Explore the vast range of titles available.

Influenza virus infections represent a serious public health threat and account for significant morbidity and mortality worldwide due to seasonal epidemics and periodic pandemics. Despite being an important countermeasure to combat influenza virus and being highly efficacious when matched to circulating influenza viruses, current preventative strategies of vaccination against influenza virus often provide incomplete protection due the continuous antigenic drift/shift of circulating strains of influenza virus. Prevention and control of influenza virus infection with vaccines is dependent on the host immune response induced by vaccination and the various vaccine platforms induce different components of the local and systemic immune response. This review focuses on the immune basis of current (inactivated influenza vaccines (IIV) and live attenuated influenza vaccines (LAIV)) as well as novel vaccine platforms against influenza virus. Particular emphasis will be placed on how each platform induces cross-protection against heterologous influenza viruses, as well as how this immunity compares to and contrasts from the “gold standard” of immunity generated by natural influenza virus infection.

Influenza A virus (IAV) causes significant morbidity and mortality worldwide due to seasonal epidemics and periodic pandemics. The antigenic drift/shift of IAV continually gives rise to new strains and subtypes, aiding IAV in circumventing previously established immunity. As a result, there has been substantial interest in developing a broadly protective IAV vaccine that induces, durable immunity against multiple IAVs. Previously, a polyanhydride nanoparticle-based vaccine or nanovaccine (IAV-nanovax) encapsulating H1N1 IAV antigens was reported, which induced pulmonary B and T cell immunity and resulted in cross-strain protection against IAV. A key feature of IAV-nanovax is its ability to easily incorporate diverse proteins/payloads, potentially increasing its ability to provide broad protection against IAV and/or other pathogens. Due to human susceptibility to both H1N1 and H3N2 IAV, several H3N2 nanovaccines were formulated herein with multiple IAV antigens to examine the “plug-and-play” nature of the polyanhydride nanovaccine platform and determine their ability to induce humoral and cellular immunity and broad-based protection similar to IAV-nanovax. The H3N2-based IAV nanovaccine formulations induced systemic and mucosal B cell responses which were associated with antigen-specific antibodies. Additionally, systemic and lung-tissue resident CD4 and CD8 T cell responses were enhanced post-vaccination. These immune responses corresponded with protection against both homologous and heterosubtypic IAV infection. Overall, these results demonstrate the plug-and-play nature of the polyanhydride nanovaccine platform and its ability to generate immunity and protection against IAV utilizing diverse antigenic payloads.

Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017. We used multiple cause-of-death data from 109 million individual death records to calculate mortality related to sepsis among each of the 282 underlying causes of death in GBD 2017. The percentage of sepsis-related deaths by underlying GBD cause in each location worldwide was modelled using mixed-effects linear regression. Sepsis-related mortality for each age group, sex, location, GBD cause, and year (1990–2017) was estimated by applying modelled cause-specific fractions to GBD 2017 cause-of-death estimates. We used data for 8·7 million individual hospital records to calculate in-hospital sepsis-associated case-fatality, stratified by underlying GBD cause. In-hospital sepsis-associated case-fatality was modelled for each location using linear regression, and sepsis incidence was estimated by applying modelled case-fatality to sepsis-related mortality estimates. In 2017, an estimated 48·9 million (95% uncertainty interval [UI] 38·9–62·9) incident cases of sepsis were recorded worldwide and 11·0 million (10·1–12·0) sepsis-related deaths were reported, representing 19·7% (18·2–21·4) of all global deaths. Age-standardised sepsis incidence fell by 37·0% (95% UI 11·8–54·5) and mortality decreased by 52·8% (47·7–57·5) from 1990 to 2017. Sepsis incidence and mortality varied substantially across regions, with the highest burden in sub-Saharan Africa, Oceania, south Asia, east Asia, and southeast Asia. Despite declining age-standardised incidence and mortality, sepsis remains a major cause of health loss worldwide and has an especially high health-related burden in sub-Saharan Africa. The Bill & Melinda Gates Foundation, the National Institutes of Health, the University of Pittsburgh, the British Columbia Children's Hospital Foundation, the Wellcome Trust, and the Fleming Fund.

