters a repolarizing region. In R-from-T, the PVC and the T wave are causally related, where steep repolarization gradients combined with enhanced ICa,L lead to PVCs emerging from the T wave. Since enhanced ICa,L was required for R-from-T to occur, suppressing window ICa,L effectively prevented arrhythmias in all 3 genotypes. Conclusions: Despite the complex molecular causes, these results suggest that R-from-T is likely a common mechanism for PVT initiation in LQTS. Targeting ICa,L properties, such as suppressing window ICa,L or preventing excessive ICa,L increase, could be an effective unified therapy for arrhythmia prevention in LQTS.

Summary Background: Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing - termed ���kick and kill��� - have been explored as a strategy towards an HIV cure. RIVER is the first randomized trial to determine the impact of ART alone versus ART plus ���kick-and-kill��� on markers of the HIV reservoir. Methods: RIVER (Trial registration: NCT02336074) was an open-label, multicenter, 1:1 randomized controlled trial of ART-only (control) versus ART plus the histone deacetylase inhibitor vorinostat (the ���kick���) and replication-deficient viral vector vaccines encoding conserved HIV sequences ChAdV63.HIVconsv-prime, MVA.HIVconsv-boost T-cell vaccination (the ���kill���) (ART+V+V; intervention) in HIV-positive adults treated in recent HIV-infection. The primary endpoint was total HIV DNA in peripheral blood CD4+ T-cells at weeks 16 and 18 post-randomization. Secondary endpoints included safety, alternative measures of the HIV reservoir including quantitative viral outgrowth, HIV-specific T-cell frequencies, and CD8+ T-cell mediated viral inhibition. Findings: Between December 2015 and November 2017, 60 HIV-positive male participants were randomized (computer-based and stratified by time since diagnosis; 30 participants in each trial arm) and completed the study interventions, with no loss-to-follow-up. There were no intervention-related serious adverse events. Mean total HIV DNA at weeks 16 and 18 was 3.02 log10 copies HIV DNA/106 CD4+ T-cells in the control and 3.06 log10 copies HIV DNA/106 CD4+ T-cells in the intervention arm, with no statistically significant difference (mean difference of 0.04 (95%CI -0.03, 0.11) log10 total HIV DNA copies/106 CD4+ T-cells (p=0.26)). Interpretation: This ���kick-and-kill��� approach conferred no significant benefit compared to ART alone on measures of the HIV reservoir. Although this does not disprove the ���kick and kill��� strategy, for future trials significant enhancement of both ���kick��� and ���kill��� agents will be required., Medical Research Council (MR/L00528X/1).