NASA Ares I Launch Vehicle First Stage Roll Control System Cold Flow Development Test Program Overview

The Ares I launch vehicle is the selected design, chosen to return humans to the moon, Mars, and beyond. It is configured in two inline stages: the First Stage is a Space Shuttle derived five-segment Solid Rocket Booster and the Upper Stage is powered by a Saturn V derived J-2X engine. During launch, roll control for the First Stage (FS) is handled by a dedicated Roll Control System (RoCS) located on the connecting Interstage. That system will provide the Ares I with the ability to counteract induced roll torque while any induced yaw or pitch moments are handled by vectoring of the booster nozzle. This paper provides an overview of NASA s Ares I FS RoCS cold flow development test program including detailed test objectives, types of tests run to meet those objectives, an overview of the results, and applicable lessons learned. The test article was built and tested at the NASA Marshall Space Flight Center in Huntsville, AL. The FS RoCS System Development Test Article (SDTA) is a full scale, flight representative water flow test article whose primary objective was to obtain fluid system performance data to evaluate integrated system level performance characteristics and verify analytical models. Development testing and model correlation was deemed necessary as there is little historical precedent for similar large flow, pulsing systems such as the FS RoCS. The cold flow development test program consisted of flight-similar tanks, pressure regulators, and thruster valves, as well as plumbing simulating flight geometries, combined with other facility grade components and structure. Orifices downstream of the thruster valves were used to simulate the pressure drop through the thrusters. Additional primary objectives of this test program were to: evaluate system surge pressure (waterhammer) characteristics due to thruster valve operation over a range of mission duty cycles at various feed system pressures, evaluate temperature transients and heat transfer in the pressurization system, including regulator blowdown and propellant ullage performance, measure system pressure drops for comparison to analysis of tubing and components, and validate system activation and re-activation procedures for the helium pressurant system. Secondary objectives included: validating system processes for loading, unloading, and purging, validating procedures and system response for multiple failure scenarios, including relief valve operation, and evaluating system performance for contingency scenarios. The test results of the cold flow development test program are essential in validating the performance and interaction of the Roll Control System and anchoring analysis tools and results to a Critical Design Review level of fidelity

The prevalence of dysphagia in a long-term care facility

Dysphagia, or difficulty in swallowing, poses a major health threat if it is not promptly diagnosed and treated. Problems secondary to dysphagia may include malnutrition, aspiration pneumonia dehydration, psychosocial problems and increased health care costs secondary to professional time for feeding, treatment of medical complications, food wastage, and the length of time required to feed residents. The objectives of this research were to 1) determine the prevalence of dysphagia population in a long-term care institution in St. John's, Newfoundland. Other objectives were to determine the medical diagnoses and conditions associated with dysphagia, to assess the extent of complications secondary to dysphagia and to document management techniques currently being used. Information for this retrospective, descriptive study was obtained by medical record review and a questionnaire completed by nursing personnel. The study population consisted of 193 subjects (138 female/55 male) with a mean age of 75.6 years. Identification of dysphagia and the level of severity were based on the following: signs and symptoms of dysphagia, history of aspiration pneumonia, diagnosed neurological condition, documented reports of dysphagia, medical complications, and dietary modifications. The prevalence of dysphagia was 45.5%. Of the subjects with dysphagia, 56%, 39% and 6% were mildly, moderately and severely dysphagic, respectively. For only 22% of dysphagic subjects was dysphagia documented in the medical record. Nursing staff identified only 39% of subjects with dysphagia. They were able to identify all severely dysphagic subjects. Dysphagia was associated with fluid and texture modifications; poor hydration status; nursing reports of subjects being "not well nourished"; use of nutritional supplements, poor skin integrity; the need for crushed medications; impaired chewing ability; feeding dependency; and level of assistance required at meal time. Dysphagia was not associated with age; sex; inadequate nutritional intake; decubitus ulcers; length of time to be fed; weight status; use of antipsychotic or tricyclic antidepressant medications; difficulty swallowing medications; reports of "not being hungry"; and needing encouragement to eat. Due to small numbers it was possible to examine associations of dysphagia with medical conditions. Recommendations are provided for future management of dysphagic individuals in long-term care facilities

