Inhibition or knock out of Inducible nitric oxide synthase result in resistance to bleomycin-induced lung injury

BACKGROUND: In the present study, by comparing the responses in wild-type mice (WT) and mice lacking (KO) the inducible (or type 2) nitric oxide synthase (iNOS), we investigated the role played by iNOS in the development of on the lung injury caused by bleomycin administration. When compared to bleomycin-treated iNOSWT mice, iNOSKO mice, which had received bleomycin, exhibited a reduced degree of the (i) lost of body weight, (ii) mortality rate, (iii) infiltration of the lung with polymorphonuclear neutrophils (MPO activity), (iv) edema formation, (v) histological evidence of lung injury, (vi) lung collagen deposition and (vii) lung Transforming Growth Factor beta1 (TGF-β1) expression. METHODS: Mice subjected to intratracheal administration of bleomycin developed a significant lung injury. Immunohistochemical analysis for nitrotyrosine revealed a positive staining in lungs from bleomycin-treated iNOSWT mice. RESULTS: The intensity and degree of nitrotyrosine staining was markedly reduced in tissue section from bleomycin-iNOSKO mice. Treatment of iNOSWT mice with of GW274150, a novel, potent and selective inhibitor of iNOS activity (5 mg/kg i.p.) also significantly attenuated all of the above indicators of lung damage and inflammation. CONCLUSION: Taken together, our results clearly demonstrate that iNOS plays an important role in the lung injury induced by bleomycin in the mice

Closed-loop insulin delivery for treatment of type 1 diabetes

Type 1 diabetes is one of the most common endocrine problems in childhood and adolescence, and remains a serious chronic disorder with increased morbidity and mortality, and reduced quality of life. Technological innovations positively affect the management of type 1 diabetes. Closed-loop insulin delivery (artificial pancreas) is a recent medical innovation, aiming to reduce the risk of hypoglycemia while achieving tight control of glucose. Characterized by real-time glucose-responsive insulin administration, closed-loop systems combine glucose-sensing and insulin-delivery components. In the most viable and researched configuration, a disposable sensor measures interstitial glucose levels, which are fed into a control algorithm controlling delivery of a rapid-acting insulin analog into the subcutaneous tissue by an insulin pump. Research progress builds on an increasing use of insulin pumps and availability of glucose monitors. We review the current status of insulin delivery, focusing on clinical evaluations of closed-loop systems. Future goals are outlined, and benefits and limitations of closed-loop therapy contrasted. The clinical utility of these systems is constrained by inaccuracies in glucose sensing, inter- and intra-patient variability, and delays due to absorption of insulin from the subcutaneous tissue, all of which are being gradually addressed.Supported by the Juvenile Diabetes Research Foundation (#22-2006-1113, #22-2007-1801, #22-2009-801), Diabetes UK (BDA07/0003549, BDA07/0003551), European Commission Framework Programme 7 (247138), NIDDK (DK085621), and NIHR Cambridge Biomedical Research Centre

The overlapping burden of the three leading causes of disability and death in sub-Saharan African children

