SR-SCARLET 1: Peregrin

This report presents a reconnaissance aircraft with a lifting body configuration. The aircraft is capable of flying a distance of 6000 nmi at Mach 5 with a payload of 7500 pounds. The aircraft does not require a runway for takeoff for it is air launched from a carrier aircraft. Specifically this report addresses the areas of external aerodynamics, cost, thermal protection systems, propulsion, stability and control, and materials. Each area is represented by a separate section. This allows for selective reading

The evolution of azole resistance in Candida albicans sterol 14α-demethylase (CYP51) through incremental amino acid substitutions

Recombinant Candida albicans CYP51 (CaCYP51) proteins containing 23 single and 5 double amino acid substitutions found in clinical strains and the wild-type enzyme were expressed in Escherichia coli and purified by Ni2+-nitrilotriacetic acid agarose chromatography. Catalytic tolerance to azole antifungals was assessed by determination of the concentration causing 50% enzyme inhibition (IC50) using CYP51 reconstitution assays. The greatest increase in the IC50 compared to that of the wild-type enzyme was observed with the five double substitutions Y132F+K143R (15.3-fold), Y132H+K143R (22.1-fold), Y132F+F145L (10.1-fold), G307S+G450E (13-fold), and D278N+G464S (3.3-fold). The single substitutions K143R, D278N, S279F, S405F, G448E, and G450E conferred at least 2-fold increases in the fluconazole IC50, and the Y132F, F145L, Y257H, Y447H, V456I, G464S, R467K, and I471T substitutions conferred increased residual CYP51 activity at high fluconazole concentrations. In vitro testing of select CaCYP51 mutations in C. albicans showed that the Y132F, Y132H, K143R, F145L, S405F, G448E, G450E, G464S, Y132F+K143R, Y132F+F145L, and D278N+G464S substitutions conferred at least a 2-fold increase in the fluconazole MIC. The catalytic tolerance of the purified proteins to voriconazole, itraconazole, and posaconazole was far lower and limited to increased residual activities at high triazole concentrations for certain mutations rather than large increases in IC50 values. Itraconazole was the most effective at inhibiting CaCYP51. However, when tested against CaCYP51 mutant strains, posaconazole seemed to be the most resistant to changes in MIC as a result of CYP51 mutation compared to itraconazole, voriconazole, or fluconazole

Changes in health in the countries of the UK and 150 English Local Authority areas 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.

BACKGROUND: Previous studies have reported national and regional Global Burden of Disease (GBD) estimates for the UK. Because of substantial variation in health within the UK, action to improve it requires comparable estimates of disease burden and risks at country and local levels. The slowdown in the rate of improvement in life expectancy requires further investigation. We use GBD 2016 data on mortality, causes of death, and disability to analyse the burden of disease in the countries of the UK and within local authorities in England by deprivation quintile. METHODS: We extracted data from the GBD 2016 to estimate years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and attributable risks from 1990 to 2016 for England, Scotland, Wales, Northern Ireland, the UK, and 150 English Upper-Tier Local Authorities. We estimated the burden of disease by cause of death, condition, year, and sex. We analysed the association between burden of disease and socioeconomic deprivation using the Index of Multiple Deprivation. We present results for all 264 GBD causes of death combined and the leading 20 specific causes, and all 84 GBD risks or risk clusters combined and 17 specific risks or risk clusters. FINDINGS: The leading causes of age-adjusted YLLs in all UK countries in 2016 were ischaemic heart disease, lung cancers, cerebrovascular disease, and chronic obstructive pulmonary disease. Age-standardised rates of YLLs for all causes varied by two times between local areas in England according to levels of socioeconomic deprivation (from 14 274 per 100 000 population [95% uncertainty interval 12 791-15 875] in Blackpool to 6888 [6145-7739] in Wokingham). Some Upper-Tier Local Authorities, particularly those in London, did better than expected for their level of deprivation. Allowing for differences in age structure, more deprived Upper-Tier Local Authorities had higher attributable YLLs for most major risk factors in the GBD. The population attributable fractions for all-cause YLLs for individual major risk factors varied across Upper-Tier Local Authorities. Life expectancy and YLLs have improved more slowly since 2010 in all UK countries compared with 1990-2010. In nine of 150 Upper-Tier Local Authorities, YLLs increased after 2010. For attributable YLLs, the rate of improvement slowed most substantially for cardiovascular disease and breast, colorectal, and lung cancers, and showed little change for Alzheimer's disease and other dementias. Morbidity makes an increasing contribution to overall burden in the UK compared with mortality. The age-standardised UK DALY rate for low back and neck pain (1795 [1258-2356]) was higher than for ischaemic heart disease (1200 [1155-1246]) or lung cancer (660 [642-679]). The leading causes of ill health (measured through YLDs) in the UK in 2016 were low back and neck pain, skin and subcutaneous diseases, migraine, depressive disorders, and sense organ disease. Age-standardised YLD rates varied much less than equivalent YLL rates across the UK, which reflects the relative scarcity of local data on causes of ill health. INTERPRETATION: These estimates at local, regional, and national level will allow policy makers to match resources and priorities to levels of burden and risk factors. Improvement in YLLs and life expectancy slowed notably after 2010, particularly in cardiovascular disease and cancer, and targeted actions are needed if the rate of improvement is to recover. A targeted policy response is also required to address the increasing proportion of burden due to morbidity, such as musculoskeletal problems and depression. Improving the quality and completeness of available data on these causes is an essential component of this response. FUNDING: Bill & Melinda Gates Foundation and Public Health England