Factors associated with month 2 smear non-conversion among category 1 tuberculosis patients in Karachi, Pakistan

Predictors of smear non-conversion at baseline can help identify cases at risk for failure of tuberculosis treatment. Retrospective data for smear-positive Category 1 patients in Karachi, Pakistan, was analyzed. Predictors of sputum conversion were determined using multiple logistic regression with sputum conversion as outcome variable and patient demographics, baseline weight, baseline sputum smear grade, case-finding approach as explanatory variables. Age ≥35 years, baseline sputum grade of 3+ were significantly associated with predicting sputum smear positivity at month 2 of treatment. Monitoring compliance to TB treatment should be considered amongst older patients and those with a high sputum grade at baseline

Assessing carbon stocks using indigenous peoples' field measurements in Amazonian Guyana

Accurate estimations of carbon stocks across large tracts of tropical forests are key for participation in programs promoting avoided deforestation and carbon sequestration, such as the UN REDD+ framework. Trained local technicians can provide such data, and this, combined with satellite imagery, allows robust carbon stock estimation across vegetation classes and large areas. In the first comprehensive survey in Guyana conducted by indigenous people, ground data from 21 study sites in the Rupununi region were used to estimate above ground tree carbon density across a diversity of ecosystems and land use types. Carbon stocks varied between village sites from 1Tg to 22.7Tg, and these amounts were related to stem density and diameter. This variation was correlated with vegetation type across the region, with savannas holding on average 14MgCha-1 and forests 153MgCha-1. The results indicated that previous estimates based on remotely sensed data for this area may be inaccurate (under estimations). There were also differences in carbon densities between village sites and uninhabited control areas, which are presumably driven by community use. Recruiting local technicians for field work allowed (a) large amounts of ground data to be collected for a wide region otherwise hard to access, and (b) ensured that local people were directly involved in Guyana's Low Carbon Development Strategy as part of REDD+. This is the first such comprehensive survey of carbon stocks, carbon density and vegetation types over a large area in Guyana, one of the first countries to develop such a program. The potential inclusion of forests held by indigenous peoples in REDD+ programs is a global issue: we clearly show that indigenous people are capable of assessing and monitoring carbon on their lands

Association between gestational weight gain, gestational diabetes risk, and obstetric outcomes: A randomized controlled trial post hoc analysis

Excess gestational weight gain (GWG) is associated with the development of gestational diabetes mellitus (GDM). Lifestyle trials have not achieved much GWG limitation, and have largely failed to prevent GDM. We compared the effect of substantial GWG limitation on maternal GDM risk. Pregnant women with a body mass index (BMI) ≥29 kg/m2 \u3c20 weeks gestation without GDM (n = 436) were randomized, in a multicenter trial, to usual care (UC), healthy eating (HE), physical activity (PA), or HE and PA lifestyle interventions. GWG over the median was associated with higher homeostasis model assessment insulin resistance (HOMA-IR) and insulin secretion (Stumvoll phases 1 and 2), a higher fasting plasma glucose (FPG) at 24–28 weeks (4.66 ± 0.43 vs. 4.61 ± 0.40 mmol/L, p \u3c 0.01), and a higher rate of caesarean section (38% vs. 27% p \u3c 0.05). The GWG over the median at 35–37 weeks was associated with a higher rate of macrosomia (25% vs. 16%, p \u3c 0.05). A post hoc comparison among women from the five sites with a GWG difference \u3e3 kg showed no significance difference in glycaemia or insulin resistance between HE and PA, and UC. We conclude that preventing even substantial increases in GWG after the first trimester has little effect on maternal glycaemia. We recommend randomized controlled trials of effective lifestyle interventions, starting in or before the first trimester

Circulating Biomarkers and Resistance to Endocrine Therapy in Metastatic Breast Cancers: Correlative Results from AZD9496 Oral SERD Phase I Trial.

