HD Physiology Project-Japanese efforts to promote multilevel integrative systems biology and physiome research.

The HD Physiology Project is a Japanese research consortium that aimed to develop methods and a computational platform in which physiological and pathological information can be described in high-level definitions across multiple scales of time and size. During the 5 years of this project, an appropriate software platform for multilevel functional simulation was developed and a whole-heart model including pharmacokinetics for the assessment of the proarrhythmic risk of drugs was developed. In this article, we outline the description and scientific strategy of this project and present the achievements and influence on multilevel integrative systems biology and physiome research

International differences in self-reported health measures in 33 major metropolitan areas in Europe.

The increasing concentration of populations into large conurbations in recent decades has not been matched by international health assessments, which remain largely focused at the country level. We aimed to demonstrate the use of routine survey data to compare the health of large metropolitan centres across Europe and determine the extent to which differences are due to socio-economic factors

Personalizing treatment in end-stage kidney disease: deciding between haemodiafiltration and haemodialysis based on individualized treatment effect prediction

Background: Previous studies suggest that haemodiafiltration reduces mortality compared with haemodialysis in patients with end-stage kidney disease (ESKD), but the controversy surrounding its benefits remains and it is unclear to what extent individual patients benefit from haemodiafiltration. This study is aimed to develop and validate a treatment effect prediction model to determine which patients would benefit most from haemodiafiltration compared with haemodialysis in terms of all-cause mortality. Methods: Individual participant data from four randomized controlled trials comparing haemodiafiltration with haemodialysis on mortality were used to derive a Royston-Parmar model for the prediction of absolute treatment effect of haemodiafiltration based on pre-specified patient and disease characteristics. Validation of the model was performed using internal-external cross validation. Results: The median predicted survival benefit was 44 (Q1-Q3: 44-46) days for every year of treatment with haemodiafiltration compared with haemodialysis. The median survival benefit with haemodiafiltration ranged from 2 to 48 months. Patients who benefitted most from haemodiafiltration were younger, less likely to have diabetes or a cardiovascular history and had higher serum creatinine and albumin levels. Internal-external cross validation showed adequate discrimination and calibration. Conclusion: Although overall mortality is reduced by haemodiafiltration compared with haemodialysis in ESKD patients, the absolute survival benefit can vary greatly between individuals. Our results indicate that the effects of haemodiafiltration on survival can be predicted using a combination of readily available patient and disease characteristics, which could guide shared decision-making

The probability of receiving a kidney transplantation in end-stage kidney disease patients who are treated with haemodiafiltration or haemodialysis: a pooled individual participant data from four randomised controlled trials

BACKGROUND: Due to a critical shortage of available kidney grafts, most patients with Stage 5 Chronic Kidney Disease (CKD5) require bridging dialysis support. It remains unclear whether treatment by different dialysis modalities changes the selection and/or preparation of a potential transplant candidate. Therefore, we assessed whether the likelihood of receiving kidney transplant (both living or deceased kidney donors) differs between haemodialysis (HD) and online haemodiafiltration (HDF) in patients with CKD5D. METHODS: Individual participant data from four randomised controlled trials comparing online HDF with HD were used. Information on kidney transplant was obtained during follow-up. The likelihood of receiving a kidney transplant was compared between HD and HDF, and evaluated across different subgroups: age, sex, diabetes, history of cardiovascular disease, albumin, dialysis vintage, fistula, and level of convection volume standardized to body surface area. Hazard ratios (HRs), with corresponding 95% confidence intervals (95% CI), comparing the effect of online HDF versus HD on the likelihood of receiving a kidney transplant, were estimated using Cox proportional hazards models with a random effect for study. RESULTS: After a median follow-up of 2.5 years (Q1 to Q3: 1.9-3.0), 331 of the 1620 (20.4%) patients with CKD5D received a kidney transplant. This concerned 22% (n = 179) of patients who were treated with online HDF compared with 19% (n = 152) of patients who were treated with HD. No differences in the likelihood of undergoing a kidney transplant were found between the two dialysis modalities in both the crude analyse (HR: 1.07, 95% CI: 0.86-1.33) and adjusted analysis for age, sex, diabetes, cardiovascular history, albumin, and creatinine (HR: 1.15, 95%-CI: 0.92-1.44). There was no evidence for a differential effect across subgroups based on patient- and disease-characteristics nor in different categories of convection volumes. CONCLUSIONS: Treatment with HD and HDF does not affect the selection and/or preparation of CKD5D patients for kidney transplant given that the likelihood of receiving a kidney transplant does not differ between the dialysis modalities. These finding persisted across a variety of subgroups differing in patient and disease characteristics and is not affected by the level of convection volume delivered during HDF treatment sessions

Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.

