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PubMed ID: 29058690 ; Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein. ; VE 196/1-1, HE 7456/1-1, Jo 1324/1-1 U.S. Public Health Service: DK-56338 National Institutes of Health: DK076683 National Institute of Diabetes and Digestive and Kidney Diseases: DK-98120 National Research Foundation of Korea, NRF: 2015R1D1A1A01056685 Department of Science and Technology, Government of Kerala NAS LPDS-2015-07 Fudan University ; We are grateful to the families and study participants for their contributions. We thank the Yale Center for Mendelian Genomics (U54HG006504) for WES analysis. FH is a William E. Harmon Professor of Pediatrics. This research was supported by the NIH (DK076683, to FH); the Young Scholars Program of Children's Hospital of Fudan University (to JR); Basic Science Research Program through the National Research Foundation of Korea 2015R1D1A1A01056685 (to HYG); DFG fellowships (VE 196/1-1, to ATvdV; Jo 1324/1-1, to TJS; and HE 7456/1-1, to TH); the German National Academy of Sciences Leopoldina (LPDS-2015-07, to EW); the Egyptian Group for Orphan Renal Diseases (EGORD) (to NAS); the Department of Science and Technology, Government of India (DST-SERB, to MAJ); the National Institute of Diabetes and Digestive and Kidney Diseases (DK-98120, to SK); and the Public Health Service (DK-56338, to SK). --

© The Author(s) 2021. There is conflicting evidence on the influence of weather on COVID-19 transmission. Our aim is to estimate weather-dependent signatures in the early phase of the pandemic, while controlling for socio-economic factors and non-pharmaceutical interventions. We identify a modest non-linear association between mean temperature and the effective reproduction number (Re) in 409 cities in 26 countries, with a decrease of 0.087 (95% CI: 0.025; 0.148) for a 10 °C increase. Early interventions have a greater effect on Re with a decrease of 0.285 (95% CI 0.223; 0.347) for a 5th - 95th percentile increase in the government response index. The variation in the effective reproduction number explained by government interventions is 6 times greater than for mean temperature. We find little evidence of meteorological conditions having influenced the early stages of local epidemics and conclude that population behaviour and government interventions are more important drivers of transmission. ; D.R. was supported by a postdoctoral research fellowship of the Xunta de Galicia (Spain). A.G. was funded by the Medical Research Council-UK (Grant ID: MR/R013349/1), the Natural Environment Research Council UK (Grant ID: NE/R009384/1) and the European Union's Horizon 2020 Project Exhaustion (Grant ID: 820655). R.L. was supported by a Royal Society Dorothy Hodgkin Fellowship. S.A. and S.M. were funded by the Wellcome Trust (grant 210758/Z/18/Z210758/Z/18/Z). The following funding sources are acknowledged as providing funding for the MCC Collaborative Research Network authors: J.K. and A.U. were supported by the Czech Science Foundation, project 18-22125S. S.T. was supported by the Shanghai Municipal Science and Technology Commission (Grant 18411951600). N.S. is supported by the NIEHS-funded HERCULES Center (P30ES019776). H.K. was supported by the National Research Foundation of Korea (BK21 Center for Integrative Response to Health Disasters, Graduate School of Public Health, Seoul National University). A.S., F.D.R. and S.R. were funded by the European Union's Horizon 2020 Project Exhaustion (Grant ID: 820655). Each member of the CMMID COVID-19 Working Group contributed to processing, cleaning and interpretation of data, interpreted findings, contributed to the manuscript and approved the work for publication. The following funding sources are acknowledged as providing funding for the CMMID COVID-19 working group authors. This research was partly funded by the Bill & Melinda Gates Foundation (INV-001754: M.Q; INV-003174: K.P., M.J., Y.L., J.L.; NTD Modelling Consortium OPP1184344: C.A.B.P., G.M.; OPP1180644: S.R.P.; OPP1183986: E.S.N.). BMGF (OPP1157270: K.E.A.). DFID/Wellcome Trust (Epidemic Preparedness Coronavirus research programme 221303/Z/20/Z: C.A.B.P.). EDCTP2 (RIA2020EF-2983-CSIGN: H.P.G.). ERC Starting Grant (#757699: M.Q.). This project has received funding from the European Union's Horizon 2020 research and innovation programme—project EpiPose (101003688: K.P., M.J., P.K., R.C.B., W.J.E., Y.L.). This research was partly funded by the Global Challenges Research Fund (GCRF) project 'RECAP' managed through RCUK and ESRC (ES/P010873/1: A.G., C.I.J., T.J.). HDR UK (MR/S003975/1: R.M.E.). MRC (MR/N013638/1: N.R.W.; MR/V027956/1: W.W.). Nakajima Foundation (A.E.). This research was partly funded by the National Institute for Health Research (NIHR) using UK aid from the UK Government to support global health research. The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR or the UK Department of Health and Social Care (16/136/46: B.J.Q.; 16/137/109: B.J.Q., F.Y.S., M.J., Y.L.; Health Protection Research Unit for Immunisation NIHR200929: N.G.D.; Health Protection Research Unit for Modelling Methodology HPRU-2012-10096: T.J.; NIHR200908: R.M.E.; NIHR200929: F.G.S., M.J.; PR-OD-1017-20002: A.R., W.J.E.). Royal Society (Dorothy Hodgkin Fellowship: R.L.; RP\EA\180004: P.K.). UK DHSC/UK Aid/NIHR (PR-OD-1017-20001: H.P.G.). UK MRC (MC_PC_19065—Covid 19: Understanding the dynamics and drivers of the COVID-19 epidemic using real-time outbreak analytics: A.G., N.G.D., R.M.E., S.C., T.J., W.J.E., Y.L.; MR/P014658/1: G.M.K.). Authors of this research receive funding from the UK Public Health Rapid Support Team funded by the United Kingdom Department of Health and Social Care (T.J.). Wellcome Trust (206250/Z/17/Z: A.J.K., T.W.R.; 206471/Z/17/Z: O.B.; 208812/Z/17/Z: S.C.; 210758/Z/18/Z: J.D.M., J.H., N.I.B.; UNS110424: F.K.). No funding (A.M.F., A.S., C.J.V.-A., D.C.T., J.W., K.E.A., Y.-W.D.C.). LSHTM, DHSC/UKRI COVID-19 Rapid Response Initiative (MR/V028456/1: Y.L.). Innovation Fund of the Joint Federal Committee (01VSF18015: F.K.). Foreign, Commonwealth and Development Office/Wellcome Trust (221303/Z/20/Z: M.K.).

