Comparative analysis of vaginal misoprostol 400 and 600 single dose for second-trimester termination of pregnancy-a prospective randomized trial

Background: This study was done to compare two dosing schedules of tablet misoprostol single dose 600 µg (M600) versus multiple doses 400 µg (M400), kept per vaginally for second termination of pregnancy and to analyze induction to abortion time, side effects, and failure to achieve termination of pregnancy. Methods: Women admitted for second-trimester pregnancy termination were considered. Inclusion and exclusion criteria were followed. The women were randomized into two groups, with one group receiving single dose of M600 per vaginal and the other one multiple doses of M400, and the two groups were compared in their outcomes. Results: In the present study no statistical significance was found between the two dosing regimens with regard to induction abortion interval, post-expulsion need for suction, and evacuation. Conclusions: The study revealed that the dose between M400 and M600 has not shown significance compared with two dosing regimens. Single dose M600 can be considered for second-trimester pregnancy termination due to better compliance

Use of Complementary and Alternative Medicine for Work Related Musculoskeletal Disorders Associated with Job Contentment in Dental Professionals: Indian Outlook

Background: High prevalence rates of work-related musculoskeletal disorders (WRMSD) among dentists have been reported. Complementary and alternative medicine (CAM) therapies can be helpful in managing and preventing work-related musculoskeletal disorders. The purpose of this study was to determine if dental professionals are using CAM for work-related musculoskeletal disorders. Who have greater job satisfaction: dentist who uses Complementary and alternative medicine (CAM) or conventional therapy (CT) as a treatment modality for WRMSDMethod: Dentists who registered in Uttar Pradesh state, India under Indian Dental Council, Uttar Pradesh branch (n=1134) were surveyed. Data were analyzed using univariate and bivariate analyses and logistic regression.Result: A response rate of 53% (n=601) was obtained, revealing that 82% (n=487) of the respondents suffered from work-related musculoskeletal disorders. The use of complementary and alternative medicine or conventional therapy was reported among 80% (n=390) of the dentists with work-related musculoskeletal disorders. Complementary and alternative medicine users reported greater overall health compared to conventional therapy users (P<0.001). Of those with work-related musculoskeletal disorders, 35.5% (n=172) considered a career change for once, and 4.0% (n=19) reported having left dentistry.Conclusion: Complementary and alternative medicine therapies may improve quality of life, reduce work disruptions and enhance job satisfaction for dentists who suffer from work-related musculoskeletal disorders. It is important that dentists incorporate complementary and alternative medicine strategies into practice to facilitate musculoskeletal health that will enable longer and healthier careers, increase productivity, provide safer workplace and prevent musculoskeletal disorders.Keywords: CAM, dentist, musculoskeletal disorder

Predicting suicidal behavior among Indian adults using childhood trauma, mental health questionnaires and machine learning cascade ensembles

Among young adults, suicide is India's leading cause of death, accounting for an alarming national suicide rate of around 16%. In recent years, machine learning algorithms have emerged to predict suicidal behavior using various behavioral traits. But to date, the efficacy of machine learning algorithms in predicting suicidal behavior in the Indian context has not been explored in literature. In this study, different machine learning algorithms and ensembles were developed to predict suicide behavior based on childhood trauma, different mental health parameters, and other behavioral factors. The dataset was acquired from 391 individuals from a wellness center in India. Information regarding their childhood trauma, psychological wellness, and other mental health issues was acquired through standardized questionnaires. Results revealed that cascade ensemble learning methods using a support vector machine, decision trees, and random forest were able to classify suicidal behavior with an accuracy of 95.04% using data from childhood trauma and mental health questionnaires. The study highlights the potential of using these machine learning ensembles to identify individuals with suicidal tendencies so that targeted interinterventions could be provided efficiently.Comment: 11 pages, presnted at the 4th International Conference on Frontiers in Computing and Systems (COMSYS 2023), Himachal Pradesh, October 202

Injury Due to Mechanical Falls: Future Directions in Gender-specific Surveillance, Screening, and Interventions in Emergency Department Patients.

