When Military Fitness Standards No Longer Apply: The High Prevalence of Metabolic Syndrome in Recent Air Force Retirees

BACKGROUND: Metabolic syndrome (MetS) is strongly associated with cardiovascular disease. With MetS prevalence rates increasing in the U.S. population, prevention efforts have largely focused on diet and exercise interventions. Before retirement, military service members have met fitness requirements for at least 20 years, and have lower MetS rates compared to age-matched U.S. population controls (23.4% vs. 39.0%), which suggests a protective effect of the lifestyle associated with military service. However, MetS rates in military retirees have not been previously reported, so it is unknown whether this protective effect extends beyond military service. The purpose of this study was to examine the prevalence of MetS and individual diagnostic criteria in a population of recent U.S. Air Force (USAF) retirees. METHODS: We obtained institutional review board approval for all participating sites at Wilford Hall Ambulatory Surgical Center. From December 2011 to May 2013, USAF retirees within 8 years of their date of retirement were recruited at five USAF bases. Consenting subjects underwent examination and laboratory studies to assess the five diagnostic criteria measures for MetS. We used binary logistic regression to examine the relationship between various factors and the presence of MetS. RESULTS: The study population (n = 381) was primarily male (81.9%), enlisted (71.1%) and had a mean age of 48.2 years. When applying the American Heart Association MetS diagnostic criteria to this population, the MetS prevalence was 37.2%. When using alternative diagnostic criteria found in other published studies that did not include the use of cholesterol medications, the MetS prevalence was 33.6%. Per American Heart Association criteria, the prevalence of each of the MetS diagnostic criteria was as follows: central obesity, 39.8%; elevated fasting glucose, 32.4%; high blood pressure, 56.8%; low-high-density lipoproteins cholesterol, 33.3%; and elevated triglycerides, 42.7%. MetS was more common among males (odds ratio [OR] = 4.05; confidence interval [CI] = 1.94, 8.48) and enlisted (OR = 2.23; CI = 1.24, 4.01). It was also strongly associated with a history of participating in the Air Force Weight Management Program (OR = 2.82; CI = 1.41, 5.63) and increased weight since retirement (OR = 4.00; CI = 1.84, 8.70). However, the study did not find an association between the presence of MetS and time since retirement or self-reported diet and exercise changes since retirement. CONCLUSIONS: The MetS prevalence among recent USAF retirees represents a shift from age-matched active duty rates toward higher rates described in the overall U.S. POPULATION: This finding suggests the protective health effects of fitness standards may be reduced shortly after retirement. This is true despite activities such as screening before and during military service and exposure to USAF health promotion efforts and fitness standards throughout a period of active duty service lasting at least 20 years. In general, military members should be counseled that on retirement, efforts to maintain a healthy weight have continued benefit and should not be forgotten. The risk of MetS after retirement is particularly increased for those identified as being overweight during their active duty careers. Interventions that prevent and reduce unhealthy weight gain may be an appropriate investment of resources and should be studied further

Successful proof-of-concept for topical delivery of novel peptide ALM201 with potential utility for treating neovascular eye disorders

PURPOSE: To evaluate the therapeutic benefit of a novel peptide, ALM201, in ocular pathologic vascularization. DESIGN: Experimental study in mouse, rat, and rabbit animal models. PARTICIPANTS: Ten-week-old Lister Hooded male rats, 8-week-old Brown Norway male rats, 9-day-old C57BL/6J mice, and 12-month-old New Zealand male rabbits. METHODS: Corneal vascularization was scored for vessel density and vessel distance to suture in a rat corneal suture model. Ocular penetration and biodistribution were evaluated by matrix-assisted laser desorption/ionization mass spectrometry imaging after topical ALM201 application to rabbit eyes. A mouse choroidal sprouting assay, with aflibercept as positive control, was used to evaluate choroidal neovascularization (CNV) in the posterior segment tissue. Efficacy of topical ALM201 was assessed using a rat laser CNV model of neovascular age-related macular degeneration. MAIN OUTCOME MEASURES: Clinical scoring and histologic analysis of vascularized corneas, sprouting area, lesion size, and vessel leakiness in posterior segments. RESULTS: Assessment of ALM201 treatment in the rat corneal suture model showed a significant decrease in vessel density (P = 0.0065) and vessel distance to suture (P = 0.021) compared with vehicle control (phosphate-buffered saline [PBS]). Infiltration of inflammatory cells into the corneal stroma also was reduced significantly compared with PBS (724.5 ± 122 cells/mm(2) vs. 1837 ± 195.9 cells/mm(2), respectively; P = 0.0029). Biodistribution in rabbit eyes confirmed ALM201 bioavailability in anterior and posterior ocular segments 1 hour after topical instillation. ALM201 treatment significantly suppressed choroid vessel sprouting when compared with PBS treatment (44.5 ± 14.31 pixels vs. 120.9 ± 33.37 pixels, respectively; P = 0.04) and was not inferior to aflibercept (65.63 ± 11.86 pixels; P = 0.7459). Furthermore, topical ALM201 significantly improved vessel leakiness (leakage scores: 2.1 ± 0.7 vs. 2.9 ± 0.1; P = 0.0274) and lesion size (144,729 ± 33,239 μm(3) vs. 187,923 ± 28,575 μm(3); P = 0.03) in the rat laser CNV model when compared with topical PBS vehicle. CONCLUSIONS: ALM201 is a promising novel molecule with anti-inflammatory and antivascularization activity and is a strong candidate to meet the clinical need of a new, topically delivered therapeutic agent for treating inflammation and pathologic vascularization in the anterior and posterior segments of the eye

