The mazEF toxin-antitoxin system as a novel antibacterial target in Acinetobacter baumannii

Although analysis of toxin-antitoxin (TA) systems can be instructive, to date, there is no information on the prevalence and identity of TA systems based on a large panel of Acinetobacter baumannii clinical isolates. The aim of the current study was to screen for functional TA systems among clinical isolates of A. baumannii and to identify the systems' locations. For this purpose, we screened 85 A. baumannii isolates collected from different clinical sources for the presence of the mazEF, relBE and higBA TA genes. The results revealed that the genes coding for the mazEF TA system were commonly present in all clinical isolates of A. baumannii. Reverse transcriptase-polymerase chain reaction analysis showed that transcripts were produced in the clinical isolates. Our findings showed that TA genes are prevalent, harboured by chromosomes and transcribed within A. baumannii. Hence, activation of the toxin proteins in the mazEF TA system should be investigated further as an effective antibacterial strategy against this bacterium

A Gradient Weighted Moving Finite-Element Method with Polynomial Approximation of Any Degree

A gradient weighted moving finite element method (GWMFE) based on piecewise polynomial of any degree is developed to solve time-dependent problems in two space dimensions. Numerical experiments are employed to test the accuracy and effciency of the proposed method with nonlinear Burger equation

Rescaled coordinate descent methods for linear programming

We propose two simple polynomial-time algorithms to find a positive solution to Ax=0Ax=0 . Both algorithms iterate between coordinate descent steps similar to von Neumann’s algorithm, and rescaling steps. In both cases, either the updating step leads to a substantial decrease in the norm, or we can infer that the condition measure is small and rescale in order to improve the geometry. We also show how the algorithms can be extended to find a solution of maximum support for the system Ax=0Ax=0 , x≥0x≥0 . This is an extended abstract. The missing proofs will be provided in the full version

The association between common C677T mutation in methylenetetrahydrofolate reductase gene and the risk of venous thrombosis in an Iranian population

Background: Venous thrombosis is a multicausal disease involving acquired and genetic factors. The prevalence of methylenetetrahydrofolate reductase (MTHFR) C677T genotypes and its association with venous thrombosis is not established in the Iranian population. In this study we investigated a possible association between fasting hyperhomocysteinemia and C677T mutation in the MTHFR gene with venous thrombosis. Materials and Methods: We studied 200 venous thrombotic patients and 100 healthy controls, of similar age and sex. Mutation analysis was carried out by PCR-RFLP, and the homocysteine level was measured by EIA. Results: No significant differences in the frequency of C677T genotypes were observed between patients and controls (P=0.2). The frequency of the T allele was 21 and 27.2 in controls and patients, respectively (odds ratio, 1.27; 95 CI, 0.83-1.94, P=0.15). Fasting homocysteine level was significantly higher in patients than controls (P=0.001). Conclusions: We concluded that hyperhomocysteinemia, but not MTHFR C677T mutation, is a significant risk factor for venous thrombosis in the Iranian population, and measuring the level of homocysteine is less expensive and more useful than the genetic test for the MTHFR mutation

Severe hematopoietic stem cell inflammation compromises chronic granulomatous disease gene therapy

X-linked chronic granulomatous disease (CGD) is associated with defective phagocytosis, life-threatening infections, and inflammatory complications. We performed a clinical trial of lentivirus-based gene therapy in four patients (NCT02757911). Two patients show stable engraftment and clinical benefits, whereas the other two have progressively lost gene-corrected cells. Single-cell transcriptomic analysis reveals a significantly lower frequency of hematopoietic stem cells (HSCs) in CGD patients, especially in the two patients with defective engraftment. These two present a profound change in HSC status, a high interferon score, and elevated myeloid progenitor frequency. We use elastic-net logistic regression to identify a set of 51 interferon genes and transcription factors that predict the failure of HSC engraftment. In one patient, an aberrant HSC state with elevated CEBPβ expression drives HSC exhaustion, as demonstrated by low repopulation in a xenotransplantation model. Targeted treatments to protect HSCs, coupled to targeted gene expression screening, might improve clinical outcomes in CGD

Global, regional, and national burden of chronic kidney disease, 1990–2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, −1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, −1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI

