Antihyperglycemic Medications and Hypoglycemia in Older Adults with Diabetes

Background: In the last decade, several new antihyperglycemic medications have been approved to treat people with diabetes. However, the hypoglycemia risk of these medications in older adults in routine clinical practice remains unclear. Further, there is limited understanding as to how these medications are being prescribed to older adults in our region. Methods: We carried out retrospective, population-based studies of adults age 66 and older in Ontario, Canada using linked healthcare databases. We first investigated the real-world hypoglycemia risk of 2 antihyperglycemic medications – glyburide and modified-release gliclazide. In an ecological study, we then examined trends in antihyperglycemic medication prescriptions, and in this setting, investigated hospital encounters for hypoglycemia. Results: Initiating glyburide vs gliclazide as monotherapy or in the presence of metformin was associated with a significantly higher risk of a hospital encounter with hypoglycemia. Over the last decade, newer and safer antihyperglycemic medications have been prescribed to older adults in our region. In this setting, the overall percentage of patients with a hospital encounter with hypoglycemia has declined. Conclusions: Antihyperglycemic medications differ in their real-world hypoglycemia risk in older patients. In the setting of newer and safer antihyperglycemic medications, encounters for hypoglycemia have declined

Seasonal variation in hospital encounters with hypoglycaemia and hyperglycaemia

Aim To assess whether rates of hospital encounters with hypoglycaemia and hyperglycaemia display seasonal variation. Methods Time series analyses of the monthly rates of hospital encounters (emergency room visits or inpatient admissions) with hypoglycaemia and hyperglycaemia from 2003 to 2012 using linked healthcare databases in Ontario, Canada. Results Over the study period, there were 129 887 hypoglycaemia and 79 773 hyperglycaemia encounters. The characteristics of people at the time of their encounters were similar across the seasons in 2008 (median age 68 years for hypoglycaemia encounters and 53 years for hyperglycaemia encounters; 50% female; 90% with diabetes). We observed moderate seasonality in both types of encounters (R2 autoregression coefficient 0.58 for hypoglycaemia; 0.59 for hyperglycaemia). The rate of hypoglycaemia encounters appeared to peak between April and June, when on average, there was an additional 49 encounters per month (0.36 encounters per 100 000 persons per month) compared with the other calendar months (5% increase). The rate of hyperglycaemia encounters appeared to peak in January, when on average, there was an additional 69 encounters per month (0.50 encounters per 100 000 persons per month) compared with the other calendar months (11% increase). Conclusions In our region, there is seasonal variation in the rate of hospital encounters with hypoglycaemia and hyperglycaemia. Our findings may help to highlight periods of vulnerability for people, may inform future epidemiological studies and may aid in the appropriate planning of healthcare resources

The moderating effect of cortisol and dehydroepiandrosterone on the relation between sleep and depression or burnout

For poor sleep quality (SQ) as well as major depressive disorder (MDD) and burnout, a dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been identified. Although poor SQ is often reported as an early symptom of MDD or burnout, it is not clear whether HPA axis-related hormones can influence the association between SQ and MDD or burnout. This manuscript addresses this question by examining HPA axis-related hormones as potential moderators influencing the association between SQ and MDD or burnout. In the fourth annual examination wave of the Dresden Burnout Study, we measured general SQ (including sleep duration and efficiency), depressive and burnout symptoms, and obtained hair samples for quantification of long-term integrated steroid concentrations (cortisol [hC], cortisone [hCn], dehydroepiandrosterone [hDHEA]) from 462 participants (67% female). Data on SQ, depressive and burnout symptoms were available from 342 participants from the preceding examination wave (average time span between examinations 13.2 months). Cross-sectional analyses showed that the negative association between sleep duration and depressive symptoms was buffered by higher levels of hC, and hCn, whereas the negative association between sleep duration and burnout symptoms was buffered by higher levels of hDHEA. The negative association between sleep efficiency and burnout symptoms was intensified by higher levels of hC and hC/hCn ratio and the negative association between general SQ and burnout symptoms was intensified by higher levels of hC/hCn ratio. With regard to longitudinal data, a significant interaction effect between sleep duration and hC/hCn ratio could be detected for burnout symptoms. Our results suggest opposed moderation effects of hair glucocorticoids on the association between SQ and depressive or burnout symptoms. This points toward opposed glucocorticoid receptor functioning in depression and burnout. To fully elucidate the negative consequences of poor SQ on MDD and burnout, the complex underlying mechanisms of action including HPA axis-related hormones need to be investigated in MDD and burnout separately

High Temperatures and Cardiovascular-Related Morbidity: A Scoping Review.