Phylesystem: a git-based data store for community-curated phylogenetic estimates

Motivation: Phylogenetic estimates from published studies can be archived using general platforms like Dryad (Vision, 2010) or TreeBASE (Sanderson et al., 1994). Such services fulfill a crucial role in ensuring transparency and reproducibility in phylogenetic research. However, digital tree data files often require some editing (e.g. rerooting) to improve the accuracy and reusability of the phylogenetic statements. Furthermore, establishing the mapping between tip labels used in a tree and taxa in a single common taxonomy dramatically improves the ability of other researchers to reuse phylogenetic estimates. As the process of curating a published phylogenetic estimate is not error-free, retaining a full record of the provenance of edits to a tree is crucial for openness, allowing editors to receive credit for their work and making errors introduced during curation easier to correct. Results: Here, we report the development of software infrastructure to support the open curation of phylogenetic data by the community of biologists. The backend of the system provides an interface for the standard database operations of creating, reading, updating and deleting records by making commits to a git repository. The record of the history of edits to a tree is preserved by git’s version control features. Hosting this data store on GitHub (http://github.com/) provides open access to the data store using tools familiar to many developers. We have deployed a server running the ‘phylesystem-api’, which wraps the interactions with git and GitHub. The Open Tree of Life project has also developed and deployed a JavaScript application that uses the phylesystem-api and other web services to enable input and curation of published phylogenetic statements

Phylotastic! Making Tree-of-Life Knowledge Accessible, Reusable and Convenient

Scientists rarely reuse expert knowledge of phylogeny, in spite of years of effort to assemble a great "Tree of Life" (ToL). A notable exception involves the use of Phylomatic, which provides tools to generate custom phylogenies from a large, pre-computed, expert phylogeny of plant taxa. This suggests great potential for a more generalized system that, starting with a query consisting of a list of any known species, would rectify non-standard names, identify expert phylogenies containing the implicated taxa, prune away unneeded parts, and supply branch lengths and annotations, resulting in a custom phylogeny suited to the user's needs. Such a system could become a sustainable community resource if implemented as a distributed system of loosely coupled parts that interact through clearly defined interfaces. Results: With the aim of building such a "phylotastic" system, the NESCent Hackathons, Interoperability, Phylogenies (HIP) working group recruited 2 dozen scientist-programmers to a weeklong programming hackathon in June 2012. During the hackathon (and a three-month follow-up period), 5 teams produced designs, implementations, documentation, presentations, and tests including: (1) a generalized scheme for integrating components; (2) proof-of-concept pruners and controllers; (3) a meta-API for taxonomic name resolution services; (4) a system for storing, finding, and retrieving phylogenies using semantic web technologies for data exchange, storage, and querying; (5) an innovative new service, DateLife.org, which synthesizes pre-computed, time-calibrated phylogenies to assign ages to nodes; and (6) demonstration projects. These outcomes are accessible via a public code repository (GitHub.com), a website (www.phylotastic.org), and a server image. Conclusions: Approximately 9 person-months of effort (centered on a software development hackathon) resulted in the design and implementation of proof-of-concept software for 4 core phylotastic components, 3 controllers, and 3 end-user demonstration tools. While these products have substantial limitations, they suggest considerable potential for a distributed system that makes phylogenetic knowledge readily accessible in computable form. Widespread use of phylotastic systems will create an electronic marketplace for sharing phylogenetic knowledge that will spur innovation in other areas of the ToL enterprise, such as annotation of sources and methods and third-party methods of quality assessment.NESCent (the National Evolutionary Synthesis Center)NSF EF-0905606iPlant Collaborative (NSF) DBI-0735191Biodiversity Synthesis Center (BioSync) of the Encyclopedia of LifeComputer Science