OBJECTIVE: Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic Stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. METHODS: Using genome wide association study (GWAS) data from METASTROKE+ (15,916 IS cases and 68,826 controls) and IGAP (17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets to identify the SNPs and molecular pathways through which disease risk may be conferred. RESULTS: We found evidence of a shared genetic contribution between AD and small vessel stroke (rG(SE)=0.37(0.17); p=0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall, or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE+ small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1), associated with both diseases (p=1.8x10-8 ). A pathway analysis identified four associated pathways, involving cholesterol transport and immune response. INTERPRETATION: Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. This article is protected by copyright. All rights reserved.Stroke Association (TSA 2013/01 & TSA 2010/10: H.S.M & M.T.), MRC/Stroke Association (Clinical Training Fellowship: P.A-S.), National Institute for Health Research (NIHR) (Senior Investigator Award: H.S.M.), Wellcome Trust (Collection of the UK Young Lacunar Stroke DNA Study (WT072952): H.S.M); NIHR Comprehensive Biomedical Research Unit at Cambridge University Hospitals Trust (H.S.M.); NIHR Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London (C.M.L.); NIHR Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London (C.M.L.). Additional sources of support are provided in the Supplementary Materials.This is the final version of the article. It first appeared from Wiley via https://doi.org/10.1002/ana.2462

Interaction between proatherosclerotic factors and right-to-left shunt on the risk of cryptogenic stroke: the Italian Project on Stroke in Young Adults.

Objective: To explore the interaction effects between cardiac interatrial right-to-left shunt (RLS) and proatherosclerotic factors on the risk of brain ischaemia. Design: Multicentre Italian caseecontrol study. Setting: University hospitals. Participants: 588 patients with cryptogenic stroke (CS) aged ≤45 years and 585 control subjects consecutively enrolled as part of the Italian Project on Stroke in Young Adults. Methods: Interaction effects between RLS and an individual proatherosclerotic score computed from the number of conventional vascular risk factors for the risk of CS were investigated. Data were examined by logistic regression models and expressed as interaction OR or interaction risk difference (RD). Results: CS risk increased with increasing number of proatherosclerotic factors in subjects without RLS (OR 2.73; 95% CI 1.98 to 3.76; RD +0.246; 95% CI +0.17 to +0.32; for subjects with one or more factors), but was higher in subjects with RLS and no additional proatherosclerotic factors (OR 5.14; 95% CI 3.49 to 7.58; RD +0.388; 95% CI +0.31 to +0.47) compared with subjects without RLS and no risk factors. Negative interaction and antagonistic effects between RLS and proatherosclerotic factors were observed (interaction OR 0.52; 95% CI 0.31 to 0.91; interaction RD -0.17; 95% CI -0.29 to -0.05). Conclusions: The influence of RLS on the risk of CS decreases with increasing number of atherosclerotic factors, and is highest when such factors are absent. Individual proatherosclerotic profiles may help to identify patients with CS whose patent foramen ovale is probably pathogenic

Relation of Statin Use and Mortality in Community-Dwelling Frail Older Patients With Coronary Artery Disease

Clinical decision-making for statin treatment in older patients with coronary artery disease (CAD) is under debate, particularly in community-dwelling frail patients at high risk of death. In this retrospective observational study on 2,597 community-dwelling patients aged >= 65 years with a previous hospitalization for CAD, we estimated mortality risk assessed with the Multidimensional Prognostic Index (MPI), based on the Standardized Multidimensional Assessment Schedule for Adults and Aged Persons (SVaMA), used to determine accessibility to homecare services/nursing home admission in 2005 to 2013 in the Padua Health District, Veneto, Italy. Participants were categorized as having mild (MPI-SVaMA-1), moderate (MPI-SVaMA-2), and high (MPI-SVaMA-3) baseline mortality risk, and propensity score-adjusted hazard ratios (HRs) of 3-year mortality rate were calculated according to statin treatment in these subgroups. Greater MPI-SVaMA scores were associated with lower rates of statin treatment and higher 3-year mortality rate (MPI-SVaMA-1 = 23.4%; MPI-SVaMA-2 = 39.1%; MPI-SVaMA-3 = 76.2%). After adjusting for propensity score quintiles, statin treatment was associated with lower 3-year mortality risk irrespective of MPI-SVaMA group (HRs [95% confidence intervals] 0.45 [0.37 to 0.55], 0.44 [0.36 to 0.53], and 0.28 [0.21 to 0.39] in MPI-SVaMA-1,-2, and-3 groups, respectively [interaction test p = 0.202]). Subgroup analyses showed that statin treatment was also beneficial irrespective of age (HRs [95% confidence intervals] 0.38 [0.27 to 0.53], 0.45 [0.38 to 0.54], and 0.44 [0.37 to 0.54] in 65 to 74, 75 to 84, and Z85 year age groups, respectively [interaction test p = 0.597]). In conclusion, in community-dwelling frail older patients with CAD, statin treatment was significantly associated with reduced 3-year mortality rate irrespective of age and multidimensional impairment, although the frailest patients were less likely to be treated with statins. (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Prognostic implications of comorbidity patterns in critically ill covid-19 patients: a multicenter, observational study