The Centers for Disease Control and Prevention report that among older adults (≥65 years), falls are the leading cause of injury-related death. Fall-related fractures among older women are more than twice as frequent as those for men. Gender-specific evidence-based fall prevention strategy and intervention studies show that improved patient-centered outcomes are elusive. There is a paucity of emergency medicine literature on the topic. As part of the 2014 Academic Emergency Medicine (AEM) consensus conference on Gender-Specific Research in Emergency Care: Investigate, Understand, and Translate How Gender Affects Patient Outcomes, a breakout group convened to generate a research agenda on priority questions to be answered on this topic. The consensus-based priority research agenda is presented in this article

Spatial and Functional Distribution of MYBPC3 Pathogenic Variants and Clinical Outcomes in Patients with Hypertrophic Cardiomyopathy

Background - Pathogenic variants in MYBPC3, encoding cardiac MyBP-C, are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped HCM cohorts have precluded detailed genotype-phenotype correlations. Methods - Patients with HCM and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Variant types and locations were analyzed, morphologic severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, LVAD/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro. Results - Among 4,756 genotyped HCM patients in SHaRe, 1,316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or non-truncating (N=22 unique variants, 191 patients) variants in MYBPC3. Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5' - 3' quartiles or by founder variant subgroup). Non-truncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, p<0.001 vs. gnomAD common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ~90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type. Conclusions - Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Non-truncating MYBPC3 pathogenic variants are regionally clustered, and a subset also cause loss-of-function through failure of myofilament incorporation and rapid degradation. Cardiac morphology and clinical outcomes are similar in patients with truncating vs. non-truncating variants

Characterization of Leishmania donovani Aquaporins Shows Presence of Subcellular Aquaporins Similar to Tonoplast Intrinsic Proteins of Plants

Leishmania donovani, a protozoan parasite, resides in the macrophages of the mammalian host. The aquaporin family of proteins form important components of the parasite-host interface. The parasite-host interface could be a potential target for chemotherapy. Analysis of L. major and L. infantum genomes showed the presence of five aquaporins (AQPs) annotated as AQP9 (230aa), AQP putative (294aa), AQP-like protein (279aa), AQP1 (314aa) and AQP-like protein (596aa). We report here the structural modeling, localization and functional characterization of the AQPs from L. donovani. LdAQP1, LdAQP9, LdAQP2860 and LdAQP2870 have the canonical NPA-NPA motifs, whereas LdAQP putative has a non-canonical NPM-NPA motif. In the carboxyl terminal to the second NPA box of all AQPs except AQP1, a valine/alanine residue was found instead of the arginine. In that respect these four AQPs are similar to tonoplast intrinsic proteins in plants, which are localized to intracellular organelles. Confocal microscopy of L. donovani expressing GFP-tagged AQPs showed an intracellular localization of LdAQP9 and LdAQP2870. Real-time PCR assays showed expression of all aquaporins except LdAQP2860, whose level was undetectable. Three-dimensional homology modeling of the AQPs showed that LdAQP1 structure bears greater topological similarity to the aquaglyceroporin than to aquaporin of E. coli. The pore of LdAQP1 was very different from the rest in shape and size. The cavity of LdAQP2860 was highly irregular and undefined in geometry. For functional characterization, four AQP proteins were heterologously expressed in yeast. In the fps1Δ yeast cells, which lacked the key aquaglyceroporin, LdAQP1 alone displayed an osmosensitive phenotype indicating glycerol transport activity. However, expression of LdAQP1 and LdAQP putative in a yeast gpd1Δ strain, deleted for glycerol production, conferred osmosensitive phenotype indicating water transport activity or aquaporin function. Our analysis for the first time shows the presence of subcellular aquaporins and provides structural and functional characterization of aquaporins in Leishmania donovani

