Oral glucose lowering with linagliptin and metformin compared with linagliptin alone as initial treatment in Asian patients with newly diagnosed type 2 diabetes and marked hyperglycemia: Subgroup analysis of a randomized clinical trial

Type 2 diabetes mellitus is an epidemic in Asia, yet clinical trials of glucose-lowering therapies often enroll predominantly Western populations. We explored the initial combination of metformin and linagliptin, a dipeptidyl peptidase-4 inhibitor, in newly diagnosed type 2 diabetes mellitus patients in Asia with marked hyperglycemia

Uplifting the voices of rural American Indian older adults to improve understanding of physical activity behavior

American Indian (AI) older adults experience pronounced health disparities and demonstrate one of the lowest levels of physical activity (PA) among racial and ethnic groups. Nearly half of AI older adults live in rural areas, indicating distinct challenges to participation in PA. Research to identify factors influencing PA in this population is missing from the literature, yet is critical to informing culturally relevant PA intervention development and implementation. The purpose was to identify barriers to and facilitators of PA among rural AI older adults using the ecological model and qualitative methods. A community-based approach was used to conduct semi-structured interviews with rural AI older adults. Interview questions were based on a multilevel ecological model. Content analysis was performed, using an iterative coding process to identify findings. The mean age of participants (n = 21) was 66 years. Barriers to and facilitators of PA were identified across ecological model levels. Barriers included factors such as caregiving and community responsibilities, lack of acceptable areas for walking, and overall lack of community-level support for older adult health. Facilitators included a personal connection to the land and ancestors through PA, multigenerational participation, and supportive tribal policies. This study addressed a gap in the literature by identifying barriers to and facilitators of PA among rural AI older adults, which can inform PA intervention development. With barriers and facilitators identified by AI older adults themselves, the voices of those directly affected are uplifted to shape efforts toward addressing longstanding health disparities through relevant public health interventions.Ye

Guiding principles for determining work shift duration and addressing the effects of work shift duration on performance, safety, and health

The article of record as published may be found at http://dx.doi.org/10.1093/sleep/zsab161Risks associated with fatigue that accumulates during work shifts have historically been managed through working time arrangements that specify fixed maximum durations of work shifts and minimum durations of time off. By themselves, such arrangements are not sufficient to curb risks to performance, safety, and health caused by misalignment between work schedules and the biological regulation of waking alertness and sleep. Science-based approaches for determining shift duration and mitigating associated risks, while addressing operational needs, require: 1) a recognition of the factors contributing to fatigue and fatigue-related risks; 2) an understanding of evidence-based countermeasures that may reduce fatigue and/or fatigue-related risks; and 3) an informed approach to selecting workplace-specific strategies for managing work hours. We propose a series of guiding principles to assist stakeholders with designing a shift duration decision-making process that effectively balances the need to meet operational demands with the need to manage fatigue-related risks.Academy of Sleep Medicine (AASM)Sleep Research Societ

Locus-Specific Ribosomal RNA Gene Silencing in Nucleolar Dominance

The silencing of one parental set of rRNA genes in a genetic hybrid is an epigenetic phenomenon known as nucleolar dominance. We showed previously that silencing is restricted to the nucleolus organizer regions (NORs), the loci where rRNA genes are tandemly arrayed, and does not spread to or from neighboring protein-coding genes. One hypothesis is that nucleolar dominance is the net result of hundreds of silencing events acting one rRNA gene at a time. A prediction of this hypothesis is that rRNA gene silencing should occur independent of chromosomal location. An alternative hypothesis is that the regulatory unit in nucleolar dominance is the NOR, rather than each individual rRNA gene, in which case NOR localization may be essential for rRNA gene silencing. To test these alternative hypotheses, we examined the fates of rRNA transgenes integrated at ectopic locations. The transgenes were accurately transcribed in all independent transgenic Arabidopsis thaliana lines tested, indicating that NOR localization is not required for rRNA gene expression. Upon crossing the transgenic A. thaliana lines as ovule parents with A. lyrata to form F1 hybrids, a new system for the study of nucleolar dominance, the endogenous rRNA genes located within the A. thaliana NORs are silenced. However, rRNA transgenes escaped silencing in multiple independent hybrids. Collectively, our data suggest that rRNA gene activation can occur in a gene-autonomous fashion, independent of chromosomal location, whereas rRNA gene silencing in nucleolar dominance is locus-dependent

