Burden of injuries in Nepal, 1990–2017: Findings from the Global Burden of Disease Study 2017

Background: Nepal is a low-income country undergoing rapid political, economic and social development. To date, there has been little evidence published on the burden of injuries during this period of transition.Methods: The Global Burden of Disease Study (GBD) is a comprehensive measurement of population health outcomes in terms of morbidity and mortality. We analysed the GBD 2017 estimates for deaths, years of life lost, years lived with disability, incidence and disability-adjusted life years (DALYs) from injuries to ascertain the burden of injuries in Nepal from 1990 to 2017.Results: There were 16 831 (95% uncertainty interval 13 323 to 20 579) deaths caused by injuries (9.21% of all-cause deaths (7.45% to 11.25%)) in 2017 while the proportion of deaths from injuries was 6.31% in 1990. Overall, the injury-specific age-standardised mortality rate declined from 88.91 (71.54 to 105.31) per 100 000 in 1990 to 70.25 (56.75 to 85.11) per 100 000 in 2017. In 2017, 4.11% (2.47% to 6.10%) of all deaths in Nepal were attributed to transport injuries, 3.54% (2.86% to 4.08%) were attributed to unintentional injuries and 1.55% (1.16% to 1.85%) were attributed to self-harm and interpersonal violence. From 1990 to 2017, road injuries, falls and self-harm all rose in rank for all causes of death.Conclusions: The increase in injury-related deaths and DALYs in Nepal between 1990 and 2017 indicates the need for further research and prevention interventions. Injuries remain an important public health burden in Nepal with the magnitude and trend of burden varying over time by cause-specific, sex and age group. Findings from this study may be used by the federal, provincial and local governments in Nepal to prioritise injury prevention as a public health agenda and as evidence for country-specific interventions

Clinical Trials in Head Injury

Traumatic brain injury (TBI) remains a major public health problem globally. In the United States the incidence of closed head injuries admitted to hospitals is conservatively estimated to be 200 per 100,000 population, and the incidence of penetrating head injury is estimated to be 12 per 100,000, the highest of any developed country in the world. This yields an approximate number of 500,000 new cases each year, a sizeable proportion of which demonstrate signficant long-term disabilities. Unfortunately, there is a paucity of proven therapies for this disease. For a variety of reasons, clinical trials for this condition have been difficult to design and perform. Despite promising pre-clinical data, most of the trials that have been performed in recent years have failed to demonstrate any significant improvement in outcomes. The reasons for these failures have not always been apparent and any insights gained were not always shared. It was therefore feared that we were running the risk of repeating our mistakes. Recognizing the importance of TBI, the National Institute of Neurological Disorders and Stroke (NINDS) sponsored a workshop that brought together experts from clinical, research, and pharmaceutical backgrounds. This workshop proved to be very informative and yielded many insights into previous and future TBI trials. This paper is an attempt to summarize the key points made at the workshop. It is hoped that these lessons will enhance the planning and design of future efforts in this important field of research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63185/1/089771502753754037.pd

HLA-DM Mediates Epitope Selection by a “Compare-Exchange” Mechanism when a Potential Peptide Pool Is Available

