Cardiac fibrosis in aging mice

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains, we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10(-13)) and Chr 4 at 122 Mb (P < 10(-11)) and 134 Mb (P < 10(-7)). At the Chr 15 locus, Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximately 6 Mb away from the Dyscalc 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single-nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits.The authors thank Jesse Hammer and Josiah Raddar for technical assistance. Research reported in this publication was supported by the Ellison Medical Foundation, Parker B. Francis Foundation, and the National Institutes of Health (R01AR055225 and K01AR064766). Mouse colonies were supported by the National Institutes of Health under Award Number AG025707 for the Jackson Aging Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Jackson Laboratory Shared Scientific Services were supported in part by a Basic Cancer Center Core Grant from the National Cancer Institute (CA34196).This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00335-016-9634-

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p&lt;0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (&lt;1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (&lt;1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Gender differences in substance use treatment utilization in the year prior to deployment in Army service members

Although military men have heavier drinking patterns, military women experience equal or higher rates of dependence symptoms and similar rates of alcohol-related problems as men at lower levels of consumption. Thus, gender may be important for understanding substance use treatment (SUT) utilization before deployment. Military health system data were analyzed to examine gender differences in both substance use diagnosis (SUDX) and SUT in 152,447 Army service members returning from deployments in FY2010. Propensity score analysis of probability of SUDX indicated that women had lower odds (AOR: 0.91, 95% CI: 0.86-0.96) of military lifetime SUDX. After adjusting for lifetime SUDX using propensity score analysis, multivariate regression found women had substantially lower odds (AOR: 0.61; 95% CI: 0.54-0.70) of using SUT the year prior to deployment. Findings suggest gender disparities in military-provided SUT and a need to consider whether military substance use assessment protocols are sensitive to gender differences

The impact of behavioral and mental health risk assessments on goal setting in primary care.

Patient-centered health risk assessments (HRAs) that screen for unhealthy behaviors, prioritize concerns, and provide feedback may improve counseling, goal setting, and health. To evaluate the effectiveness of routinely administering a patient-centered HRA, My Own Health Report, for diet, exercise, smoking, alcohol, drug use, stress, depression, anxiety, and sleep, 18 primary care practices were randomized to ask patients to complete My Own Health Report (MOHR) before an office visit (intervention) or continue usual care (control). Intervention practice patients were more likely than control practice patients to be asked about each of eight risks (range of differences 5.3-15.8&nbsp;%, p &lt; 0.001), set goals for six risks (range of differences 3.8-16.6&nbsp;%, p &lt; 0.01), and improve five risks (range of differences 5.4-13.6&nbsp;%, p &lt; 0.01). Compared to controls, intervention patients felt clinicians cared more for them and showed more interest in their concerns. Patient-centered health risk assessments improve screening and goal setting.Trial RegistrationClinicaltrials.gov identifier: NCT01825746

Behavioral and mental health risk factor profiles among diverse primary care patients.

Behavioral and mental health risk factors are prevalent among primary care patients and contribute substantially to premature morbidity and mortality and increased health care utilization and costs. Although prior studies have found most adults screen positive for multiple risk factors, limited research has attempted to identify factors that most commonly co-occur, which may guide future interventions. The purpose of this study was to identify subgroups of primary care patients with co-occurring risk factors and to examine sociodemographic characteristics associated with these subgroups. We assessed 12 behavioral health risk factors in a sample of adults (n=1628) receiving care from nine primary care practices across six U.S. states in 2013. Using latent class analysis, we identified four distinct patient subgroups: a 'Mental Health Risk' class (prevalence=14%; low physical activity, high stress, depressive symptoms, anxiety, and sleepiness), a 'Substance Use Risk' class (29%; highest tobacco, drug, alcohol use), a 'Dietary Risk' class (29%; high BMI, poor diet), and a 'Lower Risk' class (27%). Compared to the Lower Risk class, patients in the Mental Health Risk class were younger and less likely to be Latino/Hispanic, married, college educated, or employed. Patients in the Substance Use class tended to be younger, male, African American, unmarried, and less educated. African Americans were over 7 times more likely to be in the Dietary Risk versus Lower Risk class (OR 7.7, 95% CI 4.0-14.8). Given the heavy burden of behavioral health issues in primary care, efficiently addressing co-occurring risk factors in this setting is critical

Behavioral and mental health risk factor profiles among diverse primary care patients.

Behavioral and mental health risk factors are prevalent among primary care patients and contribute substantially to premature morbidity and mortality and increased health care utilization and costs. Although prior studies have found most adults screen positive for multiple risk factors, limited research has attempted to identify factors that most commonly co-occur, which may guide future interventions. The purpose of this study was to identify subgroups of primary care patients with co-occurring risk factors and to examine sociodemographic characteristics associated with these subgroups. We assessed 12 behavioral health risk factors in a sample of adults (n=1628) receiving care from nine primary care practices across six U.S. states in 2013. Using latent class analysis, we identified four distinct patient subgroups: a 'Mental Health Risk' class (prevalence=14%; low physical activity, high stress, depressive symptoms, anxiety, and sleepiness), a 'Substance Use Risk' class (29%; highest tobacco, drug, alcohol use), a 'Dietary Risk' class (29%; high BMI, poor diet), and a 'Lower Risk' class (27%). Compared to the Lower Risk class, patients in the Mental Health Risk class were younger and less likely to be Latino/Hispanic, married, college educated, or employed. Patients in the Substance Use class tended to be younger, male, African American, unmarried, and less educated. African Americans were over 7 times more likely to be in the Dietary Risk versus Lower Risk class (OR 7.7, 95% CI 4.0-14.8). Given the heavy burden of behavioral health issues in primary care, efficiently addressing co-occurring risk factors in this setting is critical

Absence of HBV and HCV, HTLV-I and -II, and human herpes virus-8 activation after allogeneic RBC transfusion in patients with advanced HIV-1 infection.

BACKGROUND:The Viral Activation Transfusion Study was a prospective, randomized, double-blind comparison of transfusion with WBC-reduced versus non-WBC-reduced RBCs to HIV+ patients. The primary study characterized the effect of transfusion on HIV and CMV activation by monitoring viral load changes. The present study analyzed HBV, HCV, HTLV-I and -II, and human herpes virus-8 (HHV-8) viral load before and after transfusion to evaluate the further hypothesis that global immune stimulation following allogeneic RBC transfusion results in activation and increased viral proliferation of chronic viral infections other than HIV and CMV. STUDY DESIGN AND METHODS:Baseline samples from 519 to 523 subjects were screened for HBV, HCV, HTLV-I and -II, and HHV-8 infection, and baseline, serial weekly, and quarterly blood samples from infected subjects in the non-WBC-reduced arm were evaluated for changes from baseline in viral nucleic acid and ALT levels. RESULTS:Seroprevalence of HBV, HCV, HTLV-I and -II, and HHV-8 was 68, 25, 5, and 30 percent, respectively. No significant induction of HBV, HCV, HHV-8, or HTLV-I and -II viral replication following allogeneic transfusion of non-WBC-reduced blood was observed. A significant, albeit small, association was observed between transfusion and ALT. CONCLUSIONS:Based on these results and our previous finding that no adverse effect on HIV and CMV viral load and disease progression results from allogeneic transfusion, no evidence is found to support the selective use of WBC-reduced blood components for HIV-infected patients