Estimation of the number and rate of deaths by age and sex is a key first stage for calculation of the burden of disease in order to constrain estimates of cause-specific mortality and to measure premature mortality in populations. We aimed to estimate life tables and annual numbers of deaths for 187 countries from 1970 to 2010. We estimated trends in under-5 mortality rate (children aged 0–4 years) and probability of adult death (15–59 years) for each country with all available data. Death registration data were available for more than 100 countries and we corrected for undercount with improved death distribution methods. We applied refined methods to survey data on sibling survival that correct for survivor, zero-sibling, and recall bias. We separately estimated mortality from natural disasters and wars. We generated final estimates of under-5 mortality and adult mortality from the data with Gaussian process regression. We used these results as input parameters in a relational model life table system. We developed a model to extrapolate mortality to 110 years of age. All death rates and numbers have been estimated with 95% uncertainty intervals (95% UIs). From 1970 to 2010, global male life expectancy at birth increased from 56·4 years (95% UI 55·5–57·2) to 67·5 years (66·9–68·1) and global female life expectancy at birth increased from 61·2 years (60·2–62·0) to 73·3 years (72·8–73·8). Life expectancy at birth rose by 3–4 years every decade from 1970, apart from during the 1990s (increase in male life expectancy of 1·4 years and in female life expectancy of 1·6 years). Substantial reductions in mortality occurred in eastern and southern sub-Saharan Africa since 2004, coinciding with increased coverage of antiretroviral therapy and preventive measures against malaria. Sex-specific changes in life expectancy from 1970 to 2010 ranged from gains of 23–29 years in the Maldives and Bhutan to declines of 1–7 years in Belarus, Lesotho, Ukraine, and Zimbabwe. Globally, 52·8 million (95% UI 51·6–54·1 million) deaths occurred in 2010, which is about 13·5% more than occurred in 1990 (46·5 million [45·7–47·4 million]), and 21·9% more than occurred in 1970 (43·3 million [42·2–44·6 million]). Proportionally more deaths in 2010 occurred at age 70 years and older (42·8% in 2010 vs 33·1% in 1990), and 22·9% occurred at 80 years or older. Deaths in children younger than 5 years declined by almost 60% since 1970 (16·4 million [16·1–16·7 million] in 1970 vs 6·8 million [6·6–7·1 million] in 2010), especially at ages 1–59 months (10·8 million [10·4–11·1 million] in 1970 vs 4·0 million [3·8–4·2 million] in 2010). In all regions, including those most affected by HIV/AIDS, we noted increases in mean ages at death. Despite global and regional health crises, global life expectancy has increased continuously and substantially in the past 40 years. Yet substantial heterogeneity exists across age groups, among countries, and over different decades. 179 of 187 countries have had increases in life expectancy after the slowdown in progress in the 1990s. Efforts should be directed to reduce mortality in low-income and middle-income countries. Potential underestimation of achievement of the Millennium Development Goal 4 might result from limitations of demographic data on child mortality for the most recent time period. Improvement of civil registration system worldwide is crucial for better tracking of global mortality. Bill & Melinda Gates Foundation.