Estimating the cost‐effectiveness of intermittently scanned continuous glucose monitoring in adults with type 1 diabetes in England

We previously showed that intermittently scanned continuous glucose monitoring (isCGM) reduces HbA1c at 24 weeks compared with self-monitoring of blood glucose with finger pricking (SMBG) in adults with type 1 diabetes and high HbA1c levels (58-97 mmol/mol [7.5%-11%]). We aim to assess the economic impact of isCGM compared with SMBG. Participant-level baseline and follow-up health status (EQ-5D-5L) and within-trial healthcare resource-use data were collected. Quality-adjusted life-years (QALYs) were derived at 24 weeks, adjusting for baseline EQ-5D-5L. Participant-level costs were generated. Using the IQVIA CORE Diabetes Model, economic analysis was performed from the National Health Service perspective over a lifetime horizon, discounted at 3.5%. Within-trial EQ-5D-5L showed non-significant adjusted incremental QALY gain of 0.006 (95% CI: -0.007 to 0.019) for isCGM compared with SMBG and an adjusted cost increase of £548 (95% CI: 381-714) per participant. The lifetime projected incremental cost (95% CI) of isCGM was £1954 (-5108 to 8904) with an incremental QALY (95% CI) gain of 0.436 (0.195-0.652) resulting in an incremental cost-per-QALY of £4477. In all subgroups, isCGM had an incremental cost-per-QALY better than £20,000 compared with SMBG; for people with baseline HbA1c >75 mmol/mol (9.0%), it was cost-saving. Sensitivity analysis suggested that isCGM remains cost-effective if its effectiveness lasts for at least 7 years. While isCGM is associated with increased short-term costs, compared with SMBG, its benefits in lowering HbA1c will lead to sufficient long-term health-gains and cost-savings to justify costs, so long as the effect lasts into the medium term. [Abstract copyright: © 2023 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Lower Resting and Exercise-Induced Circulating Angiogenic Progenitors and Angiogenic T-Cells in Older Men

Ageing is associated with a dysfunctional endothelial phenotype, as well as reduced angiogenic capabilities. Exercise exerts beneficial effects on the cardiovascular system, possibly by increasing/maintaining the number and/or function of circulating angiogenic cells (CACs) that are known to decline with age. However, the relationship between cardiorespiratory fitness (CRF) and age related changes in frequency of CACs, as well as the exercise-induced responsiveness of CACs in older individuals has not yet been determined. One hundred and seven healthy male volunteers, aged 18-75 years, participated in the study 1. CRF was estimated using submaximal cycling ergometer test. Circulating endothelial progenitor cells (EPCs), angiogenic T-cells (TANG) and their CXCR4 cell surface receptor expression were enumerated by flow cytometry using peripheral blood samples obtained under resting conditions prior to the exercise test. Study 2 recruited 17 healthy males (8 young, 18-25yrs; 9 older, 60-75yrs) and these participants undertook a 30-minute cycling exercise bout at 70% V ?O2max, with CACs enumerated pre- and immediately post-exercise. Age was inversely associated with both CD34+ progenitor cells (r2=-0.140, p=0.000) and TANG (r2=-0.176, p=0.000) cells, as well as CXCR4-expressing CACs (CD34+, r2=-0.167, p=0.000; EPCs: r2=-0.098, p=0.001; TANG, r2=-0.053, p=0.015). However, after correcting for age, CRF had no relationship with either CAC subset. In addition, older individuals displayed attenuated exercise-induced increases in CD34+ progenitor cells, TANG, CD4+ TANG, and CD8+CXCR4+ TANG cells. Older men display lower CAC levels, which may contribute to increased CVD risk, and older adults display an impaired exercise-induced responsiveness of these cells

Flash glucose monitoring with the FreeStyle Libre 2 compared with self-monitoring of blood glucose in suboptimally controlled type 1 diabetes: the FLASH-UK randomised controlled trial protocol.