The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development

Type I diabetes is caused by loss of insulin-secreting beta cells. To identify novel, pharmacologically-targetable histone-modifying proteins that enhance beta cell production from pancreatic progenitors, we performed a screen for histone modifications induced by signal transduction pathways at key pancreatic genes. The screen led us to investigate the temporal dynamics of ser-28 phosphorylated histone H3 (H3S28ph) and its upstream kinases, MSK1 and MSK2 (MSK1/2). H3S28ph and MSK1/2 were enriched at the key endocrine and acinar promoters in E12.5 multipotent pancreatic progenitors. Pharmacological inhibition of MSK1/2 in embryonic pancreatic explants promoted the specification of endocrine fates, including the beta-cell lineage, while depleting acinar fates. Germline knockout of both Msk isoforms caused enhancement of alpha cells and a reduction in acinar differentiation, while monoallelic loss of Msk1 promoted beta cell mass. Our screen of chromatin state dynamics can be applied to other developmental contexts to reveal new pathways and approaches to modulate cell fates

Nano-Stenciled RGD-Gold Patterns That Inhibit Focal Contact Maturation Induce Lamellipodia Formation in Fibroblasts

Cultured fibroblasts adhere to extracellular substrates by means of cell-matrix adhesions that are assembled in a hierarchical way, thereby gaining in protein complexity and size. Here we asked how restricting the size of cell-matrix adhesions affects cell morphology and behavior. Using a nanostencil technique, culture substrates were patterned with gold squares of a width and spacing between 250 nm and 2 µm. The gold was functionalized with RGD peptide as ligand for cellular integrins, and mouse embryo fibroblasts were plated. Limiting the length of cell-matrix adhesions to 500 nm or less disturbed the maturation of vinculin-positive focal complexes into focal contacts and fibrillar adhesions, as indicated by poor recruitment of α5-integrin. We found that on sub-micrometer patterns, fibroblasts spread extensively, but did not polarize. Instead, they formed excessive numbers of lamellipodia and a fine actin meshwork without stress fibers. Moreover, these cells showed aberrant fibronectin fibrillogenesis, and their speed of directed migration was reduced significantly compared to fibroblasts on 2 µm square patterns. Interference with RhoA/ROCK signaling eliminated the pattern-dependent differences in cell morphology. Our results indicate that manipulating the maturation of cell-matrix adhesions by nanopatterned surfaces allows to influence morphology, actin dynamics, migration and ECM assembly of adhering fibroblasts

A systematic genome-wide analysis of zebrafish protein-coding gene function

Since the publication of the human reference genome, the identities of specific genes associated with human diseases are being discovered at a rapid rate. A central problem is that the biological activity of these genes is often unclear. Detailed investigations in model vertebrate organisms, typically mice, have been essential for understanding the activities of many orthologues of these disease-associated genes. Although gene-targeting approaches1, 2, 3 and phenotype analysis have led to a detailed understanding of nearly 6,000 protein-coding genes3, 4, this number falls considerably short of the more than 22,000 mouse protein-coding genes5. Similarly, in zebrafish genetics, one-by-one gene studies using positional cloning6, insertional mutagenesis7, 8, 9, antisense morpholino oligonucleotides10, targeted re-sequencing11, 12, 13, and zinc finger and TAL endonucleases14, 15, 16, 17 have made substantial contributions to our understanding of the biological activity of vertebrate genes, but again the number of genes studied falls well short of the more than 26,000 zebrafish protein-coding genes18. Importantly, for both mice and zebrafish, none of these strategies are particularly suited to the rapid generation of knockouts in thousands of genes and the assessment of their biological activity. Here we describe an active project that aims to identify and phenotype the disruptive mutations in every zebrafish protein-coding gene, using a well-annotated zebrafish reference genome sequence18, 19, high-throughput sequencing and efficient chemical mutagenesis. So far we have identified potentially disruptive mutations in more than 38% of all known zebrafish protein-coding genes. We have developed a multi-allelic phenotyping scheme to efficiently assess the effects of each allele during embryogenesis and have analysed the phenotypic consequences of over 1,000 alleles. All mutant alleles and data are available to the community and our phenotyping scheme is adaptable to phenotypic analysis beyond embryogenesis