Quiet Supersonic Flights 2018 (QSF18) Test: Galveston, Texas Risk Reduction for Future Community Testing with a Low-Boom Flight Demonstration Vehicle

The Quiet Supersonic Flights 2018 (QSF18) Program was designed to develop tools and methods for demonstration of overland supersonic flight with an acceptable sonic boom, and collect a large dataset of responses from a representative sample of the population. Phase 1 provided the basis for a low amplitude sonic boom testing in six different climate regions that will enable international regulatory agencies to draft a noise-based standard for certifying civilian supersonic overland flight. Phase 2 successfully executed a large scale test in Galveston, Texas, developed well documented data sets, calculated dose response relationships, yielded lessons, and identified future risk reduction activities

Cluster M Mycobacteriophages Bongo, PegLeg, and Rey with Unusually Large Repertoires of tRNA Isotopes

Genomic analysis of a large set of phages infecting the common hostMycobacterium smegmatis mc2155 shows that they span considerable genetic diversity. There are more than 20 distinct types that lack nucleotide similarity with each other, and there is considerable diversity within most of the groups. Three newly isolated temperate mycobacteriophages, Bongo, PegLeg, and Rey, constitute a new group (cluster M), with the closely related phages Bongo and PegLeg forming subcluster M1 and the more distantly related Rey forming subcluster M2. The cluster M mycobacteriophages have siphoviral morphologies with unusually long tails, are homoimmune, and have larger than average genomes (80.2 to 83.7 kbp). They exhibit a variety of features not previously described in other mycobacteriophages, including noncanonical genome architectures and several unusual sets of conserved repeated sequences suggesting novel regulatory systems for both transcription and translation. In addition to containing transfer-messenger RNA and RtcB-like RNA ligase genes, their genomes encode 21 to 24 tRNA genes encompassing complete or nearly complete sets of isotypes. We predict that these tRNAs are used in late lytic growth, likely compensating for the degradation or inadequacy of host tRNAs. They may represent a complete set of tRNAs necessary for late lytic growth, especially when taken together with the apparent lack of codons in the same late genes that correspond to tRNAs that the genomes of the phages do not obviously encode

Waveforms and Sonic Boom Perception and Response (WSPR): Low-Boom Community Response Program Pilot Test Design, Execution, and Analysis

The Waveforms and Sonic boom Perception and Response (WSPR) Program was designed to test and demonstrate the applicability and effectiveness of techniques to gather data relating human subjective response to multiple low-amplitude sonic booms. It was in essence a practice session for future wider scale testing on naive communities, using a purpose built low-boom demonstrator aircraft. The low-boom community response pilot experiment was conducted in California in November 2011. The WSPR team acquired sufficient data to assess and evaluate the effectiveness of the various physical and psychological data gathering techniques and analysis methods

Quiet Supersonic Flights 2018 (QSF18) Test: Galveston, Texas Risk Reduction for Future Community Testing with a Low-Boom Flight Demonstration Vehicle

The Quiet Supersonic Flights 2018 (QSF18) Program was designed to develop tools and methods for demonstration of overland supersonic flight with an acceptable sonic boom, and collect a large dataset of responses from a representative sample of the population. Phase 1 provided the basis for a low amplitude sonic boom testing in six different climate regions that will enable international regulatory agencies to draft a noise-based standard for certifying civilian supersonic overland flight. Phase 2 successfully executed a large scale test in Galveston, Texas, developed well documented data sets, calculated dose response relationships, yielded lessons, and identified future risk reduction activities

Developing indicators and measures of high-quality for Australian general practice

Background: Rising health costs and health inequity are major challenges in Australia, as internationally. Strong primary health care is well evidenced to address these challenges. Primary Health Networks (PHNs) work with general practices to collect data and support quality improvement; however, there is no consensus regarding what defines high quality. This paper describes the development of an evidence-based suite of indicators and measures of high-quality general practice for the Australian context. Methods: We reviewed the literature to develop a suitable framework and revise quality assurance measures currently in use, then reviewed these in three workshops with general practitioners, practice managers, nurses, consumers and PHN staff in western Sydney. We used a descriptive qualitative research approach to analyse the data. Results: A total of 125 evidence-based indicators were agreed to be relevant, and 80 were deemed both relevant and feasible. These were arranged across a framework based on the Quadruple Aim, and include structure, process and outcome measures. Conclusions: The agreed suite of indicators and measures will be further validated in collaboration with PHNs across Australia. This work has the potential to inform health systems innovation both nationally and internationally