PURPOSE: Common resistance mechanisms to endocrine therapy (ET) in estrogen receptor (ER)-positive metastatic breast cancers include, among others, ER loss and acquired activating mutations in the ligand-binding domain of the ER gene (ESR1LBDm). ESR1 mutational mediated resistance may be overcome by selective ER degraders (SERD). During the first-in-human study of oral SERD AZD9496, early changes in circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) were explored as potential noninvasive tools, alongside paired tumor biopsies, to assess pharmacodynamics and early efficacy. EXPERIMENTAL DESIGN: CTC were enumerated/phenotyped for ER and Ki67 using CellSearch in serial blood draws. ctDNA was assessed for the most common ESR1LBDm by droplet digital PCR (BioRad). RESULTS: Before starting AZD9496, 11 of 43 (25%) patients had ≥5 CTC/7.5 mL whole blood (WB), none of whom underwent reduction to <5 CTC/7.5 mL WB on C1D15. Five of 11 patients had baseline CTC-ER+, two of whom had CTC-ER+ reduction. CTC-Ki67 status did not change appreciably. Patients with ≥5 CTC/7.5 mL WB before treatment had worse progression-free survival (PFS) than patients with <5 CTC (P = 0.0003). Fourteen of 45 (31%) patients had ESR1LBDm + ctDNA at baseline, five of whom had ≥2 unique mutations. Baseline ESR1LBDm status was not prognostic. Patients with persistently elevated CTC and/or ESR1LBDm + ctDNA at C1D15 had worse PFS than patients who did not (P = 0.0007). CONCLUSIONS: Elevated CTC at baseline was a strong prognostic factor in this cohort. Early on-treatment changes were observed in CTC-ER+ and ESR1LBDm + ctDNA, but not in overall CTC number. Integrating multiple biomarkers in prospective trials may improve outcome prediction and ET resistance mechanisms' identification over a single biomarker

Tight Junction-Related Barrier Contributes to the Electrophysiological Asymmetry across Vocal Fold Epithelium

Electrophysiological homeostasis is indispensable to vocal fold hydration. We investigate tight junction (TJ)-associated components, occludin and ZO-1, and permeability with or without the challenge of a permeability-augmenting agent, histamine. Freshly excised ovine larynges are obtained from a local abattoir. TJ markers are explored via reverse transcriptase polymerase chain reaction (RT-PCR). Paracellular permeabilities are measured in an Ussing system. The gene expression of both TJ markers is detected in native ovine vocal fold epithelium. Luminal histamine treatment significantly decreases transepithelial resistance (TER) (N = 72, p<0.01) and increases penetration of protein tracer (N = 35, p<0.001), respectively, in a time-, and dose-dependent fashion. The present study demonstrates that histamine compromises TJ-related paracellular barrier across vocal fold epithelium. The detection of TJ markers indicates the existence of typical TJ components in non-keratinized, stratified vocal fold epithelium. The responsiveness of paracellular permeabilities to histamine would highlight the functional significance of this TJ-equivalent system to the electrophysiological homeostasis, which, in turn, regulates the vocal fold superficial hydration

