Eliminating Hepatitis C Virus From a Prevalent Kidney Transplant Recipient Population: A Single-Center Study in Belgium in the Direct-Acting Antivirals Era

Background: Direct-acting antivirals (DAAs) have revolutionized the treatment of hepatitis C virus (HCV) infection. Although previous studies have reported positive results with DAAs after kidney transplantation (KT), their impact on the prevalence of HCV viremia (HCVv) in prevalent kidney transplant recipients (KTRs) remains ill defined. Methods: We retrospectively reviewed the HCV status of all patients followed at Cliniques Universitaires Saint-Luc, Brussels, Belgium, outpatient KT clinic between January 2014 and December 2018. We collected the clinical features of KTRs treated with DAAs during this period and calculated the annual prevalence of HCVv over this period. Results: Out of 1451 KTRs, 22 (1.52%) had HCVv in 2014 to 2018. From 2014 to 2018, the annual prevalence of HCVv dropped from 1.97% to 0.43%, (P < .001). Fourteen KTRs were treated with DAAs a median of 197 months (range: 5-374) after KT, mostly (79%) in 2017 after reimbursement restrictions of DAAs for KTRs in Belgium were removed. DAA treatment was safe with a sustained virological response rate at 12 weeks after treatment (SVR12) of 93%. Two patients died 14 months (lymphoma, despite SVR12) and 7 months (hepatocarcinoma, no SVR12) after DAAs initiation, respectively. Among HCVv KTRs not treated with DAAs (n = 8), 2 lost their graft, 5 died, and 1 is initiating therapy. The current prevalence of HCVv in the cohort is 0.08%, with a single patient currently on treatment. Conclusion: Treatment with DAAs led to a dramatic decrease of HCVv prevalence in this KTR cohort. DAA use was safe and effective. Elimination of HCV is possible at KT clinics

Intermittent Surface Oxygenation Results in Similar Mitochondrial Protection and Maintenance of Aerobic Metabolism as Compared to Continuous Oxygenation during Hypothermic Machine Kidney Machine Perfusion

Short bubble and subsequent surface oxygenation is an innovative oxygenation technique and alternative for membrane oxygenation during hypothermic machine perfusion (HMP). The metabolic effect of the interruption of surface oxygenation for 4 h (mimicking organ transport) during HMP was compared to continuous surface and membrane oxygenation in a pig kidney ex situ preservation model. After 30 min of warm ischemia by vascular clamping, a kidney of a ±40 kg pig was procured and subsequently preserved according to one of the following groups: (1) 22-h HMP + intermittent surface oxygenation ( = 12); (2) 22-h HMP + continuous membrane oxygenation ( = 6); and (3) 22-h HMP + continuous surface oxygenation ( = 7). Brief perfusate O uploading before kidney perfusion was either obtained by direct bubble (groups 1, 3) or by membrane (group 2) oxygenation. Bubble oxygenation during minimum 15 min was as efficient as membrane oxygenation in achieving supraphysiological perfusate pO levels before kidney perfusion. Metabolic tissue analysis (i.e., lactate, succinate, ATP, NADH, and FMN) during and at the end of the preservation period demonstrated similar mitochondrial protection between all study groups. Short bubble and subsequent intermittent surface oxygenation of the perfusate of an HMP-kidney might be an effective and cheap preservation strategy to protect mitochondria, eliminating the need/costs of a membrane oxygenator and oxygen source during transport

Predicting Outcomes in Pediatric Crohn’s Disease for Management Optimization: Systematic Review and Consensus Statements from PIBD-Ahead Program

A better understanding of prognostic factors within the heterogeneous spectrum of pediatric Crohn's disease (CD) should improve patient management and reduce complications. We aimed to identify evidence-based predictors of outcomes with the goal of optimizing individual patient management. A survey of 202 experts in pediatric CD identified and prioritized adverse outcomes to be avoided. A systematic review of the literature with meta-analysis, when possible, was performed to identify clinical studies that investigated predictors of these outcomes. Multiple national and international face-to-face meetings were held to draft consensus statements based on the published evidence. Consensus was reached on 27 statements regarding prognostic factors for surgery, complications, chronically active pediatric CD, and hospitalization. Prognostic factors for surgery included CD diagnosis during adolescence, growth impairment, NOD2/CARD15 polymorphisms, disease behavior, and positive anti-Saccharomyces cerevisiae antibody status. Isolated colonic disease was associated with fewer surgeries. Older age at presentation, small bowel disease, serology (anti-Saccharomyces cerevisiae antibody, antiflagellin, and OmpC), NOD2/CARD15 polymorphisms, perianal disease, and ethnicity were risk factors for penetrating (B3) and/or stenotic disease (B2). Male sex, young age at onset, small bowel disease, more active disease, and diagnostic delay may be associated with growth impairment. Malnutrition and higher disease activity were associated with reduced bone density. These evidence-based consensus statements offer insight into predictors of poor outcomes in pediatric CD and are valuable when developing treatment algorithms and planning future studies. Targeted longitudinal studies are needed to further characterize prognostic factors in pediatric CD and to evaluate the impact of treatment algorithms tailored to individual patient risk