The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990�2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: The burden of inflammatory bowel disease (IBD) is rising globally, with substantial variation in levels and trends of disease in different countries and regions. Understanding these geographical differences is crucial for formulating effective strategies for preventing and treating IBD. We report the prevalence, mortality, and overall burden of IBD in 195 countries and territories between 1990 and 2017, based on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Methods: We modelled mortality due to IBD using a standard Cause of Death Ensemble model including data mainly from vital registrations. To estimate the non-fatal burden, we used data presented in primary studies, hospital discharges, and claims data, and used DisMod-MR 2.1, a Bayesian meta-regression tool, to ensure consistency between measures. Mortality, prevalence, years of life lost (YLLs) due to premature death, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) were estimated. All of the estimates were reported as numbers and rates per 100 000 population, with 95 uncertainty intervals (UI). Findings: In 2017, there were 6·8 million (95 UI 6·4�7·3) cases of IBD globally. The age-standardised prevalence rate increased from 79·5 (75·9�83·5) per 100 000 population in 1990 to 84·3 (79·2�89·9) per 100 000 population in 2017. The age-standardised death rate decreased from 0·61 (0·55�0·69) per 100 000 population in 1990 to 0·51 (0·42�0·54) per 100 000 population in 2017. At the GBD regional level, the highest age-standardised prevalence rate in 2017 occurred in high-income North America (422·0 398·7�446·1 per 100 000) and the lowest age-standardised prevalence rates were observed in the Caribbean (6·7 6·3�7·2 per 100 000 population). High Socio-demographic Index (SDI) locations had the highest age-standardised prevalence rate, while low SDI regions had the lowest age-standardised prevalence rate. At the national level, the USA had the highest age-standardised prevalence rate (464·5 438·6�490·9 per 100 000 population), followed by the UK (449·6 420·6�481·6 per 100 000). Vanuatu had the highest age-standardised death rate in 2017 (1·8 0·8�3·2 per 100 000 population) and Singapore had the lowest (0·08 0·06�0·14 per 100 000 population). The total YLDs attributed to IBD almost doubled over the study period, from 0·56 million (0·39�0·77) in 1990 to 1·02 million (0·71�1·38) in 2017. The age-standardised rate of DALYs decreased from 26·5 (21·0�33·0) per 100 000 population in 1990 to 23·2 (19·1�27·8) per 100 000 population in 2017. Interpretation: The prevalence of IBD increased substantially in many regions from 1990 to 2017, which might pose a substantial social and economic burden on governments and health systems in the coming years. Our findings can be useful for policy makers developing strategies to tackle IBD, including the education of specialised personnel to address the burden of this complex disease. Funding: Bill & Melinda Gates Foundation. © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licens

The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017 : a systematic analysis for the Global Burden of Disease Study 2017

Background The burden of inflammatory bowel disease (IBD) is rising globally, with substantial variation in levels and trends of disease in different countries and regions. Understanding these geographical differences is crucial for formulating effective strategies for preventing and treating IBD. We report the prevalence, mortality, and overall burden of IBD in 195 countries and territories between 1990 and 2017, based on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Methods We modelled mortality due to IBD using a standard Cause of Death Ensemble model including data mainly from vital registrations. To estimate the non-fatal burden, we used data presented in primary studies, hospital discharges, and claims data, and used DisMod-MR 2.1, a Bayesian meta-regression tool, to ensure consistency between measures. Mortality, prevalence, years of life lost (YLLs) due to premature death, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) were estimated. All of the estimates were reported as numbers and rates per 100 000 population, with 95% uncertainty intervals (UI). Findings In 2017, there were 6.8 million (95% UI 6.4-7.3) cases of IBD globally. The age-standardised prevalence rate increased from 79.5 (75.9-83.5) per 100 000 population in 1990 to 84.3 (79.2-89.9) per 100 000 population in 2017. The age-standardised death rate decreased from 0.61 (0.55-0.69) per 100 000 population in 1990 to 0.51 (0.42-0.54) per 100 000 population in 2017. At the GBD regional level, the highest age-standardised prevalence rate in 2017 occurred in high-income North America (422.0 [398.7-446.1] per 100 000) and the lowest age-standardised prevalence rates were observed in the Caribbean (6.7 [6.3-7.2] per 100 000 population). High Sociodemographic Index (SDI) locations had the highest age-standardised prevalence rate, while low SDI regions had the lowest age-standardised prevalence rate. At the national level, the USA had the highest age-standardised prevalence rate (464.5 [438.6-490.9] per 100 000 population), followed by the UK (449.6 [420.6-481.6] per 100 000). Vanuatu had the highest age-standardised death rate in 2017 (1.8 [0.8-3.2] per 100 000 population) and Singapore had the lowest (0.08 [0.06-0.14] per 100 000 population). The total YLDs attributed to IBD almost doubled over the study period, from 0.56 million (0.39-0.77) in 1990 to 1.02 million (0.71-1.38) in 2017. The age-standardised rate of DALYs decreased from 26.5 (21.0-33.0) per 100 000 population in 1990 to 23.2 (19.1-27.8) per 100 000 population in 2017. Interpretation The prevalence of IBD increased substantially in many regions from 1990 to 2017, which might pose a substantial social and economic burden on governments and health systems in the coming years. Our findings can be useful for policy makers developing strategies to tackle IBD, including the education of specialised personnel to address the burden of this complex disease. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation

Health sector spending and spending on HIV/AIDS, tuberculosis, and malaria, and development assistance for health: progress towards Sustainable Development Goal 3

Sustainable Development Goal (SDG) 3 aims to “ensure healthy lives and promote well-being for all at all ages”. While a substantial effort has been made to quantify progress towards SDG3, less research has focused on tracking spending towards this goal. We used spending estimates to measure progress in financing the priority areas of SDG3, examine the association between outcomes and financing, and identify where resource gains are most needed to achieve the SDG3 indicators for which data are available