Phase 3 trials of ixekizumab in moderate-to-severe plaque psoriasis

BACKGROUND Two phase 3 trials (UNCOVER-2 and UNCOVER-3) showed that at 12 weeks of treatment, ixekizumab, a monoclonal antibody against interleukin-17A, was superior to placebo and etanercept in the treatment of moderate-to-severe psoriasis. We report the 60-week data from the UNCOVER-2 and UNCOVER-3 trials, as well as 12-week and 60-week data from a third phase 3 trial, UNCOVER-1. METHODS We randomly assigned 1296 patients in the UNCOVER-1 trial, 1224 patients in the UNCOVER-2 trial, and 1346 patients in the UNCOVER-3 trial to receive subcutaneous injections of placebo (placebo group), 80 mg of ixekizumab every 2 weeks after a starting dose of 160 mg (2-wk dosing group), or 80 mg of ixekizumab every 4 weeks after a starting dose of 160 mg (4-wk dosing group). Additional cohorts in the UNCOVER-2 and UNCOVER-3 trials were randomly assigned to receive 50 mg of etanercept twice weekly. At week 12 in the UNCOVER-3 trial, the patients entered a long-term extension period during which they received 80 mg of ixekizumab every 4 weeks through week 60; at week 12 in the UNCOVER-1 and UNCOVER-2 trials, the patients who had a response to ixekizumab (defined as a static Physicians Global Assessment [sPGA] score of 0 [clear] or 1 [minimal psoriasis]) were randomly reassigned to receive placebo, 80 mg of ixekizumab every 4 weeks, or 80 mg of ixekizumab every 12 weeks through week 60. Coprimary end points were the percentage of patients who had a score on the sPGA of 0 or 1 and a 75% or greater reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at week 12. RESULTS In the UNCOVER-1 trial, at week 12, the patients had better responses to ixekizumab than to placebo; in the 2-wk dosing group, 81.8% had an sPGA score of 0 or 1 and 89.1% had a PASI 75 response; in the 4-wk dosing group, the respective rates were 76.4% and 82.6%; and in the placebo group, the rates were 3.2% and 3.9% (P<0.001 for all comparisons of ixekizumab with placebo). In the UNCOVER-1 and UNCOVER-2 trials, among the patients who were randomly reassigned at week 12 to receive 80 mg of ixekizumab every 4 weeks, 80 mg of ixekizumab every 12 weeks, or placebo, an sPGA score of 0 or 1 was maintained by 73.8%, 39.0%, and 7.0% of the patients, respectively. Patients in the UNCOVER-3 trial received continuous treatment of ixekizumab from weeks 0 through 60, and at week 60, at least 73% had an sPGA score of 0 or 1 and at least 80% had a PASI 75 response. Adverse events reported during ixekizumab use included neutropenia, candidal infections, and inflammatory bowel disease. CONCLUSIONS In three phase 3 trials involving patients with psoriasis, ixekizumab was effective through 60 weeks of treatment. As with any treatment, the benefits need to be weighed against the risks of adverse events. The efficacy and safety of ixekizumab beyond 60 weeks of treatment are not yet known

Mapping 123 million neonatal, infant and child deaths between 2000 and 2017

Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2—to end preventable child deaths by 2030—we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000–2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations

Isorhapontigenin, a resveratrol analogue selectively inhibits ADP-stimulated platelet activation

Isorhapontigenin is a polyphenolic compound found in Chinese herbs and grapes. It is a methoxylated analogue of a stilbenoid, resveratrol, which is well-known for its various beneficial effects including anti-platelet activity. Isorhapontigenin possesses greater oral bioavailability than resveratrol and has also been identified to possess anti-cancer and anti-inflammatory properties. However, its effects on platelet function have not been reported previously. In this study, we report the effects of isorhapontigenin on the modulation of platelet function. Isorhapontigenin was found to selectively inhibit ADP-induced platelet aggregation with an IC50 of 1.85µM although it displayed marginal inhibition on platelet aggregation induced by other platelet agonists at 100µM. However, resveratrol exhibited weaker inhibition on ADP-induced platelet aggregation (IC50>100µM) but inhibited collagen induced platelet aggregation at 50µM and 100µM. Isorhapontigenin also inhibited integrin αIIbβ3 mediated inside-out and outside-in signalling and dense granule secretion in ADP-induced platelet activation but interestingly, no effect was observed on α-granule secretion. Isorhapontigenin did not exert any cytotoxicity on platelets at the concentrations of up to 100µM. Furthermore, it did not affect haemostasis in mice at the IC50 concentration (1.85µM). In addition, the mechanistic studies demonstrated that isorhapontigenin increased cAMP levels and VASP phosphorylation at Ser157 and decreased Akt phosphorylation. This suggests that isorhapontigenin may interfere with cAMP and PI3K signalling pathways that are associated with the P2Y12 receptor. Molecular docking studies emphasised that isorhapontigenin has greater binding affinity to P2Y12 receptor than resveratrol. Our results demonstrate that isorhapontigenin has selective inhibitory effects on ADP-stimulated platelet activation possibly via P2Y12 receptor