Despite substantial declines since 2000, lower respiratory infections (LRIs), diarrhoeal diseases, and malaria remain among the leading causes of nonfatal and fatal disease burden for children under 5 years of age (under 5), primarily in sub-Saharan Africa (SSA). The spatial burden of each of these diseases has been estimated subnationally across SSA, yet no prior analyses have examined the pattern of their combined burden. Here we synthesise subnational estimates of the burden of LRIs, diarrhoea, and malaria in children under-5 from 2000 to 2017 for 43 sub-Saharan countries. Some units faced a relatively equal burden from each of the three diseases, while others had one or two dominant sources of unit-level burden, with no consistent pattern geographically across the entire subcontinent. Using a subnational counterfactual analysis, we show that nearly 300 million DALYs could have been averted since 2000 by raising all units to their national average. Our findings are directly relevant for decision-makers in determining which and targeting where the most appropriate interventions are for increasing child survival. © 2022, The Author(s).Funding text 1: This work was primarily supported by grant OPP1132415 from the Bill & Melinda Gates Foundation. ; Funding text 2: This study was funded by the Bill & Melinda Gates Foundation. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The non-consortium authors have no competing interests . Competing interests for consortium authors is as follows: Robert Ancuceanu reports receiving consultancy or speaker feeds from UCB, Sandoz, Abbvie, Zentiva, Teva, Laropharm, CEGEDIM, Angelini, Biessen Pharma, Hofigal, AstraZeneca, and Stada. Jacek Jerzy Jozwiak reports personal fees from Amgen, ALAB Laboratories, Teva, Synexus, Boehringer Ingelheim, and Zentiva, all outside the submitted work. Kewal Krishan reports non-financial support from UGC Centre of Advanced Study, CAS II, Department of Anthropology, Panjab University, Chandigarh, India, outside the submitted work. Walter Mendoza is a Program Analyst in Population and Development at the United Nations Population Fund-UNFPA Country Office in Peru, which does not necessarily endorse or support these findings. Maarten J Postma reports grants and personal fees from MSD, GSK, Pfizer, Boehringer Ingelheim, Novavax, BMS, Seqirus, Astra Zeneca, Sanofi, IQVIA, grants from Bayer, BioMerieux, WHO, EU, FIND, Antilope, DIKTI, LPDP, Budi, personal fees from Novartis, Quintiles, Pharmerit, owning stock options in Health-Ecore and PAG Ltd, and being advisor to Asc Academics, all outside the submitted work. Jasviner A Singh reports personal fees from Crealta/Horizon, Medisys, Fidia, UBM LLC, Trio health, Medscape, WebMD, Clinical Care options, Clearview healthcare partners, Putnam associates, Focus forward, Navigant consulting, Spherix, Practice Point communications, the National Institutes of Health, the American College of Rheumatology, and Simply Speaking, owning stock options in Amarin, Viking, Moderna, Vaxart pharmaceuticals and Charlotte’s Web Holdings, being a member of FDA Arthritis Advisory Committee, the steering committee of OMERACT, an international organization that develops measures for clinical trials and receives arm’s length funding from 12 pharmaceutical companies, and the Veterans Affairs Rheumatology Field Advisory Committee, and acting as Editor and Director of the UAB Cochrane Musculoskeletal Group Satellite Center on Network Meta-analysis, all outside the submitted work. Era Upadhyay has a patent A system and method of reusable filters for anti-pollution mask pending, and a patent A system and method for electricity generation through crop stubble by using microbial fuel cells pending

Use of multidimensional item response theory methods for dementia prevalence prediction: an example using the Health and Retirement Survey and the Aging, Demographics, and Memory Study.

BACKGROUND: Data sparsity is a major limitation to estimating national and global dementia burden. Surveys with full diagnostic evaluations of dementia prevalence are prohibitively resource-intensive in many settings. However, validation samples from nationally representative surveys allow for the development of algorithms for the prediction of dementia prevalence nationally. METHODS: Using cognitive testing data and data on functional limitations from Wave A (2001-2003) of the ADAMS study (n = 744) and the 2000 wave of the HRS study (n = 6358) we estimated a two-dimensional item response theory model to calculate cognition and function scores for all individuals over 70. Based on diagnostic information from the formal clinical adjudication in ADAMS, we fit a logistic regression model for the classification of dementia status using cognition and function scores and applied this algorithm to the full HRS sample to calculate dementia prevalence by age and sex. RESULTS: Our algorithm had a cross-validated predictive accuracy of 88% (86-90), and an area under the curve of 0.97 (0.97-0.98) in ADAMS. Prevalence was higher in females than males and increased over age, with a prevalence of 4% (3-4) in individuals 70-79, 11% (9-12) in individuals 80-89 years old, and 28% (22-35) in those 90 and older. CONCLUSIONS: Our model had similar or better accuracy as compared to previously reviewed algorithms for the prediction of dementia prevalence in HRS, while utilizing more flexible methods. These methods could be more easily generalized and utilized to estimate dementia prevalence in other national surveys

