Lean mass and peak bone mineral density.

ObjectivesThe association between body composition parameters and peak bone mineral density is not well documented. The aim of this study is to assess the relative contributions of lean mass and fat mass on peak bone mineral density (BMD).MethodsThe study involved 416 women and 334 men aged between 20 and 30 years who were participants in the population-based Vietnam Osteoporosis Study. Whole body composition parameters (eg, fat mass and lean mass) and BMD at the lumbar spine and femoral neck were measured by dual-energy X-ray absorptiometry. The association between lean mass and fat mass and BMD was analyzed by the linear regression model using the Least Absolute Shrinkage and Selection Operator (LASSO).ResultsPeak BMD in men was higher than women, and the difference was more pronounced at the femoral neck (average difference: 0.123 g/cm2; 95% confidence interval [CI] 0.105-0.141 g/cm2) than at the lumbar spine (average difference 0.019 g/cm2; 95% CI, 0.005-0.036 g/cm2). Results of LASSO regression indicated that lean mass was the only predictor of BMD for either men or women. Each kilogram increase in lean mass was associated with ∼0.01 g/cm2 increase in BMD. Lean mass alone explained 16% and 36% of variation in lumbar spine and femoral neck BMD, respectively.ConclusionsLean mass, not fat mass, is the main determinant of peak bone mineral density. This finding implies that good physical activity during adulthood can contribute to the maximization of peak bone mass during adulthood

Mechanography assessment of fall risk in older adults: the Vietnam Osteoporosis Study

Background Jumping mechanography is a technology for quantitatively assessing muscular function and balance in older adults. This study sought to define the association between jumping mechanography parameters and fall risk in Vietnamese individuals. Methods The study involved 375 women and 244 men aged 50 years and older, who were recruited from the general population in Ho Chi Minh City (Vietnam). The individuals had been followed for 2 years. At baseline, Esslinger Fitness index (EFI), jumping power, force, velocity of lower limbs, and the ability to maintain balance were measured by a Leonardo Mechanograph Ground Reaction Force system (Novotec Medical, Pforxheim, Germany). The incidence of falls during the follow-up period was ascertained from self-report. Logistic regression analysis was used to analyse the association between jumping mechanography parameters and fall risk. Results The average age of participants at baseline was 56.7 years (SD 5.85). During the 2 year follow-up, 92 falls were reported, making the incidence of fall at ~15% [95% confidence interval (CI), 12.1 to 18.2]. The incidence of fall increased with advancing age, and women had a higher incidence than men (17.6% vs. 10.7%; P = 0.024). In univariate analysis, maximal velocity [odds ratio (OR) 0.65; 95% CI, 0.52 to 0.82], maximal force (OR 0.83; 95% CI, 0.65 to 1.04), and maximal power (OR 0.68; 95% CI, 0.52 to 0.88) were each significantly associated with fall risk. EFI was not significantly associated with fall risk (OR 1.09; 95% CI, 0.86 to 1.39). However, in a multiple logistic regression model, greater maximum velocity was associated with lower odds of fall (OR 0.38; 95% CI, 0.16 to 0.92). Conclusions These data suggest that jumping mechanography is a useful tool for assessing fall risk in older adults of Vietnamese background

Dihydroisoxazole inhibitors of Anopheles gambiae seminal transglutaminase AgTG3

Background: Current vector-based malaria control strategies are threatened by the rise of biochemical and behavioural resistance in mosquitoes. Researching mosquito traits of immunity and fertility is required to find potential targets for new vector control strategies. The seminal transglutaminase AgTG3 coagulates male Anopheles gambiae seminal fluids, forming a ‘mating plug’ that is required for male reproductive success. Inhibitors of AgTG3 can be useful both as chemical probes of A. gambiae reproductive biology and may further the development of new chemosterilants for mosquito population control. Methods: A targeted library of 3-bromo-4,5-dihydroxoisoxazole inhibitors were synthesized and screened for inhibition of AgTG3 in a fluorescent, plate-based assay. Positive hits were tested for in vitro activity using cross-linking and mass spectrometry, and in vivo efficacy in laboratory mating assays. Results: A targeted chemical library was screened for inhibition of AgTG3 in a fluorescent plate-based assay using its native substrate, plugin. Several inhibitors were identified with IC50 < 10 μM. Preliminary structure-activity relationships within the library support the stereo-specificity and preference for aromatic substituents in the chemical scaffold. Both inhibition of plugin cross-linking and covalent modification of the active site cysteine of AgTG3 were verified. Administration of an AgTG3 inhibitor to A. gambiae males by intrathoracic injection led to a 15% reduction in mating plug transfer in laboratory mating assays. Conclusions: A targeted screen has identified chemical inhibitors of A. gambiae transglutaminase 3 (AgTG3). The most potent inhibitors are known inhibitors of human transglutaminase 2, suggesting a common binding pose may exist within the active site of both enzymes. Future efforts to develop additional inhibitors will provide chemical tools to address important biological questions regarding the role of the A. gambiae mating plug. A second use for transglutaminase inhibitors exists for the study of haemolymph coagulation and immune responses to wound healing in insects

