Analysis of the Learjet 35/36 Wing and Correlation with Experimental Results

Two NASTRAN models of the Gates Learjet Corporation Model 35/36 Wing were developed. The models and the problems encountered in their development are discussed. A skin buckling analysis used for the ultimate loading conditions is presented. A discussion of the static tests and the correlation of the static test with the NASTRAN results and the results of a supplementary semimonocoque beam analysis are also included

Injury burden in individuals aged 50 years or older in the Eastern Mediterranean region, 1990–2019: a systematic analysis from the Global Burden of Disease Study 2019

BackgroundInjury poses a major threat to health and longevity in adults aged 50 years or older. The increased life expectancy in the Eastern Mediterranean region warrants a further understanding of the ageing population's inevitable changing health demands and challenges. We aimed to examine injury-related morbidity and mortality among adults aged 50 years or older in 22 Eastern Mediterranean countries. MethodsDrawing on data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we categorised the population into adults aged 50–69 years and adults aged 70 years and older. We examined estimates for transport injuries, self-harm injuries, and unintentional injuries for both age groups, with sex differences reported, and analysed the percentage changes from 1990 to 2019. We reported injury-related mortality rates and disability-adjusted life-years (DALYs). The Socio-demographic Index (SDI) and the Healthcare Access and Quality (HAQ) Index were used to better understand the association of socioeconomic factors and health-care system performance, respectively, with injuries and health status in older people. Healthy life expectancy (HALE) was compared with injury-related deaths and DALYs and to the SDI and HAQ Index to understand the effect of injuries on healthy ageing. Finally, risk factors for injury deaths between 1990 and 2019 were assessed. 95% uncertainty intervals (UIs) are given for all estimates. FindingsEstimated injury mortality rates in the Eastern Mediterranean region exceeded the global rates in 2019, with higher injury mortality rates in males than in females for both age groups. Transport injuries were the leading cause of deaths in adults aged 50–69 years (43·0 [95% UI 31·0–51·8] per 100 000 population) and in adults aged 70 years or older (66·2 [52·5–75·5] per 100 000 population), closely followed by conflict and terrorism for both age groups (10·2 [9·3–11·3] deaths per 100 000 population for 50–69 years and 45·7 [41·5–50·3] deaths per 100 000 population for ≥70 years). The highest annual percentage change in mortality rates due to injury was observed in Afghanistan among people aged 70 years or older (400·4% increase; mortality rate 1109·7 [1017·7–1214·7] per 100 000 population). The leading cause of DALYs was transport injuries for people aged 50–69 years (1798·8 [1394·1–2116·0] per 100 000 population) and unintentional injuries for those aged 70 years or older (2013·2 [1682·2–2408·7] per 100 000 population). The estimates for HALE at 50 years and at 70 years in the Eastern Mediterranean region were lower than global estimates. Eastern Mediterranean countries with the lowest SDIs and HAQ Index values had high prevalence of injury DALYs and ranked the lowest for HALE at 50 years of age and HALE at 70 years. The leading injury mortality risk factors were occupational exposure in people aged 50–69 years and low bone mineral density in those aged 70 years or older. InterpretationInjuries still pose a real threat to people aged 50 years or older living in the Eastern Mediterranean region, mainly due to transport and violence-related injuries. Dedicated efforts should be implemented to devise injury prevention strategies that are appropriate for older adults and cost-effective injury programmes tailored to the needs and resources of local health-care systems, and to curtail injury-associated risk and promote healthy ageing. FundingBill & Melinda Gates Foundation.We acknowledge the Bill & Melinda Gates Foundation for funding this study

Primary Central Nervous System Burkitt Lymphoma With Non-Immunoglobulin Heavy Chain Translocation in Right Ventricle: Case Report

Primary central nervous system Burkitt lymphoma (PCNSBL) is rare. Few cases of primary central nervous system involvement with sporadic Burkitt lymphoma have been reported and its treatment is now controversial. Here, the authors report a case of a 14-year-old boy suffering from non-immunoglobulin heavy chain (IgH) translocation PCNSBL. To the authors' knowledge, this is the second case report describing primary Burkitt lymphoma involving cerebral ventricles. After receiving combination treatment with surgery, stereotacticradiosurgery, and a chemotherapy regimen including high-dose methotrexate, the patient had a disease-free survival of 18 months

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission

GPs' opinions of public and industrial information regarding drugs: a cross-sectional study

Background: General Practitioners {GP} in Sweden prescribe more than 50% of all prescriptions. Scientific knowledge on the opinions of GPs regarding drug information has been sparse. Such knowledge could be valuable when designing evidence-based drug information to GPs. GPs' opinions on public- and industry-provided drug information are presented in this article. Methods: A cross-sectional study using a questionnaire was answered by 368 GPs at 97 primary-health care centres {PHCC}. The centres were invited to participate by eight out of 29 drug and therapeutic committees {DTCs}. A multilevel model was used to analyse associations between opinions of GPs regarding drug information and whether the GPs worked in public sector or in a private enterprise, their age, sex, and work experience. PHCC and geographical area were included as random effects. Results: About 85% of the GPs perceived they received too much information from the industry, that the quality of public information was high and useful, and that the main task of public authorities was to increase the GPs' knowledge of drugs. Female GPs valued information from public authorities to a much greater extent than male GPs. Out of the GPs, 93% considered the main task of the industry was to promote sales. Differences between the GPs' opinions between PHCCs were generally more visible than differences between areas. Conclusions: Some kind of incentives could be considered for PHCCs that actively reduce drug promotion from the industry. That female GPs valued information from public authorities to a much greater extent than male GPs should be taken into consideration when designing evidence-based drug information from public authorities to make implementation easier

Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183.

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a \u3e 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission

Support for UNRWA's survival

The United Nations Relief and Works Agency for Palestine Refugees in the Near East (UNRWA) provides life-saving humanitarian aid for 5·4 million Palestine refugees now entering their eighth decade of statelessness and conflict. About a third of Palestine refugees still live in 58 recognised camps. UNRWA operates 702 schools and 144 health centres, some of which are affected by the ongoing humanitarian disasters in Syria and the Gaza Strip. It has dramatically reduced the prevalence of infectious diseases, mortality, and illiteracy. Its social services include rebuilding infrastructure and homes that have been destroyed by conflict and providing cash assistance and micro-finance loans for Palestinians whose rights are curtailed and who are denied the right of return to their homeland

Apparent Lack of BRAFV600E Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8+ T Cells in Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic BRAFV600E driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like BRAFV600E can be a source of neoantigens capable of eliciting effective antitumor CD8+ T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8+ T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8+ T cell density in n = 101 LCH-lesions, with BRAFV600E mutated lesions displaying significantly lower CD8+ T cell:CD1a+ LCH-cell ratios (p = 0.01) than BRAF wildtype lesions. Because LCH-lesional CD8+ T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed BRAFV600E protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding BRAFV600E derived neopeptide (KIGDFGLATEK), which indeed displayed strong to intermediate binding capacity to HLA-A*03:01 and HLA-A*11:01 in an in vitro peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several BRAFV600E expressing cell lines with various HLA genotypes. While the HLA-A*02:01 binding BRAF wildtype peptide KIGDFGLATV was traced in peptides isolated from a