The Genitourinary Pathology Society (GUPS) undertook a critical review of the recent advances in renal neoplasia, particularly focusing on the newly accumulated evidence post-2016 World Health Organization (WHO) classification. In the era of evolving histo-molecular classification of renal neoplasia, morphology is still key. However, entities (or groups of entities) are increasingly characterized by specific molecular features, often associated either with recognizable, specific morphologies or constellations of morphologies and corresponding immunohistochemical profiles. The correct diagnosis has clinical implications leading to better prognosis, potential clinical management with targeted therapies, may identify hereditary or syndromic associations, which may necessitate appropriate genetic testing. We hope that this undertaking will further facilitate the identification of these entities in practice. We also hope that this update will bring more clarity regarding the evolving classification of renal neoplasia and will further reduce the category of “unclassifiable renal carcinomas/tumors”. We propose three categories of novel entities: (1) “Novel entity”, validated by multiple independent studies; (2) “Emerging entity”, good compelling data available from at least two or more independent studies, but additional validation is needed; and (3) “Provisional entity”, limited data available from one or two studies, with more work required to validate them. For some entities initially described using different names, we propose new terminologies, to facilitate their recognition and to avoid further diagnostic dilemmas. Following these criteria, we propose as novel entities: eosinophilic solid and cystic renal cell carcinoma (ESC RCC), renal cell carcinoma with fibromyomatous stroma (RCC FMS) (formerly RCC with leiomyomatous or smooth muscle stroma), and anaplastic lymphoma kinase rearrangement-associated renal cell carcinoma (ALK-RCC). Emerging entities include: eosinophilic vacuolated tumor (EVT) and thyroid-like follicular renal cell carcinoma (TLFRCC). Finally, as provisional entities, we propose low-grade oncocytic tumor (LOT), atrophic kidney-like lesion (AKLL), and biphasic hyalinizing psammomatous renal cell carcinoma (BHP RCC).

Asymptomatic left ventricular dysfunction (ALVD) is present in 3–6% of the general population, is associated with reduced quality of life and longevity, and is treatable when found1–4. An inexpensive, noninvasive screening tool for ALVD in the doctor’s office is not available. We tested the hypothesis that application of artificial intelligence (AI) to the electrocardiogram (ECG), a routine method of measuring the heart’s electrical activity, could identify ALVD. Using paired 12-lead ECG and echocardiogram data, including the left ventricular ejection fraction (a measure of contractile function), from 44,959 patients at the Mayo Clinic, we trained a convolutional neural network to identify patients with ventricular dysfunction, defined as ejection fraction ≤35%, using the ECG data alone. When tested on an independent set of 52,870 patients, the network model yielded values for the area under the curve, sensitivity, specificity, and accuracy of 0.93, 86.3%, 85.7%, and 85.7%, respectively. In patients without ventricular dysfunction, those with a positive AI screen were at 4 times the risk (hazard ratio, 4.1; 95% confidence interval, 3.3 to 5.0) of developing future ventricular dysfunction compared with those with a negative screen. Application of AI to the ECG—a ubiquitous, low-cost test—permits the ECG to serve as a powerful screening tool in asymptomatic individuals to identify ALVD.

Our intestine is host to a large microbial community (microbiota) that educates the immune system and confers niche protection. Profiling of the gut‐associated microbial community reveals a dominance of obligate anaerobic bacteria in healthy individuals. However, intestinal inflammation is associated with a disturbance of the microbiota—known as dysbiosis—that often includes an increased prevalence of facultative anaerobic bacteria. This group contains potentially harmful bacterial species, the bloom of which can further exacerbate inflammation. Here, we review the mechanisms that generate changes in the microbial community structure during inflammation. One emerging concept is that electron acceptors generated as by‐products of the host inflammatory response feed facultative anaerobic bacteria selectively, thereby increasing their prevalence within the community. This new paradigm has broad implications for understanding dysbiosis during gut inflammation and identifies potential targets for intervention strategies. Intestinal inflammation is associated with alterations of the microbiota and outgrowth of potentially harmful bacterial species. How these changes in microbial community structure occur is discussed here, highlighting the role of electron acceptors in feeding facultative anaerobic bacteria.