Evolutionary Multi-Objective Design of SARS-CoV-2 Protease Inhibitor Candidates

Computational drug design based on artificial intelligence is an emerging research area. At the time of writing this paper, the world suffers from an outbreak of the coronavirus SARS-CoV-2. A promising way to stop the virus replication is via protease inhibition. We propose an evolutionary multi-objective algorithm (EMOA) to design potential protease inhibitors for SARS-CoV-2's main protease. Based on the SELFIES representation the EMOA maximizes the binding of candidate ligands to the protein using the docking tool QuickVina 2, while at the same time taking into account further objectives like drug-likeliness or the fulfillment of filter constraints. The experimental part analyzes the evolutionary process and discusses the inhibitor candidates.Comment: 15 pages, 7 figures, submitted to PPSN 202

Using small molecules to facilitate exchange of bicarbonate and chloride anions across liposomal membranes

Bicarbonate is involved in a wide range of biological processes, which include respiration, regulation of intracellular pH and fertilization. In this study we use a combination of NMR spectroscopy and ion-selective electrode techniques to show that the natural product prodigiosin, a tripyrrolic molecule produced by microorganisms such as Streptomyces and Serratia, facilitates chloride/bicarbonate exchange (antiport) across liposomal membranes. Higher concentrations of simple synthetic molecules based on a 4,6-dihydroxyisophthalamide core are also shown to facilitate this antiport process. Although it is well known that proteins regulate Cl-/HCO3- exchange in cells, these results suggest that small molecules may also be able to regulate the concentration of these anions in biological systems

Block of death-receptor apoptosis protects mouse cytomegalovirus from macrophages and is a determinant of virulence in immunodeficient hosts.

The inhibition of death-receptor apoptosis is a conserved viral function. The murine cytomegalovirus (MCMV) gene M36 is a sequence and functional homologue of the human cytomegalovirus gene UL36, and it encodes an inhibitor of apoptosis that binds to caspase-8, blocks downstream signaling and thus contributes to viral fitness in macrophages and in vivo. Here we show a direct link between the inability of mutants lacking the M36 gene (ΔM36) to inhibit apoptosis, poor viral growth in macrophage cell cultures and viral in vivo fitness and virulence. ΔM36 grew poorly in RAG1 knockout mice and in RAG/IL-2-receptor common gamma chain double knockout mice (RAGγC(-/-)), but the depletion of macrophages in either mouse strain rescued the growth of ΔM36 to almost wild-type levels. This was consistent with the observation that activated macrophages were sufficient to impair ΔM36 growth in vitro. Namely, spiking fibroblast cell cultures with activated macrophages had a suppressive effect on ΔM36 growth, which could be reverted by z-VAD-fmk, a chemical apoptosis inhibitor. TNFα from activated macrophages synergized with IFNγ in target cells to inhibit ΔM36 growth. Hence, our data show that poor ΔM36 growth in macrophages does not reflect a defect in tropism, but rather a defect in the suppression of antiviral mediators secreted by macrophages. To the best of our knowledge, this shows for the first time an immune evasion mechanism that protects MCMV selectively from the antiviral activity of macrophages, and thus critically contributes to viral pathogenicity in the immunocompromised host devoid of the adaptive immune system

The script concordance test in radiation oncology: validation study of a new tool to assess clinical reasoning

