Design of the advanced regional aircraft, the DART-75

This design analysis is intended to show the capabilities of the DART-75, a 75 passenger medium-range regional transport. Included are the detailed descriptions of the structures, performance, stability and control, weight and balance, and engine design. The design should allow for the DART to become the premier regional aircraft of the future due to some advanced features like the canard, semi-composite construction, and advanced engines

Social, Economic, and Political Events Affect Gender Equity in China, Nepal, and Nicaragua: A Matched, Interrupted Time-Series Study

: Progress in gender equity can improve health at the individual and country levels.: This study\u27s objective was to analyze recent trends in gender equity and identify historical and contextual factors that contributed to changes in gender equity in three countries: China, Nepal, and Nicaragua.: To assess gender equity trends, we used the Gender Gap Index (GGI) from the World Economic Forum\u27s Global Gender Gap Report (2006-2017). The GGI incorporated data on economic participation, educational attainment, health, and political empowerment for almost 150 countries. We selected China, Nepal, and Nicaragua because of their major changes in GGI and diversity in geographical location and economic status. We reviewed major social, economic, and political events during 2006-2017, and identified key events in each country. We compared countries\u27 GGI with matched controls average using interrupted time-series analysis.: Nepal and Nicaragua both had dramatic increases in GGI (improvement in equity), Nepal (β = 0.029; 95% CI: 0.003, 0.056) and Nicaragua (β = 0.035; 95% CI: 0.005, 0.065). This was strongly influenced by political empowerment, which likely impacted access to education and employment opportunities. Despite major economic growth and new policies to address gender inequities (e.g. the One-Child Policy), China saw a significant decline in GGI between 2010 and 2017 (β = -0.014; 95% CI: -0.024, -0.004), largely resulting from decreased gender equity in educational attainment, economic participation, and health/survival sub-indices.: Key social, economic, and political events helped explain trends in countries\u27 gender equity. Our study suggested that supportive social and political environments would play important roles in empowering women, which would advance human rights and promote health and well-being of individuals, households, communities, and countries

National Nutrition Strategies That Focus on Maternal, Infant, and Young Child Nutrition in Southeast Asia Do Not Consistently Align With Regional and International Recommendations

We examined the consistency of national nutrition strategies and action plans (NNS) focusing on maternal, infant, and young child nutrition in Southeast Asia with regional and international recommendations. Between July and December 2017, we identified and extracted information on context, objectives, interventions, indicators, strategies, and coordination mechanisms from the most recent NNS in nine Southeast Asian countries. All NNS described context, objectives, and the following interventions: antenatal care, micronutrient supplementation during pregnancy, breastfeeding promotion, improved complementary feeding, nutrition in emergencies, and food fortification or dietary diversity. Micronutrient supplementation for young children was included in eight NNS; breastfeeding promotion during pregnancy and support at birth in seven; and school feeding, deworming, and treatment of severe acute malnutrition in six. All NNS contained programme monitoring and evaluation plans with measurable indicators and targets. Not all NNS covered wasting, exclusive breastfeeding, low birthweight, and childhood overweight. Strategies for achieving NNS goals and objectives were health system strengthening (nine), social and behaviour change communication (nine), targeting vulnerable groups (eight), and social or community mobilization (four). All addressed involvement, roles and responsibilities, and collaboration mechanisms among sectors and stakeholders. There was a delay in releasing NNS in Indonesia, Myanmar, and the Philippines. In conclusion, although Southeast Asian NNS have similarities in structure and contents, some interventions and indicators vary by country and do not consistently align with regional and international recommendations. A database with regularly updated information on NNS components would facilitate cross-checking completeness within a country, comparison across countries, and knowledge sharing and learning

SAMHD1 promotes DNA end resection to facilitate DNA repair by homologous recombination

DNA double-strand break (DSB) repair by homologous recombination (HR) is initiated by CtIP/MRN-mediated DNA end resection to maintain genome integrity. SAMHD1 is a dNTP triphosphohydrolase, which restricts HIV- 1 infection, and mutations are associated with Aicardi-Goutières syndrome and cancer. We show that SAMHD1 has a dNTPase-independent function in promoting DNA end resection to facilitate DSB repair by HR. SAMHD1 deficiency or Vpx-mediated degradation causes hypersensitivity to DSB-inducing agents, and SAMHD1 is recruited to DSBs. SAMHD1 complexes with CtIP via a conserved C-terminal domain and recruits CtIP to DSBs to facilitate end resection and HR. Significantly, a cancer-associated mutant with impaired CtIP interaction, but not dNTPase-inactive SAMHD1, fails to rescue the end resection impairment of SAMHD1 depletion. Our findings define a dNTPase-independent function for SAMHD1 in HR-mediated DSB repair by facilitating CtIP accrual to promote DNA end resection, providing insight into how SAMHD1 promotes genome integrity

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Social, economic, and political events affect gender equity in China, Nepal, and Nicaragua: a matched, interrupted time-series study

Background: Progress in gender equity can improve health at the individual and country levels. Objectives: This study’s objective was to analyze recent trends in gender equity and identify historical and contextual factors that contributed to changes in gender equity in three countries: China, Nepal, and Nicaragua. Methods: To assess gender equity trends, we used the Gender Gap Index (GGI) from the World Economic Forum’s Global Gender Gap Report (2006–2017). The GGI incorporated data on economic participation, educational attainment, health, and political empowerment for almost 150 countries. We selected China, Nepal, and Nicaragua because of their major changes in GGI and diversity in geographical location and economic status. We reviewed major social, economic, and political events during 2006–2017, and identified key events in each country. We compared countries’ GGI with matched controls average using interrupted time-series analysis. Results: Nepal and Nicaragua both had dramatic increases in GGI (improvement in equity), Nepal (β = 0.029; 95% CI: 0.003, 0.056) and Nicaragua (β = 0.035; 95% CI: 0.005, 0.065). This was strongly influenced by political empowerment, which likely impacted access to education and employment opportunities. Despite major economic growth and new policies to address gender inequities (e.g. the One-Child Policy), China saw a significant decline in GGI between 2010 and 2017 (β = −0.014; 95% CI: −0.024, −0.004), largely resulting from decreased gender equity in educational attainment, economic participation, and health/survival sub-indices. Conclusions: Key social, economic, and political events helped explain trends in countries’ gender equity. Our study suggested that supportive social and political environments would play important roles in empowering women, which would advance human rights and promote health and well-being of individuals, households, communities, and countries