Tungstate inhibits molybdenum-cofactor-dependent microbial respiratory pathways and shows potential as a selective treatment for microbial imbalances that occur during inflammation of the gastrointestinal tract. Countering colon inflammation Expansion of facultative anaerobic bacteria of the Enterobacteriaceae family in the gut is associated with dysbiosis—an imbalance in the microbiota—and inflammatory bowel disease. Sebastian Winter and colleagues show that tungstate treatment, which selectively inhibits molybdenum-cofactor-dependent microbial respiratory pathways that operate only during episodes of inflammation, mitigates inflammation in mouse models of colitis without causing any compositional alterations to the gut microbiota. This is a promising strategy for precision therapy of the microbiota in response to inflammatory disorders, but future work is needed to determine whether similar approaches could be relevant in humans. Inflammatory diseases of the gastrointestinal tract are frequently associated with dysbiosis 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , characterized by changes in gut microbial communities that include an expansion of facultative anaerobic bacteria of the Enterobacteriaceae family (phylum Proteobacteria). Here we show that a dysbiotic expansion of Enterobacteriaceae during gut inflammation could be prevented by tungstate treatment, which selectively inhibited molybdenum-cofactor-dependent microbial respiratory pathways that are operational only during episodes of inflammation. By contrast, we found that tungstate treatment caused minimal changes in the microbiota composition under homeostatic conditions. Notably, tungstate-mediated microbiota editing reduced the severity of intestinal inflammation in mouse models of colitis. We conclude that precision editing of the microbiota composition by tungstate treatment ameliorates the adverse effects of dysbiosis in the inflamed gut.

Summary When the rate of photosynthesis is greatly diminished, such as during severe drought, extreme temperature or low light, it seems advantageous for plants to close stomata and completely halt water loss. However, water loss continues through the cuticle and incompletely closed stomata, together constituting the leaf minimum conductance (gmin). In this review, we critically evaluate the sources of variation in gmin, quantitatively compare various methods for its estimation, and illustrate the role of gmin in models of leaf gas exchange. A literature compilation of gmin as measured by the weight loss of detached leaves is presented, which shows much variation in this trait, which is not clearly related to species groups, climate of origin or leaf type. Much evidence points to the idea that gmin is highly responsive to the growing conditions of the plant, including soil water availability, temperature and air humidity – as we further demonstrate with two case studies. We pay special attention to the role of the minimum conductance in the Ball–Berry model of stomatal conductance, and caution against the usual regression-based method for its estimation. The synthesis presented here provides guidelines for the use of gmin in ecosystem models, and points to clear research gaps for this drought tolerance trait.

Since 2000, the scale-up of malaria control interventions has substantially reduced morbidity and mortality caused by the disease globally, fuelling bold aims for disease elimination. In tandem with increased availability of geospatially resolved data, malaria control programmes increasingly use high-resolution maps to characterise spatially heterogeneous patterns of disease risk and thus efficiently target areas of high burden. We updated and refined the Plasmodium falciparum parasite rate and clinical incidence models for sub-Saharan Africa, which rely on cross-sectional survey data for parasite rate and intervention coverage. For malaria endemic countries outside of sub-Saharan Africa, we produced estimates of parasite rate and incidence by applying an ecological downscaling approach to malaria incidence data acquired via routine surveillance. Mortality estimates were derived by linking incidence to systematically derived vital registration and verbal autopsy data. Informed by high-resolution covariate surfaces, we estimated P falciparum parasite rate, clinical incidence, and mortality at national, subnational, and 5 × 5 km pixel scales with corresponding uncertainty metrics. We present the first global, high-resolution map of P falciparum malaria mortality and the first global prevalence and incidence maps since 2010. These results are combined with those for Plasmodium vivax (published separately) to form the malaria estimates for the Global Burden of Disease 2017 study. The P falciparum estimates span the period 2000–17, and illustrate the rapid decline in burden between 2005 and 2017, with incidence declining by 27·9% and mortality declining by 42·5%. Despite a growing population in endemic regions, P falciparum cases declined between 2005 and 2017, from 232·3 million (95% uncertainty interval 198·8–277·7) to 193·9 million (156·6–240·2) and deaths declined from 925 800 (596 900–1 341 100) to 618 700 (368 600–952 200). Despite the declines in burden, 90·1% of people within sub-Saharan Africa continue to reside in endemic areas, and this region accounted for 79·4% of cases and 87·6% of deaths in 2017. High-resolution maps of P falciparum provide a contemporary resource for informing global policy and malaria control planning, programme implementation, and monitoring initiatives. Amid progress in reducing global malaria burden, areas where incidence trends have plateaued or increased in the past 5 years underscore the fragility of hard-won gains against malaria. Efforts towards elimination should be strengthened in such areas, and those where burden remained high throughout the study period. Bill & Melinda Gates Foundation.