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

The Effects of a “Tell-Show-Try-Apply” Professional Development Package on Teachers of Students With Severe Developmental Disabilities

The What Works Clearinghouse guidelines for high-quality professional development were used to develop a Tell, Show, Try, and Apply (TSTA) method of training. This method was used to train teachers to align instruction to grade-level content for students with severe developmental disabilities. A total of 193 teachers of students who participate in alternate assessment based on alternate achievement standards from three states participated in the first 2 days of training. A subset of 37 teachers participated in a 3rd day of training and submitted products from classroom applications. The impact of the TSTA training was evaluated to determine its effect on teachers instructional fidelity across three content areas (e.g., English language arts [ELA], mathematics, science) with their own students. In addition, generalization to new academic content aligned to grade-aligned standards developed by the teachers was taken. Results indicated that the professional development was effective not only in increasing teachers knowledge of alignment but also grade-aligned instruction with generalization across content. Future research questions and practical application also are discussed

Protocol for a seamless phase 2A-phase 2B randomized double-blind placebo-controlled trial to evaluate the safety and efficacy of benfotiamine in patients with early Alzheimers disease (BenfoTeam).

BACKGROUND: Benfotiamine provides an important novel therapeutic direction in Alzheimers disease (AD) with possible additive or synergistic effects to amyloid targeting therapeutic approaches. OBJECTIVE: To conduct a seamless phase 2A-2B proof of concept trial investigating tolerability, safety, and efficacy of benfotiamine, a prodrug of thiamine, as a first-in-class small molecule oral treatment for early AD. METHODS: This is the protocol for a randomized, double-blind, placebo-controlled 72-week clinical trial of benfotiamine in 406 participants with early AD. Phase 2A determines the highest safe and well-tolerated dose of benfotiamine to be carried forward to phase 2B. During phase 2A, real-time monitoring of pre-defined safety stopping criteria in the first approximately 150 enrollees will help determine which dose (600 mg or 1200 mg) will be carried forward into phase 2B. The phase 2A primary analysis will test whether the rate of tolerability events (TEs) is unacceptably high in the high-dose arm compared to placebo. The primary safety endpoint in phase 2A is the rate of TEs compared between active and placebo arms, at each dose. The completion of phase 2A will seamlessly transition to phase 2B without pausing or stopping the trial. Phase 2B will assess efficacy and longer-term safety of benfotiamine in a larger group of participants through 72 weeks of treatment, at the selected dose. The co-primary efficacy endpoints in phase 2B are CDR-Sum of Boxes and ADAS-Cog13. Secondary endpoints include safety and tolerability measures; pharmacokinetic measures of thiamine and its esters, erythrocyte transketolase activity as blood markers of efficacy of drug delivery; ADCS-ADL-MCI; and MoCA. CONCLUSION: The BenfoTeam trial utilizes an innovative seamless phase 2A-2B design to achieve proof of concept. It includes an adaptive dose decision rule, thus optimizing exposure to the highest and best-tolerated dose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT06223360, registered on January 25, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06223360