Optimizing huddle engagement through leadership and problem-solving within primary care: A study protocol for a cluster randomized trial

Abstract Background Team-based care has been identified as a key component in transforming primary care. An important factor in implementing team-based care is the requirement for teams to have daily huddles. During huddles, the care team, comprising physicians, nurses, and administrative staff, come together to discuss their daily schedules, track problems, and develop countermeasures to fix these problems. However, the impact of these huddles on staff burnout over time and patient outcomes are not clear. Further, there are challenges to implementing huddles in fast-paced primary care clinics. We will test whether the impact of a behavioral intervention of leadership training and problem-solving during the daily huddling process will result in higher consistent huddling in the intervention arm and result in higher team morale, reduced burnout, and improved patient outcomes. Methods/design We will conduct a care-team-level cluster randomized trial within primary care practices in two Midwestern states. The intervention will comprise a 1-day training retreat for leaders of primary care teams, biweekly sessions between huddle optimization coaches and members of the primary care teams, as well as coaching site visits at 30 and 100 days post intervention. This behavioral intervention will be compared to standard care, in which care teams have huddles without any support or training. Surveys of primary care team members will be administered at baseline (prior to training), 100 days (for the intervention arm only), and 180 days to assess team dynamics. The primary outcome of this trial will be team morale. Secondary outcomes will assess the impact of this intervention on clinician burnout, patient satisfaction, and quality of care. Discussion This trial will provide evidence on the impact of a behavioral intervention to implement huddles as a key component of team-based care models. Knowledge gained from this trial will be critical to broader deployment and successful implementation of team-based care models. Trial registration Clinicaltrials.gov , NCT03062670 . Registered on 23 February 2017

The GALAH Survey: Chemical tagging and chrono-chemodynamics of accreted halo stars with GALAH+ DR3 and GaiaGaia eDR3

© 2021 The Author(s) Published by Oxford University Press on behalf of Royal Astronomical Society. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1093/mnras/stab3504Since the advent of $Gaia$ astrometry, it is possible to identify massive accreted systems within the Galaxy through their unique dynamical signatures. One such system, $Gaia$-Sausage-Enceladus (GSE), appears to be an early "building block" given its virial mass $> 10^{10}\,\mathrm{M_\odot}$ at infall ($z\sim1-3$). In order to separate the progenitor population from the background stars, we investigate its chemical properties with up to 30 element abundances from the GALAH+ Survey Data Release 3 (DR3). To inform our choice of elements for purely chemically selecting accreted stars, we analyse 4164 stars with low-$\alpha$ abundances and halo kinematics. These are most different to the Milky Way stars for abundances of Mg, Si, Na, Al, Mn, Fe, Ni, and Cu. Based on the significance of abundance differences and detection rates, we apply Gaussian mixture models to various element abundance combinations. We find the most populated and least contaminated component, which we confirm to represent GSE, contains 1049 stars selected via [Na/Fe] vs. [Mg/Mn] in GALAH+ DR3. We provide tables of our selections and report the chrono-chemodynamical properties (age, chemistry, and dynamics). Through a previously reported clean dynamical selection of GSE stars, including $30 < \sqrt{J_R~/~\mathrm{kpc\,km\,s^{-1}}} < 55$, we can characterise an unprecedented 24 abundances of this structure with GALAH+ DR3. Our chemical selection allows us to prevent circular reasoning and characterise the dynamical properties of the GSE, for example mean $\sqrt{J_R~/~\mathrm{kpc\,km\,s^{-1}}} = 26_{-14}^{+9}$. We find only $(29\pm1)\%$ of the GSE stars within the clean dynamical selection region. Our methodology will improve future studies of accreted structures and their importance for the formation of the Milky Way.Peer reviewedFinal Accepted Versio