<p>Abstract</p> <p>Background</p> <p>The Script Concordance test (SCT) is a reliable and valid tool to evaluate clinical reasoning in complex situations where experts' opinions may be divided. Scores reflect the degree of concordance between the performance of examinees and that of a reference panel of experienced physicians. The purpose of this study is to demonstrate SCT's usefulness in radiation oncology.</p> <p>Methods</p> <p>A 90 items radiation oncology SCT was administered to 155 participants. Three levels of experience were tested: medical students (n = 70), radiation oncology residents (n = 38) and radiation oncologists (n = 47). Statistical tests were performed to assess reliability and to document validity.</p> <p>Results</p> <p>After item optimization, the test comprised 30 cases and 70 questions. Cronbach alpha was 0.90. Mean scores were 51.62 (± 8.19) for students, 71.20 (± 9.45) for residents and 76.67 (± 6.14) for radiation oncologists. The difference between the three groups was statistically significant when compared by the Kruskall-Wallis test (p < 0.001).</p> <p>Conclusion</p> <p>The SCT is reliable and useful to discriminate among participants according to their level of experience in radiation oncology. It appears as a useful tool to document the progression of reasoning during residency training.</p

Religious Participation and DSM IV Major Depressive Disorder Among Black Caribbeans in the United States

This study examines the relationship between religious involvement and 12-month and lifetime DSM-IV major depressive disorder (MDD) within a nationally rep- resentative sample of Black Caribbean adults. MDD was assessed using the DSM-IV World Mental Health Com- posite International Diagnostic Interview (WMH-CIDI). Religious involvement included measures of religious coping, organizational and nonorganizational involvement, and subjective religiosity. Study findings indicate that religious involvement is associated with 12-month and lifetime prevalence of MDD. Multivariate relationships between religious involvement and MDD indicate lower prevalence of 12-month and lifetime MDD among persons who use religious coping and characterize themselves as being religious (for lifetime prevalence only); persons who frequently listen to religious radio programs report higher lifetime MDD. Lower rates of 12-month and lifetime MDD are noted for persons who attend religious services at least once a week (as compared to both higher and lower levels of attendance), indicating a curvilinear relationship. The findings are discussed in relation to previous research on religion and mental health concerns, conceptual models of the role of religion in mental health (e.g., prevention, resource mobilization) that specify multiple and often divergent pathways and mechanisms of religious effects on health outcomes, and the role of religion among Caribbean Blacks.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/107411/1/Religious Participation and DSM IV Major Depressive Disorder Among Black Caribbeans in the United States.pdfDescription of Religious Participation and DSM IV Major Depressive Disorder Among Black Caribbeans in the United States.pdf : Main articl

From evidence to best practice in the management of fractures of the distal radius in adults: working towards a research agenda

BACKGROUND: Fracture of the distal radius is a common clinical problem, particularly in older white women with osteoporosis. We report our work towards evidence-based and patient-centred care for adults with these injuries. METHODS: We developed a systematic programme of research that built on our systematic review of the evidence of effectiveness of treatment interventions for these fractures. We devised schemata showing 'typical' care pathways and identified over 100 patient management questions. These depicted the more important decisions taken when progressing along each care pathway. We compiled a comprehensive document summarising the evidence available for each decision point from our reviews of randomised trials of treatment interventions. Using these documents, we undertook a formal and structured consultation process involving key players, including a patient representative, to obtain their views on the available evidence and to establish a research agenda. The resulting feedback was then processed and interpreted, using systematic methods. RESULTS: Some evidence from 114 randomised trials was available for 31 of the 117 patient management questions. However, there was sufficient evidence to base some conclusions of effectiveness for particular interventions in only five of these. Though only 60% of those approached responded, the responses received from the consultation group were often comprehensive and provided important insights into treatment practice and policy. There was a clear acceptance of the aims of the project and, aside from some suggestions for the more explicit inclusion of secondary prevention and management of complications, of the care pathways scheme. Though some respondents stressed that randomised trials were not always appropriate, there was no direct overall criticism of the evidence document and underlying processes. We were able to identify important core themes that underpin management decisions and research from the feedback of the consultation exercise. CONCLUSIONS: Overall, this project is an important advance towards evidence-based and patient-centred management of adults with distal radial fractures. It exposes the serious deficiency in the available evidence but also provides a template for further action. As well as being a valuable basis for viewing and informing current practice, the insights gained from this project should inform a future research agenda