Global, regional, and national incidence, prevalence, and mortality of HIV, 1980–2017, and forecasts to 2030, for 195 countries and territories: a systematic analysis for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017

Background Understanding the patterns of HIV/AIDS epidemics is crucial to tracking and monitoring the progress of prevention and control efforts in countries. We provide a comprehensive assessment of the levels and trends of HIV/AIDS incidence, prevalence, mortality, and coverage of antiretroviral therapy (ART) for 1980–2017 and forecast these estimates to 2030 for 195 countries and territories. Methods We determined a modelling strategy for each country on the basis of the availability and quality of data. For countries and territories with data from population-based seroprevalence surveys or antenatal care clinics, we estimated prevalence and incidence using an open-source version of the Estimation and Projection Package—a natural history model originally developed by the UNAIDS Reference Group on Estimates, Modelling, and Projections. For countries with cause-specific vital registration data, we corrected data for garbage coding (ie, deaths coded to an intermediate, immediate, or poorly defined cause) and HIV misclassification. We developed a process of cohort incidence bias adjustment to use information on survival and deaths recorded in vital registration to back-calculate HIV incidence. For countries without any representative data on HIV, we produced incidence estimates by pulling information from observed bias in the geographical region. We used a re-coded version of the Spectrum model (a cohort component model that uses rates of disease progression and HIV mortality on and off ART) to produce age-sex-specific incidence, prevalence, and mortality, and treatment coverage results for all countries, and forecast these measures to 2030 using Spectrum with inputs that were extended on the basis of past trends in treatment scale-up and new infections. Findings Global HIV mortality peaked in 2006 with 1·95 million deaths (95% uncertainty interval 1·87–2·04) and has since decreased to 0·95 million deaths (0·91–1·01) in 2017. New cases of HIV globally peaked in 1999 (3·16 million, 2·79–3·67) and since then have gradually decreased to 1·94 million (1·63–2·29) in 2017. These trends, along with ART scale-up, have globally resulted in increased prevalence, with 36·8 million (34·8–39·2) people living with HIV in 2017. Prevalence of HIV was highest in southern sub-Saharan Africa in 2017, and countries in the region had ART coverage ranging from 65·7% in Lesotho to 85·7% in eSwatini. Our forecasts showed that 54 countries will meet the UNAIDS target of 81% ART coverage by 2020 and 12 countries are on track to meet 90% ART coverage by 2030. Forecasted results estimate that few countries will meet the UNAIDS 2020 and 2030 mortality and incidence targets. Interpretation Despite progress in reducing HIV-related mortality over the past decade, slow decreases in incidence, combined with the current context of stagnated funding for related interventions, mean that many countries are not on track to reach the 2020 and 2030 global targets for reduction in incidence and mortality. With a growing population of people living with HIV, it will continue to be a major threat to public health for years to come. The pace of progress needs to be hastened by continuing to expand access to ART and increasing investments in proven HIV prevention initiatives that can be scaled up to have population-level impact

Mapping geographical inequalities in access to drinking water and sanitation facilities in low-income and middle-income countries, 2000-17