Rat model of metastatic breast cancer monitored by MRI at 3 tesla and bioluminescence imaging with histological correlation

<p>Abstract</p> <p>Background</p> <p>Establishing a large rodent model of brain metastasis that can be monitored using clinically relevant magnetic resonance imaging (MRI) techniques is challenging. Non-invasive imaging of brain metastasis in mice usually requires high field strength MR units and long imaging acquisition times. Using the brain seeking MDA-MB-231BR transfected with luciferase gene, a metastatic breast cancer brain tumor model was investigated in the nude rat. Serial MRI and bioluminescence imaging (BLI) was performed and findings were correlated with histology. Results demonstrated the utility of multimodality imaging in identifying unexpected sights of metastasis and monitoring the progression of disease in the nude rat.</p> <p>Methods</p> <p>Brain seeking breast cancer cells MDA-MB-231BR transfected with firefly luciferase (231BRL) were labeled with ferumoxides-protamine sulfate (FEPro) and 1-3 × 10⁶cells were intracardiac (IC) injected. MRI and BLI were performed up to 4 weeks to monitor the early breast cancer cell infiltration into the brain and formation of metastases. Rats were euthanized at different time points and the imaging findings were correlated with histological analysis to validate the presence of metastases in tissues.</p> <p>Results</p> <p>Early metastasis of the FEPro labeled 231BRL were demonstrated onT2*-weighted MRI and BLI within 1 week post IC injection of cells. Micro-metastatic tumors were detected in the brain on T2-weighted MRI as early as 2 weeks post-injection in greater than 85% of rats. Unexpected skeletal metastases from the 231BRL cells were demonstrated and validated by multimodal imaging. Brain metastases were clearly visible on T2 weighted MRI by 3-4 weeks post infusion of 231BRL cells, however BLI did not demonstrate photon flux activity originating from the brain in all animals due to scattering of the photons from tumors.</p> <p>Conclusion</p> <p>A model of metastatic breast cancer in the nude rat was successfully developed and evaluated using multimodal imaging including MRI and BLI providing the ability to study the temporal and spatial distribution of metastases in the brain and skeleton.</p

Neutrophils incite and macrophages avert electrical storm after myocardial infarction

Sudden cardiac death, arising from abnormal electrical conduction, occurs frequently in patients with coronary heart disease. Myocardial ischemia simultaneously induces arrhythmia and massive myocardial leukocyte changes. In this study, we optimized a mouse model in which hypokalemia combined with myocardial infarction triggered spontaneous ventricular tachycardia in ambulatory mice, and we showed that major leukocyte subsets have opposing effects on cardiac conduction. Neutrophils increased ventricular tachycardia via lipocalin-2 in mice, whereas neutrophilia associated with ventricular tachycardia in patients. In contrast, macrophages protected against arrhythmia. Depleting recruited macrophages in Ccr2−/− mice or all macrophage subsets with Csf1 receptor inhibition increased both ventricular tachycardia and fibrillation. Higher arrhythmia burden and mortality in Cd36−/− and Mertk−/− mice, viewed together with reduced mitochondrial integrity and accelerated cardiomyocyte death in the absence of macrophages, indicated that receptor-mediated phagocytosis protects against lethal electrical storm. Thus, modulation of leukocyte function provides a potential therapeutic pathway for reducing the risk of sudden cardiac death

A combined genome-wide linkage and association approach to find susceptibility loci for platelet function phenotypes in European American and African American families with coronary artery disease