North-south gradients in plasma concentrations of B-vitamins and other components of one-carbon metabolism in Western Europe: results from the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

Different lifestyle patterns across Europe may influence plasma concentrations of B-vitamins and one-carbon metabolites and their relation to chronic disease. Comparison of published data on one-carbon metabolites in Western European regions is difficult due to differences in sampling procedures and analytical methods between studies. The present study aimed, to compare plasma concentrations of one-carbon metabolites in Western European regions with one laboratory performing all biochemical analyses. We performed the present study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort among 5446 presumptively healthy individuals. Quantile regression was used to compare sex-specific median concentrations between Northern (Denmark and Sweden), Central (France, Germany, The Netherlands and United Kingdom) and Southern (Greece, Spain and Italy) European regions. The lowest folate concentrations were observed in Northern Europe (men, 10·4 nmol/l; women, 10·7 nmol/l) and highest concentrations in Central Europe. Cobalamin concentrations were slightly higher in Northern Europe (men, 330 pmol/l; women, 352 pmol/l) compared with Central and Southern Europe, but did not show a clear north-south gradient. Vitamin B₂ concentrations were highest in Northern Europe (men, 22·2 nmol/l; women, 26·0 nmol/l) and decreased towards Southern Europe (P trend< 0·001). Vitamin B(6) concentrations were highest in Central Europe in men (77·3 nmol/l) and highest in the North among women (70·4 nmol/l), with decreasing concentrations towards Southern Europe in women (P trend< 0·001). In men, concentrations of serine, glycine and sarcosine increased from the north to south. In women, sarcosine increased from Northern to Southern Europe. These findings may provide relevant information for the study of regional differences of chronic disease incidence in association with lifestyle

Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling.

BACKGROUND: Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. METHOD AND FINDINGS: The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. CONCLUSION: The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study

Mental practice-based rehabilitation training to improve arm function and daily activity performance in stroke patients: a randomized clinical trial

<p>Abstract</p> <p>Background</p> <p>Over 50% of patients with upper limb paresis resulting from stroke face long-term impaired arm function and ensuing disability in daily life. Unfortunately, the number of effective treatments aimed at improving arm function due to stroke is still low. This study aims to evaluate a new therapy for improving arm function in sub-acute stroke patients based on mental practice theories and functional task-oriented training, and to study the predictors for a positive treatment result. It is hypothesized that a six-week, mental practice-based training program (additional to regular therapy) targeting the specific upper extremity skills important to the individual patient will significantly improve both arm function and daily activity performance, as well as being cost effective.</p> <p>Methods/design</p> <p>One hundred and sixty sub-acute stroke patients with upper limb paresis (MRC grade 1–3) will participate in a single-blinded, multi-centre RCT. The experimental group will undertake a six-week, individually tailored therapy regime focused on improving arm function using mental practice. The control group will perform bimanual upper extremity exercises in addition to regular therapy. Total contact time and training intensity will be similar for both groups. Measurements will be taken at therapy onset, after its cessation and during the follow-up period (after 6 and 12 months). Primary outcome measures will assess upper extremity functioning on the ICF level of daily life activity (Wolf Motor Function Test, Frenchay Arm Test, accelerometry), while secondary outcome measures cover the ICF impairment level (Brunnstrom-Fu-Meyer test). Level of societal participation (IPA) and quality of life (EuroQol; SS-Qol) will also be tested. Costs will be based on a cost questionnaire, and statistical analyses on MAN(C)OVA and GEE (generalized estimated equations).</p> <p>Discussion</p> <p>The results of this study will provide evidence on the effectiveness of this mental practice-based rehabilitation training, as well as the cost-effectiveness.</p> <p>Trial registration</p> <p>Current Controlled Trials [ISRCTN33487341)</p

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness

Fine-Scale Mapping of the 4q24 Locus Identifies Two Independent Loci Associated with Breast Cancer Risk

Background: A recent association study identified a common variant (rs9790517) at 4q24 to be associated with breast cancer risk. Independent association signals and potential functional variants in this locus have not been explored. Methods: We conducted a fine-mapping analysis in 55,540 breast cancer cases and 51,168 controls from the Breast Cancer Association Consortium. Results: Conditional analyses identified two independent association signals among women of European ancestry, represented by rs9790517 [conditional P = 2.51 × 10−4; OR, 1.04; 95% confidence interval (CI), 1.02–1.07] and rs77928427 (P = 1.86 × 10−4; OR, 1.04; 95% CI, 1.02–1.07). Functional annotation using data from the Encyclopedia of DNA Elements (ENCODE) project revealed two putative functional variants, rs62331150 and rs73838678 in linkage disequilibrium (LD) with rs9790517 (r2 ≥ 0.90) residing in the active promoter or enhancer, respectively, of the nearest gene, TET2. Both variants are located in DNase I hypersensitivity and transcription factor–binding sites. Using data from both The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), we showed that rs62331150 was associated with level of expression of TET2 in breast normal and tumor tissue. Conclusion: Our study identified two independent association signals at 4q24 in relation to breast cancer risk and suggested that observed association in this locus may be mediated through the regulation of TET2. Impact: Fine-mapping study with large sample size warranted for identification of independent loci for breast cancer risk