INTRODUCTION: Optimising glycaemic control in type 1 diabetes (T1D) remains challenging. Flash glucose monitoring with FreeStyle Libre 2 (FSL2) is a novel alternative to the current standard of care self-monitoring of blood glucose (SMBG). No randomised controlled trials to date have explored the potential benefits of FSL2 in T1D. We aim to assess the impact of FSL2 in people with suboptimal glycaemic control T1D in comparison with SMBG. METHODS: This open-label, multicentre, randomised (via stochastic minimisation), parallel design study conducted at eight UK secondary and primary care centres will aim to recruit 180 people age ≥16 years with T1D for >1 year and glycated haemoglobin (HbA1c) 7.5%-11%. Eligible participants will be randomised to 24 weeks of FSL2 (intervention) or SMBG (control) periods, after 2-week of blinded sensor wear. Participants will be assessed virtually or in-person owing to the COVID-19 pandemic. HbA1c will be measured at baseline, 12 and 24 weeks (primary outcome). Participants will be contacted at 4 and 12 weeks for glucose optimisation. Control participants will wear a blinded sensor during the last 2 weeks. Psychosocial outcomes will be measured at baseline and 24 weeks. Secondary outcomes include sensor-based metrics, insulin doses, adverse events and self-report psychosocial measures. Utility, acceptability, expectations and experience of using FSL2 will be explored. Data on health service resource utilisation will be collected. ANALYSIS: Efficacy analyses will follow intention-to-treat principle. Outcomes will be analysed using analysis of covariance, adjusted for the baseline value of the corresponding outcome, minimisation factors and other known prognostic factors. Both within-trial and life-time economic evaluations, informed by modelling from the perspective of the National Health Service setting, will be performed. ETHICS: The study was approved by Greater Manchester West Research Ethics Committee (reference 19/NW/0081). Informed consent will be sought from all participants. TRIAL REGISTRATION NUMBER: NCT03815006. PROTOCOL VERSION: 4.0 dated 29 June 2020.Diabetes U

Recurrent Hypoglycemia Is Associated with Loss of Activation in Rat Brain Cingulate Cortex

A subset of people with diabetes fail to mount defensive counterregulatory responses (CRR) to hypoglycemia. Although the mechanisms by which this occurs remain unclear, recurrent exposure to hypoglycemia may be an important etiological factor. We hypothesized that loss of CRR to recurrent exposure to hypoglycemia represents a type of stress desensitization, in which limbic brain circuitry involved in modulating stress responses might be implicated. Here, we compared activation of limbic brain regions associated with stress desensitization during acute hypoglycemia (AH) and recurrent hypoglycemia (RH). Healthy Sprague Dawley rats were exposed to either acute or recurrent 3-d hypoglycemia. We also examined whether changes in neuronal activation were caused directly by the CRR itself by infusing epinephrine, glucagon, and corticosterone without hypoglycemia. AH increased neuronal activity as quantified by c-fos immunoreactivity (FOS-IR) in the cingulate cortex and associated ectorhinal and perirhinal cortices but not in an adjacent control area (primary somatosensory cortex). FOS-IR was not observed after hormone infusion, suggesting that AH-associated activation was caused by hypoglycemia rather than by CRR. Importantly, AH FOS-IR activation was significantly blunted in rats exposed to RH. In conclusion, analogous with other models of stress habituation, activation in the cingulate cortex and associated brain areas is lost with exposure to RH. Our data support the hypothesis that limbic brain areas may be associated with the loss of CRR to RH in diabetes

The PARP inhibitor AZD2461 provides insights into the role of PARP3 inhibition for both synthetic lethality and tolerability with chemotherapy in preclinical models

The PARP inhibitor AZD2461 was developed as a next-generation agent following olaparib, the first PARP inhibitor approved for cancer therapy. In BRCA1-deficient mouse models, olaparib resistance predominantly involves overexpression of P-glycoprotein,so AZD2461 was developed as a poor substrate for drug transporters. Here we demonstrate the efficacy of this compound against olaparib-resistant tumors that overexpress P-glycoprotein. In addition, AZD2461 was better tolerated in combination with chemotherapy than olaparib in mice, which suggests that AZD2461 could have significant advantages over olaparib in the clinic. However, this superior toxicity profile did not extend to rats. Investigations of this difference revealed a differential PARP3 inhibitory activity for each compound and a higher level of PARP3 expression in bone marrow cells from mice as compared with rats and humans. Our findings have implications for the use of mouse models to assess bone marrow toxicity for DNA-damaging agents and inhibitors of the DNA damage response. Finally, structural modeling of the PARP3-active site with different PARP inhibitors also highlights the potential to develop compounds with different PARP family member specificity profiles for optimal antitumor activity and tolerability