Abstract There is conflicting evidence on the influence of weather on COVID-19 transmission. Our aim is to estimate weather-dependent signatures in the early phase of the pandemic, while controlling for socio-economic factors and non-pharmaceutical interventions. We identify a modest non-linear association between mean temperature and the effective reproduction number (Re) in 409 cities in 26 countries, with a decrease of 0.087 (95% CI: 0.025; 0.148) for a 10 °C increase. Early interventions have a greater effect on Re with a decrease of 0.285 (95% CI 0.223; 0.347) for a 5th-95th percentile increase in the government response index. The variation in the effective reproduction number explained by government interventions is 6 times greater than for mean temperature. We find little evidence of meteorological conditions having influenced the early stages of local epidemics and conclude that population behaviour and government interventions are more important drivers of transmission.

Postoperative cognitive impairment is among the most common medical complications associated with surgical interventions - particularly in elderly patients. In our aging society, it is an urgent medical need to determine preoperative individual risk prediction to allow more accurate cost-benefit decisions prior to elective surgeries. So far, risk prediction is mainly based on clinical parameters. However, these parameters only give a rough estimate of the individual risk. At present, there are no molecular or neuroimaging biomarkers available to improve risk prediction and little is known about the etiology and pathophysiology of this clinical condition. In this short review, we summarize the current state of knowledge and briefly present the recently started BioCog project (Biomarker Development for Postoperative Cognitive Impairment in the Elderly), which is funded by the European Union. It is the goal of this research and development (R&D) project, which involves academic and industry partners throughout Europe, to deliver a multivariate algorithm based on clinical assessments as well as molecular and neuroimaging biomarkers to overcome the currently unsatisfying situation. (C) 2017 Published by Elsevier Masson SAS.

Medicine and healthcare are undergoing profound changes. Whole-genome sequencing and high-resolution imaging technologies are key drivers of this rapid and crucial transformation. Technological innovation combined with automation and miniaturization has triggered an explosion in data production that will soon reach exabyte proportions. How are we going to deal with this exponential increase in data production? The potential of "big data" for improving health is enormous but, at the same time, we face a wide range of challenges to overcome urgently. Europe is very proud of its cultural diversity; however, exploitation of the data made available through advances in genomic medicine, imaging, and a wide range of mobile health applications or connected devices is hampered by numerous historical, technical, legal, and political barriers. European health systems and databases are diverse and fragmented. There is a lack of harmonization of data formats, processing, analysis, and data transfer, which leads to incompatibilities and lost opportunities. Legal frameworks for data sharing are evolving. Clinicians, researchers, and citizens need improved methods, tools, and training to generate, analyze, and query data effectively. Addressing these barriers will contribute to creating the European Single Market for health, which will improve health and healthcare for all Europeans.