Glucocorticoid receptor alters isovolumetric contraction and restrains cardiac fibrosis

Corticosteroids directly affect the heart and vasculature and are implicated in the pathogenesis of heart failure. Attention is focussed upon the role of the mineralocorticoid receptor (MR) in mediating pro-fibrotic and other adverse effects of corticosteroids upon the heart. In contrast, the role of the glucocorticoid receptor (GR) in the heart and vasculature is less well understood. We addressed this in mice with cardiomyocyte and vascular smooth muscle deletion of GR (SMGRKO mice). Survival of SMGRKO mice to weaning was reduced compared with that of littermate controls. Doppler measurements of blood flow across the mitral valve showed an elongated isovolumetric contraction time in surviving adult SMGRKO mice, indicating impairment of the initial left ventricular contractile phase. Although heart weight was elevated in both genders, only male SMGRKO mice showed evidence of pathological cardiomyocyte hypertrophy, associated with increased myosin heavy chain-β expression. Left ventricular fibrosis, evident in both genders, was associated with elevated levels of mRNA encoding MR as well as proteins involved in cardiac remodelling and fibrosis. However, MR antagonism with spironolactone from birth only modestly attenuated the increase in pro-fibrotic gene expression in SMGRKO mice, suggesting that elevated MR signalling is not the primary driver of cardiac fibrosis in SMGRKO mice, and cardiac fibrosis can be dissociated from MR activation. Thus, GR contributes to systolic function and restrains normal cardiac growth, the latter through gender-specific mechanisms. Our findings suggest the GR:MR balance is critical in corticosteroid signalling in specific cardiac cell types

A Crowdsourcing Open Contest to Design Pre-Exposure Prophylaxis Promotion Messages: Protocol for an Exploratory Mixed Methods Study.

BACKGROUND: In the United States, black men who have sex with men (BMSM) are disproportionately affected by HIV. Pre-exposure prophylaxis (PrEP) can reduce HIV incidence. However, real-world implementation of PrEP outside of clinical trials has identified racial disparities in PrEP awareness, uptake, and adherence. In the context of a long history of medical mistrust and power imbalances between scientists and community members, strategies to increase uptake of PrEP among BMSM should consider ways to ensure messages address the needs and priorities of the community. Crowdsourcing contests shift traditional individual tasks to a large group and may enhance community engagement. OBJECTIVE: This paper describes the research protocol of a contest approach to soliciting PrEP promotion messages among BMSM in Baltimore. METHODS: Open-contest implementation and evaluation will proceed as follows: (1) organize a community steering group; (2) develop platforms to solicit crowd input; (3) engage the community to contribute ideas through a Web-based forum and in-person events; (4) evaluate contest entries using both community panel judge assessment and crowd voting; (5) utilize mixed methods to evaluate feasibility, acceptability, and community engagement; and (6) disseminate contest results. RESULTS: This study was funded by the National Institutes of Health (National Institute of Mental Health: R34MH116725) in May 2018 and was approved by the institutional review board in April 2018. The open contest started in February 2019, and data analyses for the mixed method evaluation are expected to complete in December 2019. CONCLUSIONS: The contest will potentially bring new ideas in developing more impactful and locally defined PrEP promotion campaigns. We will determine whether an open-contest approach is acceptable among BMSM in Baltimore. If successful, this study can inform future projects using a similar approach on how to identify and implement programs and policies that are more responsive to community needs and that build up community assets. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15590

In-depth phenotyping for clinical stratification of Gaucher disease.

BackgroundThe Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study.ResultsAt baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery.ConclusionGaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability