Staphylococcus aureus is a prominent human pathogen and leading cause of bacterial infection in hospitals and the community. Community-associated methicillin-resistant S. aureus (CA-MRSA) strains ...such as USA300 are highly virulent and, unlike hospital strains, often cause disease in otherwise healthy individuals. The enhanced virulence of CA-MRSA is based in part on increased ability to produce high levels of secreted molecules that facilitate evasion of the innate immune response. Although progress has been made, the factors that contribute to CA-MRSA virulence are incompletely defined. We analyzed the cell surface proteome (surfome) of USA300 strain LAC to better understand extracellular factors that contribute to the enhanced virulence phenotype. A total of 113 identified proteins were associated with the surface of USA300 during the late-exponential phase of growth in vitro. Protein A was the most abundant surface molecule of USA300, as indicated by combined Mascot score following analysis of peptides by tandem mass spectrometry. Unexpectedly, we identified a previously uncharacterized two-component leukotoxin-herein named LukS-H and LukF-G (LukGH)-as two of the most abundant surface-associated proteins of USA300. Rabbit antibody specific for LukG indicated it was also freely secreted by USA300 into culture media. We used wild-type and isogenic lukGH deletion strains of USA300 in combination with human PMN pore formation and lysis assays to identify this molecule as a leukotoxin. Moreover, LukGH synergized with PVL to enhance lysis of human PMNs in vitro, and contributed to lysis of PMNs after phagocytosis. We conclude LukGH is a novel two-component leukotoxin with cytolytic activity toward neutrophils, and thus potentially contributes to S. aureus virulence.
As Indonesia moves to provide health coverage for all citizens, understanding patterns of morbidity and mortality is important to allocate resources and address inequality. The Global Burden of ...Disease 2016 study (GBD 2016) estimates sources of early death and disability, which can inform policies to improve health care.
We used GBD 2016 results for cause-specific deaths, years of life lost, years lived with disability, disability-adjusted life-years (DALYs), life expectancy at birth, healthy life expectancy, and risk factors for 333 causes in Indonesia and in seven comparator countries. Estimates were produced by location, year, age, and sex using methods outlined in GBD 2016. Using the Socio-demographic Index, we generated expected values for each metric and compared these against observed results.
In Indonesia between 1990 and 2016, life expectancy increased by 8·0 years (95% uncertainty interval UI 7·3–8·8) to 71·7 years (71·0–72·3): the increase was 7·4 years (6·4–8·6) for males and 8·7 years (7·8–9·5) for females. Total DALYs due to communicable, maternal, neonatal, and nutritional causes decreased by 58·6% (95% UI 55·6–61·6), from 43·8 million (95% UI 41·4–46·5) to 18·1 million (16·8–19·6), whereas total DALYs from non-communicable diseases rose. DALYs due to injuries decreased, both in crude rates and in age-standardised rates. The three leading causes of DALYs in 2016 were ischaemic heart disease, cerebrovascular disease, and diabetes. Dietary risks were a leading contributor to the DALY burden, accounting for 13·6% (11·8–15·4) of DALYs in 2016.
Over the past 27 years, health across many indicators has improved in Indonesia. Improvements are partly offset by rising deaths and a growing burden of non-communicable diseases. To maintain and increase health gains, further work is needed to identify successful interventions and improve health equity.
The Bill & Melinda Gates Foundation.
The present study considers the effects of process parameters on the microstructural development and mechanical properties of SLM Inconel 718. A continuous scanning strategy was used in conjunction ...with changes in laser spot size to emphasize texture development in the samples; it was found that aligned laser scan vectors (continuous scans) enhanced the crystallographic and morphological texture that forms during solidification when compared to multi-directional scan vectors (island scans). Although room temperature tensile testing did not exhibit variation in material properties, creep rupture testing showed a significant difference in ductility and time to failure. As texture and preferred crystallographic orientation were increased parallel to the loading direction, an increase of 51% in creep elongation was observed for the continuous scanning strategy. This behavior is linked to differences in damage accumulation mechanisms in the microstructure based on grain boundary orientation and precipitation. Furthermore, comparison of the mechanical behavior of SLM and wrought materials showed that wrought had ~10% greater tensile yield strength at room temperature, while in creep rupture the increase in elongation was as high as 640%. The primary difference between SLM and wrought material contributing to this discrepancy was the difference in NbC distribution. Although small differences in mechanical behavior can be induced in SLM material through process parameter variation, the separation in properties when compared to a wrought product are more significant.
•Laser focal shift and scanning strategy can enhance microstructural texture.•Microstructural texture persists through HIP and heat treatment.•SLM IN718 is shown to be environmentally sensitive due to NbC precipitation.•Wrought material displays superior high temperature ductility when compared to SLM.
The elevated temperature tensile properties of SLM IN718 were measured as a function of strain rate and test temperature to better understand the time-dependent and thermal aspects of environmental ...sensitivity. SLM and wrought materials were solution treated, aged, and tested over the range of 550–750 °C and 10−3 to 10−6 s−1. The SLM material tested across all conditions had inferior strength and ductility compared to wrought material of the same heat treatment because of environmental sensitivity in the form of dynamic embrittlement. SLM samples show evidence of brittle intergranular fracture, crack growth, and oxidized NbC particles on the fracture surface, which all contribute to the observed poor ductility. These features, and subsequent embrittlement, are intensified with decreasing strain rate and increasing temperature. Higher strain rates and lower temperatures are shown to improve the ductility in SLM IN718 but despite this recovery it remains susceptible to environmental attack even in the extreme cases of the current study. The prevalence of NbC at grain boundaries in the SLM material is the principal source of dynamic embrittlement and environmental sensitivity.