Medical Research Council-UK (Grant ID: MR/M022625/1); Natural Environment Research Council UK (Grant ID: NE/R009384/1); European Union's Horizon 2020 Project Exhaustion (Grant ID: 820655); N. Scovronick was supported by the NIEHS-funded HERCULES Center (P30ES019776); Y. Honda was supported by the Environment Research and Technology Development Fund of the Environmental Restoration and Conservation Agency, Japan (JPMEERF15S11412); J. Jaakkola was supported by Academy of Finland (Grant No. 310372); V. Huber was supported by the Spanish Ministry of Economy, Industry and Competitiveness (Grant ID: PCIN-2017-046) and the German Federal Ministry of Education and Research (Grant ID: 01LS1201A2); J Kysely and A. Urban were supported by the Czech Science Foundation (Grant ID: 20-28560S); J. Madureira was supported by the Fundação para a Ciência e a Tecnologia (FCT) (SFRH/BPD/115112/2016); S. Rao and F. di Ruscio were supported by European Union's Horizon 2020 Project EXHAUSTION (Grant ID: 820655); M. Hashizume was supported by the Japan Science and Technology Agency (JST) as part of SICORP, Grant Number JPMJSC20E4; Y. Guo was supported by the Career Development Fellowship of the Australian National Health and Medical Research Council (#APP1163693); S. Lee was support by the Early Career Fellowship of the Australian National Health and Medical Research Council (#APP1109193).

Background Surgery is the main modality of cure for solid cancers and was prioritised to continue during COVID-19 outbreaks. This study aimed to identify immediate areas for system strengthening by comparing the delivery of elective cancer surgery during the COVID-19 pandemic in periods of lockdown versus light restriction. Methods This international, prospective, cohort study enrolled 20 006 adult (≥18 years) patients from 466 hospitals in 61 countries with 15 cancer types, who had a decision for curative surgery during the COVID-19 pandemic and were followed up until the point of surgery or cessation of follow-up (Aug 31, 2020). Average national Oxford COVID-19 Stringency Index scores were calculated to define the government response to COVID-19 for each patient for the period they awaited surgery, and classified into light restrictions (index 60). The primary outcome was the non-operation rate (defined as the proportion of patients who did not undergo planned surgery). Cox proportional-hazards regression models were used to explore the associations between lockdowns and non-operation. Intervals from diagnosis to surgery were compared across COVID-19 government response index groups. This study was registered at ClinicalTrials.gov, NCT04384926. Findings Of eligible patients awaiting surgery, 2003 (10·0%) of 20 006 did not receive surgery after a median follow-up of 23 weeks (IQR 16–30), all of whom had a COVID-19-related reason given for non-operation. Light restrictions were associated with a 0·6% non-operation rate (26 of 4521), moderate lockdowns with a 5·5% rate (201 of 3646; adjusted hazard ratio [HR] 0·81, 95% CI 0·77–0·84; p<0·0001), and full lockdowns with a 15·0% rate (1775 of 11 827; HR 0·51, 0·50–0·53; p<0·0001). In sensitivity analyses, including adjustment for SARS-CoV-2 case notification rates, moderate lockdowns (HR 0·84, 95% CI 0·80–0·88; p<0·001), and full lockdowns (0·57, 0·54–0·60; p<0·001), remained independently associated with non-operation. Surgery beyond 12 weeks from diagnosis in patients without neoadjuvant therapy increased during lockdowns (374 [9·1%] of 4521 in light restrictions, 317 [10·4%] of 3646 in moderate lockdowns, 2001 [23·8%] of 11 827 in full lockdowns), although there were no differences in resectability rates observed with longer delays. Interpretation Cancer surgery systems worldwide were fragile to lockdowns, with one in seven patients who were in regions with full lockdowns not undergoing planned surgery and experiencing longer preoperative delays. Although short-term oncological outcomes were not compromised in those selected for surgery, delays and non-operations might lead to long-term reductions in survival. During current and future periods of societal restriction, the resilience of elective surgery systems requires strengthening, which might include protected elective surgical pathways and long-term investment in surge capacity for acute care during public health emergencies to protect elective staff and services. Funding National Institute for Health Research Global Health Research Unit, Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, Medtronic, Sarcoma UK, The Urology Foundation, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research.