Background Universal access to safe drinking water and sanitation facilities is an essential human right, recognised in the Sustainable Development Goals as crucial for preventing disease and improving human wellbeing. Comprehensive, high-resolution estimates are important to inform progress towards achieving this goal. We aimed to produce high-resolution geospatial estimates of access to drinking water and sanitation facilities. Methods We used a Bayesian geostatistical model and data from 600 sources across more than 88 low-income and middle-income countries (LMICs) to estimate access to drinking water and sanitation facilities on continuous continent-wide surfaces from 2000 to 2017, and aggregated results to policy-relevant administrative units. We estimated mutually exclusive and collectively exhaustive subcategories of facilities for drinking water (piped water on or off premises, other improved facilities, unimproved, and surface water) and sanitation facilities (septic or sewer sanitation, other improved, unimproved, and open defecation) with use of ordinal regression. We also estimated the number of diarrhoeal deaths in children younger than 5 years attributed to unsafe facilities and estimated deaths that were averted by increased access to safe facilities in 2017, and analysed geographical inequality in access within LMICs. Findings Across LMICs, access to both piped water and improved water overall increased between 2000 and 2017, with progress varying spatially. For piped water, the safest water facility type, access increased from 40.0% (95% uncertainty interval [UI] 39.4-40.7) to 50.3% (50.0-50.5), but was lowest in sub-Saharan Africa, where access to piped water was mostly concentrated in urban centres. Access to both sewer or septic sanitation and improved sanitation overall also increased across all LMICs during the study period. For sewer or septic sanitation, access was 46.3% (95% UI 46.1-46.5) in 2017, compared with 28.7% (28.5-29.0) in 2000. Although some units improved access to the safest drinking water or sanitation facilities since 2000, a large absolute number of people continued to not have access in several units with high access to such facilities (>80%) in 2017. More than 253 000 people did not have access to sewer or septic sanitation facilities in the city of Harare, Zimbabwe, despite 88.6% (95% UI 87.2-89.7) access overall. Many units were able to transition from the least safe facilities in 2000 to safe facilities by 2017; for units in which populations primarily practised open defecation in 2000, 686 (95% UI 664-711) of the 1830 (1797-1863) units transitioned to the use of improved sanitation. Geographical disparities in access to improved water across units decreased in 76.1% (95% UI 71.6-80.7) of countries from 2000 to 2017, and in 53.9% (50.6-59.6) of countries for access to improved sanitation, but remained evident subnationally in most countries in 2017. Interpretation Our estimates, combined with geospatial trends in diarrhoeal burden, identify where efforts to increase access to safe drinking water and sanitation facilities are most needed. By highlighting areas with successful approaches or in need of targeted interventions, our estimates can enable precision public health to effectively progress towards universal access to safe water and sanitation. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd.Peer reviewe

Mapping inequalities in exclusive breastfeeding in low- and middle-income countries, 2000–2018