<p>Abstract</p> <p>Background</p> <p>The inability of aspirin (ASA) to adequately suppress platelet aggregation is associated with future risk of coronary artery disease (CAD). Heritability studies of agonist-induced platelet function phenotypes suggest that genetic variation may be responsible for ASA responsiveness. In this study, we leverage independent information from genome-wide linkage and association data to determine loci controlling platelet phenotypes before and after treatment with ASA.</p> <p>Methods</p> <p>Clinical data on 37 agonist-induced platelet function phenotypes were evaluated before and after a 2-week trial of ASA (81 mg/day) in 1231 European American and 846 African American healthy subjects with a family history of premature CAD. Principal component analysis was performed to minimize the number of independent factors underlying the covariance of these various phenotypes. Multi-point sib-pair based linkage analysis was performed using a microsatellite marker set, and single-SNP association tests were performed using markers from the Illumina 1 M genotyping chip from deCODE Genetics, Inc. All analyses were performed separately within each ethnic group.</p> <p>Results</p> <p>Several genomic regions appear to be linked to ASA response factors: a 10 cM region in African Americans on chromosome 5q11.2 had several STRs with suggestive (p-value < 7 × 10^-4) and significant (p-value < 2 × 10^-5) linkage to post aspirin platelet response to ADP, and ten additional factors had suggestive evidence for linkage (p-value < 7 × 10^-4) to thirteen genomic regions. All but one of these factors were aspirin <it>response </it>variables. While the strength of genome-wide SNP association signals for factors showing evidence for linkage is limited, especially at the strict thresholds of genome-wide criteria (N = 9 SNPs for 11 factors), more signals were considered significant when the association signal was weighted by evidence for linkage (N = 30 SNPs).</p> <p>Conclusions</p> <p>Our study supports the hypothesis that platelet phenotypes in response to ASA likely have genetic control and the combined approach of linkage and association offers an alternative approach to prioritizing regions of interest for subsequent follow-up.</p

VapC Toxins from Mycobacterium tuberculosis Are Ribonucleases that Differentially Inhibit Growth and Are Neutralized by Cognate VapB Antitoxins

The chromosome of Mycobacterium tuberculosis (Mtb) encodes forty seven toxin-antitoxin modules belonging to the VapBC family. The role of these modules in the physiology of Mtb and the function(s) served by their expansion are unknown. We investigated ten vapBC modules from Mtb and the single vapBC from M. smegmatis. Of the Mtb vapCs assessed, only Rv0549c, Rv0595c, Rv2549c and Rv2829c were toxic when expressed from a tetracycline-regulated promoter in M. smegmatis. The same genes displayed toxicity when conditionally expressed in Mtb. Toxicity of Rv2549c in M. smegmatis correlated with the level of protein expressed, suggesting that the VapC level must exceed a threshold for toxicity to be observed. In addition, the level of Rv2456 protein induced in M. smegmatis was markedly lower than Rv2549c, which may account for the lack of toxicity of this and other VapCs scored as ‘non-toxic’. The growth inhibitory effects of toxic VapCs were neutralized by expression of the cognate VapB as part of a vapBC operon or from a different chromosomal locus, while that of non-cognate antitoxins did not. These results demonstrated a specificity of interaction between VapCs and their cognate VapBs, a finding corroborated by yeast two-hybrid analyses. Deletion of selected vapC or vapBC genes did not affect mycobacterial growth in vitro, but rendered the organisms more susceptible to growth inhibition following toxic VapC expression. However, toxicity of ‘non-toxic’ VapCs was not unveiled in deletion mutant strains, even when the mutation eliminated the corresponding cognate VapB, presumably due to insufficient levels of VapC protein. Together with the ribonuclease (RNase) activity demonstrated for Rv0065 and Rv0617 – VapC proteins with similarity to Rv0549c and Rv3320c, respectively – these results suggest that the VapBC family potentially provides an abundant source of RNase activity in Mtb, which may profoundly impact the physiology of the organism