Mental disorders are among the leading causes of non-fatal disease burden in India, but a systematic understanding of their prevalence, disease burden, and risk factors is not readily available for ...each state of India. In this report, we describe the prevalence and disease burden of each mental disorder for the states of India, from 1990 to 2017.
We used all accessible data from multiple sources to estimate the prevalence of mental disorders, years lived with disability (YLDs), and disability-adjusted life-years (DALYs) caused by these disorders for all the states of India from 1990 to 2017, as part of the Global Burden of Diseases, Injuries, and Risk Factors Study. We assessed the heterogeneity and time trends of mental disorders across the states of India. We grouped states on the basis of their Socio-demographic Index (SDI), which is a composite measure of per-capita income, mean education, and fertility rate in women younger than 25 years. We also assessed the association of major mental disorders with suicide deaths. We calculated 95% uncertainty intervals (UIs) for the point estimates.
In 2017, 197·3 million (95% UI 178·4–216·4) people had mental disorders in India, including 45·7 million (42·4–49·8) with depressive disorders and 44·9 million (41·2–48·9) with anxiety disorders. We found a significant, but modest, correlation between the prevalence of depressive disorders and suicide death rate at the state level for females (r2=0·33, p=0·0009) and males (r2=0·19, p=0·015). The contribution of mental disorders to the total DALYs in India increased from 2·5% (2·0–3·1) in 1990 to 4·7% (3·7–5·6) in 2017. In 2017, depressive disorders contributed the most to the total mental disorders DALYs (33·8%, 29·5–38·5), followed by anxiety disorders (19·0%, 15·9–22·4), idiopathic developmental intellectual disability (IDID; 10·8%, 6·3–15·9), schizophrenia (9·8%, 7·7–12·4), bipolar disorder (6·9%, 4·9–9·6), conduct disorder (5·9%, 4·0–8·1), autism spectrum disorders (3·2%, 2·7–3·8), eating disorders (2·2%, 1·7–2·8), and attention-deficit hyperactivity disorder (ADHD; 0·3%, 0·2–0·5); other mental disorders comprised 8·0% (6·1–10·1) of DALYs. Almost all (>99·9%) of these DALYs were made up of YLDs. The DALY rate point estimates of mental disorders with onset predominantly in childhood and adolescence (IDID, conduct disorder, autism spectrum disorders, and ADHD) were higher in low SDI states than in middle SDI and high SDI states in 2017, whereas the trend was reversed for mental disorders that manifest predominantly during adulthood. Although the prevalence of mental disorders with onset in childhood and adolescence decreased in India from 1990 to 2017, with a stronger decrease in high SDI and middle SDI states than in low SDI states, the prevalence of mental disorders that manifest predominantly during adulthood increased during this period.
One in seven Indians were affected by mental disorders of varying severity in 2017. The proportional contribution of mental disorders to the total disease burden in India has almost doubled since 1990. Substantial variations exist between states in the burden from different mental disorders and in their trends over time. These state-specific trends of each mental disorder reported here could guide appropriate policies and health system response to more effectively address the burden of mental disorders in India.
Bill & Melinda Gates Foundation; and Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India.
In this paper, a case is made for the use of model-based approaches for the analysis of community data. This involves the direct specification of a statistical model for the observed multivariate ...data. Recent advances in statistical modelling mean that it is now possible to build models that are appropriate for the data which address key ecological questions in a statistically coherent manner. Key advantages of this approach include interpretability, flexibility, and efficiency, which we explain in detail and illustrate by example. The steps in a model-based approach to analysis are outlined, with an emphasis on key features arising in a multivariate context. A key distinction in the model-based approach is the emphasis on diagnostic checking to ensure that the model provides reasonable agreement with the observed data. Two examples are presented that illustrate how the model-based approach can provide insights into ecological problems not previously available. In the first example, we test for a treatment effect in a study where different sites had different sampling intensities, which was handled by adding an offset term to the model. In the second example, we incorporate trait information into a model for ordinal response in order to identify the main reasons why species differ in their environmental response.
The Microbiome and Sexual Health Werneburg, Glenn T; Lundy, Scott D; Bajic, Petar
Journal of sexual medicine,
11/2022, Volume:
19, Issue:
11
Journal Article
To understand differences between asymptomatic colonized and infected states of indwelling medical devices, we sought to determine penile prosthesis biofilm composition, microbe-metabolite ...interaction networks, and association with clinical factors. Patients scheduled for penile prosthesis removal/revision were included. Samples from swabbed devices and controls underwent next-generation sequencing, metabolomics, and culture-based assessments. Biofilm formation from device isolates was reconstituted in a continuous-flow stir tank bioreactor. 93% of 27 analyzed devices harbored demonstrable biofilm. Seven genera including Faecalibaculum and Jeotgalicoccus were more abundant in infected than uninfected device biofilms (p < 0.001). Smokers and those with diabetes mellitus or cardiac disease had lower total normalized microbial counts than those without the conditions (p < 0.001). We identified microbe-metabolite interaction networks enriched in devices explanted for infection and pain. Biofilm formation was recapitulated on medical device materials including silicone, PTFE, polyurethane, and titanium in vitro to facilitate further mechanistic studies. Nearly all penile prosthesis devices harbor biofilms. Staphylococcus and Escherichia, the most common causative organisms of prosthesis infection, had similar abundance irrespective of infection status. A series of other uncommon genera and metabolites were differentially abundant, suggesting a complex microbe-metabolite pattern-rather than a single organism-is responsible for the transition from asymptomatic to infected or painful states.
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