BACKGROUND: HLA-DM (DM) mediates exchange of peptides bound to MHC class II (MHCII) during the epitope selection process. Although DM has been shown to have two activities, peptide release and MHC class II refolding, a clear characterization of the mechanism by which DM facilitates peptide exchange has remained elusive. METHODOLOGY/PRINCIPAL FINDINGS: We have previously demonstrated that peptide binding to and dissociation from MHCII in the absence of DM are cooperative processes, likely related to conformational changes in the peptide-MHCII complex. Here we show that DM promotes peptide release by a non-cooperative process, whereas it enhances cooperative folding of the exchange peptide. Through electron paramagnetic resonance (EPR) and fluorescence polarization (FP) we show that DM releases prebound peptide very poorly in the absence of a candidate peptide for the exchange process. The affinity and concentration of the candidate peptide are also important for the release of the prebound peptide. Increased fluorescence energy transfer between the prebound and exchange peptides in the presence of DM is evidence for a tetramolecular complex which resolves in favor of the peptide that has superior folding properties. CONCLUSION/SIGNIFICANCE: This study shows that both the peptide releasing activity on loaded MHCII and the facilitating of MHCII binding by a candidate exchange peptide are integral to DM mediated epitope selection. The exchange process is initiated only in the presence of candidate peptides, avoiding possible release of a prebound peptide and loss of a potential epitope. In a tetramolecular transitional complex, the candidate peptides are checked for their ability to replace the pre-bound peptide with a geometry that allows the rebinding of the original peptide. Thus, DM promotes a "compare-exchange" sorting algorithm on an available peptide pool. Such a "third party"-mediated mechanism may be generally applicable for diverse ligand recognition in other biological systems

Are clinicians being prepared to care for abused women? A survey of health professional education in Ontario, Canada

Background: The current project undertook a province-wide survey and environmental scan of educational opportunities available to future health care providers on the topic of intimate partner violence (IPV) against women. Methods: A team of experts identified university and college programs in Ontario, Canada as potential providers of IPV education to students in health care professions at the undergraduate and post-graduate levels. A telephone survey with contacts representing these programs was conducted between October 2005 and March 2006. The survey asked whether IPV-specific education was provided to learners, and if so, how and by whom. Results: In total, 222 eligible programs in dentistry, medicine, nursing and other allied health professions were surveyed, and 95% (212/222) of programs responded. Of these, 57% reported offering some form of IPV-specific education, with undergraduate nursing (83%) and allied health (82%) programs having the highest rates. Fewer than half of undergraduate medical (43%) and dentistry (46%) programs offered IPV content. Postgraduate programs ranged from no IPV content provision (dentistry) to 41% offering content (nursing). Conclusion: Significant variability exists across program areas regarding the methods for IPV education, its delivery and evaluation. The results of this project highlight that expectations for an active and consistent response by health care professionals to women experiencing the effects of violence may not match the realities of professional preparation

Gene Expression during the Generation and Activation of Mouse Neutrophils: Implication of Novel Functional and Regulatory Pathways

As part of the Immunological Genome Project (ImmGen), gene expression was determined in unstimulated (circulating) mouse neutrophils and three populations of neutrophils activated in vivo, with comparison among these populations and to other leukocytes. Activation conditions included serum-transfer arthritis (mediated by immune complexes), thioglycollate-induced peritonitis, and uric acid-induced peritonitis. Neutrophils expressed fewer genes than any other leukocyte population studied in ImmGen, and down-regulation of genes related to translation was particularly striking. However, genes with expression relatively specific to neutrophils were also identified, particularly three genes of unknown function: Stfa2l1, Mrgpr2a and Mrgpr2b. Comparison of genes up-regulated in activated neutrophils led to several novel findings: increased expression of genes related to synthesis and use of glutathione and of genes related to uptake and metabolism of modified lipoproteins, particularly in neutrophils elicited by thioglycollate; increased expression of genes for transcription factors in the Nr4a family, only in neutrophils elicited by serum-transfer arthritis; and increased expression of genes important in synthesis of prostaglandins and response to leukotrienes, particularly in neutrophils elicited by uric acid. Up-regulation of genes related to apoptosis, response to microbial products, NFkB family members and their regulators, and MHC class II expression was also seen, in agreement with previous studies. A regulatory model developed from the ImmGen data was used to infer regulatory genes involved in the changes in gene expression during neutrophil activation. Among 64, mostly novel, regulatory genes predicted to influence these changes in gene expression, Irf5 was shown to be important for optimal secretion of IL-10, IP-10, MIP-1α, MIP-1β, and TNF-α by mouse neutrophils in vitro after stimulation through TLR9. This data-set and its analysis using the ImmGen regulatory model provide a basis for additional hypothesis-based research on the importance of changes in gene expression in neutrophils in different conditions