RNAi-Based Functional Genomics Identifies New Virulence Determinants in Mucormycosis

Mucorales are an emerging group of human pathogens that are responsible for the lethal disease mucormycosis. Unfortunately, functional studies on the genetic factors behind the virulence of these organisms are hampered by their limited genetic tractability, since they are reluctant to classical genetic tools like transposable elements or gene mapping. Here, we describe an RNAi-based functional genomic platform that allows the identification of new virulence factors through a forward genetic approach firstly described in Mucorales. This platform contains a whole-genome collection of Mucor circinelloides silenced transformants that presented a broad assortment of phenotypes related to the main physiological processes in fungi, including virulence, hyphae morphology, mycelial and yeast growth, carotenogenesis and asexual sporulation. Selection of transformants with reduced virulence allowed the identification of mcplD, which encodes a Phospholipase D, and mcmyo5, encoding a probably essential cargo transporter of the Myosin V family, as required for a fully virulent phenotype of M. circinelloides. Knock-out mutants for those genes showed reduced virulence in both Galleria mellonella and Mus musculus models, probably due to a delayed germination and polarized growth within macrophages. This study provides a robust approach to study virulence in Mucorales and as a proof of concept identified new virulence determinants in M. circinelloides that could represent promising targets for future antifungal therapies

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

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

Background Gastro-oesophageal reflux disease is a common chronic ailment that causes uncomfortable symptoms and increases the risk of oesophageal adenocarcinoma. We aimed to report the burden of gastro-oesophageal reflux disease in 195 countries and territories between 1990 and 2017, using data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017. Methods We did a systematic review to identify measurements of the prevalence of gastro-oesophageal reflux disease in geographically defined populations worldwide between 1990 and 2017. These estimates were analysed with DisMod-MR, a Bayesian mixed-effects meta-regression tool that incorporates predictive covariates and adjustments for differences in study design in a geographical cascade of models. Fitted values for broader geographical units inform prior distributions for finer geographical units. Prevalence was estimated for 195 countries and territories. Reports of the frequency and severity of symptoms among individuals with gastro-oesophageal reflux disease were used to estimate the prevalence of cases with no, mild to moderate, or severe to very severe symptoms at a given time; these estimates were multiplied by disability weights to estimate years lived with disability (YLD). Findings Data to estimate gastro-oesophageal reflux disease burden were scant, totalling 144 location-years (unique measurements from a year and location, regardless of whether a study reported them alongside measurements for other locations or years) of prevalence data. These came from six (86%) of seven GBD super-regions, 11 (52%) of 21 GBD regions, and 39 (20%) of 195 countries and territories. Mean estimates of age-standardised prevalence for all locations in 2017 ranged from 4408 cases per 100 000 population to 14 035 cases per 100 000 population. Age-standardised prevalence was highest (>11 000 cases per 100 000 population) in the USA, Italy, Greece, New Zealand, and several countries in Latin America and the Caribbean, north Africa and the Middle East, and eastern Europe; it was lowest (<7000 cases per 100 000 population) in the high-income Asia Pacific, east Asia, Iceland, France, Denmark, and Switzerland. Global prevalence peaked at ages 75–79 years, at 18 820 (95% uncertainty interval [95% UI] 13 770–24 000) cases per 100 000 population. Global age-standardised prevalence was stable between 1990 and 2017 (8791 [95% UI 7772–9834] cases per 100 000 population in 1990 and 8819 [7781–9863] cases per 100 000 population in 2017, percentage change 0·3% [–0·3 to 0·9]), but all-age prevalence increased by 18·1% (15·6–20·4) between 1990 and 2017, from 7859 (6905–8851) cases per 100  000 population in 1990 to 9283 (8189–10 400) cases per 100  000 population in 2017. YLDs increased by 67·1% (95% UI 63·5–70·3) between 1990 and 2017, from 3·60 million (1·93–6·12) in 1990 to 6·01 million (3·22–10·19) in 2017. Interpretation Gastro-oesophageal reflux disease is common worldwide, although less so in much of eastern Asia. The stability of our global age-standardised prevalence estimates over time suggests that the epidemiology of the disease has not changed, but the estimates of all-age prevalence and YLDs, which increased between 1990 and 2017, suggest that the burden of gastro-oesophageal reflux disease is nonetheless increasing as a result of ageing and population growth. Funding Bill & Melinda Gates Foundation

Prevalence, years lived with disability, and trends in anaemia burden by severity and cause, 1990-2021: findings from the Global Burden of Disease Study 2021

Background Anaemia is a major health problem worldwide. Global estimates of anaemia burden are crucial for developing appropriate interventions to meet current international targets for disease mitigation. We describe the prevalence, years lived with disability, and trends of anaemia and its underlying causes in 204 countries and territories. Methods We estimated population-level distributions of haemoglobin concentration by age and sex for each location from 1990 to 2021. We then calculated anaemia burden by severity and associated years lived with disability (YLDs). With data on prevalence of the causes of anaemia and associated cause-specific shifts in haemoglobin concentrations, we modelled the proportion of anaemia attributed to 37 underlying causes for all locations, years, and demographics in the Global Burden of Disease Study 2021. Findings In 2021, the global prevalence of anaemia across all ages was 24·3% (95% uncertainty interval [UI] 23·9–24·7), corresponding to 1·92 billion (1·89–1·95) prevalent cases, compared with a prevalence of 28·2% (27·8–28·5) and 1·50 billion (1·48–1·52) prevalent cases in 1990. Large variations were observed in anaemia burden by age, sex, and geography, with children younger than 5 years, women, and countries in sub-Saharan Africa and south Asia being particularly affected. Anaemia caused 52·0 million (35·1–75·1) YLDs in 2021, and the YLD rate due to anaemia declined with increasing Socio-demographic Index. The most common causes of anaemia YLDs in 2021 were dietary iron deficiency (cause-specific anaemia YLD rate per 100 000 population: 422·4 [95% UI 286·1–612·9]), haemoglobinopathies and haemolytic anaemias (89·0 [58·2–123·7]), and other neglected tropical diseases (36·3 [24·4–52·8]), collectively accounting for 84·7% (84·1–85·2) of anaemia YLDs. Interpretation Anaemia remains a substantial global health challenge, with persistent disparities according to age, sex, and geography. Estimates of cause-specific anaemia burden can be used to design locally relevant health interventions aimed at improving anaemia management and prevention. Funding Bill & Melinda Gates Foundation