Exclusive breastfeeding (EBF)-giving infants only breast-milk for the first 6 months of life-is a component of optimal breastfeeding practices effective in preventing child morbidity and mortality. EBF practices are known to vary by population and comparable subnational estimates of prevalence and progress across low- and middle-income countries (LMICs) are required for planning policy and interventions. Here we present a geospatial analysis of EBF prevalence estimates from 2000 to 2018 across 94 LMICs mapped to policy-relevant administrative units (for example, districts), quantify subnational inequalities and their changes over time, and estimate probabilities of meeting the World Health Organization's Global Nutrition Target (WHO GNT) of ≥70% EBF prevalence by 2030. While six LMICs are projected to meet the WHO GNT of ≥70% EBF prevalence at a national scale, only three are predicted to meet the target in all their district-level units by 2030.This work was primarily supported by grant no. OPP1132415 from the Bill & Melinda Gates Foundation. Co-authors used by the Bill & Melinda Gates Foundation (E.G.P. and R.R.3) provided feedback on initial maps and drafts of this manuscript. L.G.A. has received support from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior, Brasil (CAPES), Código de Financiamento 001 and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (grant nos. 404710/2018-2 and 310797/2019-5). O.O.Adetokunboh acknowledges the National Research Foundation, Department of Science and Innovation and South African Centre for Epidemiological Modelling and Analysis. M.Ausloos, A.Pana and C.H. are partially supported by a grant from the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project no. PN-III-P4-ID-PCCF-2016-0084. P.C.B. would like to acknowledge the support of F. Alam and A. Hussain. T.W.B. was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, funded by the German Federal Ministry of Education and Research. K.Deribe is supported by the Wellcome Trust (grant no. 201900/Z/16/Z) as part of his international intermediate fellowship. C.H. and A.Pana are partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project no. PN-III-P2-2.1-SOL-2020-2-0351. B.Hwang is partially supported by China Medical University (CMU109-MF-63), Taichung, Taiwan. M.Khan acknowledges Jatiya Kabi Kazi Nazrul Islam University for their support. A.M.K. acknowledges the other collaborators and the corresponding author. Y.K. was supported by the Research Management Centre, Xiamen University Malaysia (grant no. XMUMRF/2020-C6/ITM/0004). K.Krishan is supported by a DST PURSE grant and UGC Centre of Advanced Study (CAS II) awarded to the Department of Anthropology, Panjab University, Chandigarh, India. M.Kumar would like to acknowledge FIC/NIH K43 TW010716-03. I.L. is a member of the Sistema Nacional de Investigación (SNI), which is supported by the Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT), Panamá. M.L. was supported by China Medical University, Taiwan (CMU109-N-22 and CMU109-MF-118). W.M. is currently a programme analyst in Population and Development at the United Nations Population Fund (UNFPA) Country Office in Peru, which does not necessarily endorses this study. D.E.N. acknowledges Cochrane South Africa, South African Medical Research Council. G.C.P. is supported by an NHMRC research fellowship. P.Rathi acknowledges support from Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal, India. Ramu Rawat acknowledges the support of the GBD Secretariat for supporting the reviewing and collaboration of this paper. B.R. acknowledges support from Manipal College of Health Professions, Manipal Academy of Higher Education, Manipal. A.Ribeiro was supported by National Funds through FCT, under the programme of ‘Stimulus of Scientific Employment—Individual Support’ within the contract no. info:eu-repo/grantAgreement/FCT/CEEC IND 2018/CEECIND/02386/2018/CP1538/CT0001/PT. S.Sajadi acknowledges colleagues at Global Burden of Diseases and Local Burden of Disease. A.M.S. acknowledges the support from the Egyptian Fulbright Mission Program. F.S. was supported by the Shenzhen Science and Technology Program (grant no. KQTD20190929172835662). A.Sheikh is supported by Health Data Research UK. B.K.S. acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal for all the academic support. B.U. acknowledges support from Manipal Academy of Higher Education, Manipal. C.S.W. is supported by the South African Medical Research Council. Y.Z. was supported by Science and Technology Research Project of Hubei Provincial Department of Education (grant no. Q20201104) and Outstanding Young and Middle-aged Technology Innovation Team Project of Hubei Provincial Department of Education (grant no. T2020003). The funders of the study had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. All maps presented in this study are generated by the authors and no permissions are required to publish them

Estimating global injuries morbidity and mortality: methods and data used in the Global Burden of Disease 2017 study

BACKGROUND: While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. METHODS: In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. RESULTS: GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. CONCLUSIONS: GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future

Five insights from the Global Burden of Disease Study 2019

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 provides a rules-based synthesis of the available evidence on levels and trends in health outcomes, a diverse set of risk factors, and health system responses. GBD 2019 covered 204 countries and territories, as well as first administrative level disaggregations for 22 countries, from 1990 to 2019. Because GBD is highly standardised and comprehensive, spanning both fatal and non-fatal outcomes, and uses a mutually exclusive and collectively exhaustive list of hierarchical disease and injury causes, the study provides a powerful basis for detailed and broad insights on global health trends and emerging challenges. GBD 2019 incorporates data from 281 586 sources and provides more than 3.5 billion estimates of health outcome and health system measures of interest for global, national, and subnational policy dialogue. All GBD estimates are publicly available and adhere to the Guidelines on Accurate and Transparent Health Estimate Reporting. From this vast amount of information, five key insights that are important for health, social, and economic development strategies have been distilled. These insights are subject to the many limitations outlined in each of the component GBD capstone papers.Peer reviewe