Financial support was provided by Instituto de Salud Carlos III (CIBERESUCICOVID, COV20/00110), co- funded by Fondo Europeo de Desarrollo Regional (FEDER), “Una manera de hacer Europa”, Centro de Investigaci on Biom edica en Red − Enfermedades Res- piratorias (CIBERES) and Donation Program “estar pre- parados”, UNESPA, Madrid, Spain. JdB acknowledges receiving financial support from Instituto de Salud Car- los III (ISCIII; Miguel Servet 2019: CP19/00108), co- funded by the European Social Fund (ESF), “Investing in your future”. DdGC acknowledges receiving financial support from Instituto de Salud Carlos III (ISCIII; Miguel Servet 2019: CP20/00041), co-funded by the European Social Fund (ESF), “Investing in your future”. AC acknowledges receiving financial support from Instituto de Salud Carlos III (ISCIII; Sara Borrell 2021: CD21/00087).Benítez ID, de Batlle J, Torres G, González J, de Gonzalo-Calvo D, Targa ADS, Gort-Paniello C, Moncusí-Moix A, Ceccato A, Fernández-Barat L, Ferrer R, Garcia-Gasulla D, Menéndez R, Motos A, Peñuelas O, Riera J, Bermejo-Martin JF, Peñasco Y, Ricart P, Martin Delgado MC, Aguilera L, Rodríguez A, Boado Varela MV, Suarez-Sipmann F, Pozo-Laderas JC, Solé-Violan J, Nieto M, Novo MA, Barberán J, Amaya Villar R, Garnacho-Montero J, García-Garmendia JL, Gómez JM, Lorente JÁ, Blandino Ortiz A, Tamayo Lomas L, López-Ramos E, Úbeda A, Catalán-González M, Sánchez-Miralles A, Martínez Varela I, Jorge García RN, Franco N, Gumucio-Sanguino VD, Huerta Garcia A, Bustamante-Munguira E, Valdivia LJ, Caballero J, Gallego E, Martínez de la Gándara A, Castellanos-Ortega Á, Trenado J, Marin-Corral J, Albaiceta GM, de la Torre MDC, Loza-Vázquez A, Vidal P, Lopez Messa J, Añón JM, Carbajales Pérez C, Sagredo V, Bofill N, Carbonell N, Socias L, Barberà C, Estella A, Valledor Mendez M, Diaz E, López Lago A, Torres A, Barbé F; CIBERESUCICOVID Project (COV20/00110, ISCIII

Long-term peridialytic blood pressure changes are related to mortality

Background: In chronic haemodialysis (HD) patients, the relationship between long-term peridialytic blood pressure (BP) changes and mortality has not been investigated. Methods: To evaluate whether long-term changes in peridialytic BP are related to mortality and whether treatment with HD or haemodiafiltration (HDF) differs in this respect, the combined individual participant data of three randomized controlled trials comparing HD with HDF were used. Time-varying Cox regression and joint models were applied. Results: During a median follow-up of 2.94 years, 609 of 2011 patients died. As for pre-dialytic systolic BP (pre-SBP), a severe decline (≥21 mmHg) in the preceding 6 months was independently related to increased mortality [hazard ratio (HR) 1.61, P =. 01] when compared with a moderate increase. Likewise, a severe decline in post-dialytic diastolic BP (DBP) was associated with increased mortality (adjusted HR 1.96, P <. 0005). In contrast, joint models showed that every 5-mmHg increase in pre-SBP and post-DBP during total follow-up was related to reduced mortality (adjusted HR 0.97, P =. 01 and 0.94, P =. 03, respectively). No interaction was observed between BP changes and treatment modality. Conclusion: Severe declines in pre-SBP and post-DBP in the preceding 6 months were independently related to mortality. Therefore peridialytic BP values should be interpreted in the context of their changes and not solely as an absolute value

Correlations between arm motor behavior and brain function following bilateral arm training after stroke:A systematic review

Background Bilateral training (BT) of the upper limb (UL) might enhance recovery of arm function after stroke. To better understand the therapeutic potential of BT, this study aimed to determine the correlation between arm motor behavior and brain structure/function as a result of bilateral arm training poststroke. Methods A systematic review of quantitative studies of BT evaluating both UL motor behavior and neuroplasticity was conducted. Eleven electronic databases were searched. Two reviewers independently selected studies, extracted data and assessed methodological quality, using the Effective Public Health Practice Project (EPHPP) tool. Results Eight studies comprising 164 participants met the inclusion criteria. Only two studies rated “strong” on the EPHPP tool. Considerable heterogeneity of participants, BT modes, comparator interventions and measures contraindicated pooled outcome analysis. Modes of BT included: in-phase and anti-phase; functional movements involving objects; and movements only. Movements were mechanically coupled, free, auditory-cued, or self-paced. The Fugl-Meyer Assessment (UL section) was used in six of eight studies, however, different subsections were used by different studies. Neural correlates were measured using fMRI and TMS in three and five studies, respectively, using a wide variety of variables. Associations between changes in UL function and neural plasticity were inconsistent and only two studies reported a statistical correlation following BT. Conclusions No clear pattern of association between UL motor and neural response to BT was apparent from this review, indicating that the neural correlates of motor behavior response to BT after stroke remain unknown. To understand the full therapeutic potential of BT and its different modes, further investigation is required