The primary objective of this review was to synthesize studies assessing the relationships between high temperatures and cardiovascular disease (CVD)-related hospital encounters (i.e., emergency department (ED) visits or hospitalizations) in urban Canada and other comparable populations, and to identify areas for future research. Ovid MEDLINE, EMBASE, CINAHL, Cochrane Database of Systematic Reviews, and Scopus were searched between 6 April and 11 April 2020, and on 21 March 2021, to identify articles examining the relationship between high temperatures and CVD-related hospital encounters. Studies involving patients with pre-existing CVD were also included. English language studies from North America and Europe were included. Twenty-two articles were included in the review. Studies reported an inconsistent association between high temperatures and ischemic heart disease (IHD), heart failure, dysrhythmia, and some cerebrovascular-related hospital encounters. There was consistent evidence that high temperatures may be associated with increased ED visits and hospitalizations related to total CVD, hyper/hypotension, acute myocardial infarction (AMI), and ischemic stroke. Age, sex, and gender appear to modify high temperature-CVD morbidity relationships. Two studies examined the influence of pre-existing CVD on the relationship between high temperatures and morbidity. Pre-existing heart failure, AMI, and total CVD did not appear to affect the relationship, while evidence was inconsistent for pre-existing hypertension. There is inconsistent evidence that high temperatures are associated with CVD-related hospital encounters. Continued research on this topic is needed, particularly in the Canadian context and with a focus on individuals with pre-existing CVD

Evaluating the association between extreme heat and mortality in urban Southwestern Ontario using different temperature data sources

Urban areas have complex thermal distribution. We examined the association between extreme temperature and mortality in urban Ontario, using two temperature data sources: high-resolution and weather station data. We used distributed lag non-linear Poisson models to examine census division-specific temperature–mortality associations between May and September 2005–2012. We used random-effect multivariate meta-analysis to pool results, adjusted for air pollution and temporal trends, and presented risks at the 99th percentile compared to minimum mortality temperature. As additional analyses, we varied knots, examined associations using different temperature metrics (humidex and minimum temperature), and explored relationships using different referent values (most frequent temperature, 75th percentile of temperature distribution). Weather stations yielded lower temperatures across study months. U-shaped associations between temperature and mortality were observed using both high-resolution and weather station data. Temperature–mortality relationships were not statistically significant; however, weather stations yielded estimates with wider confidence intervals. Similar findings were noted in additional analyses. In urban environmental health studies, high-resolution temperature data is ideal where station observations do not fully capture population exposure or where the magnitude of exposure at a local level is important. If focused upon temperature–mortality associations using time series, either source produces similar temperature–mortality relationships

Higher-dose sitagliptin and the risk of congestive heart failure in older adults with CKD

Background and objectives Sitagliptin, a dipeptidylpeptidase-4 inhibitor, is commonlyprescribed to patientswith type 2 diabetes. As this drug is primarily eliminated by the kidney, a reduced dose is recommended for patients with CKD. Some evidence suggests that sitagliptin is associated with a higher risk of congestive heart failure, particularly at higher doses.Wecompare the 1-year risk of death or hospitalizationwith congestive heart failure in patients with CKD newly prescribed sitagliptin at \u3c50 versus ≤50 mg/d. Design, setting, participants, & measurements This population-based cohort study included older adults (\u3e66 years) with type 2 diabetes and an eGFR\u3c45 ml/min per 1.73 m2 (but not receiving dialysis) who were newly prescribed sitagliptin between 2010 and 2017 in Ontario, Canada. We used inverse probability of treatment weighting on the basis of propensity scores to balance baseline characteristics. The primary composite outcome was death or hospitalization with congestive heart failure. Secondary outcomes included hospitalization with pancreatitis or hypoglycemia, all-cause hospitalization, and glycemic control. Weighted hazard ratios were obtained using Cox proportional hazards regression, and 95%confidence intervalswere obtained using bootstrap variance estimators. Results Of 9215 patients, 6518 started sitagliptin at \u3e50 mg/d, and 2697 started sitagliptin at ≤50 mg/d. The 1-year risk of death or hospitalization with congestive heart failure did not differ significantly between groups (79 versus 126 events per 1000 person-years; weighted hazard ratio, 0.88; 95% confidence interval, 0.67 to 1.14); hospitalization with pancreatitis (weighted hazard ratio, 0.98; 95% confidence interval, 0.32 to 3.03) and hypoglycemia (weighted hazard ratio, 1.10; 95% confidence interval, 0.64 to 1.90) also did not differ significantly between groups. Patients starting sitagliptin at \u3e50 mg/d had lower mean glycated hemoglobin concentrations (weighted between-group difference, 20.12%; 95% confidence interval, 20.19 to 20.06) and a lower risk of allcause hospitalization (weighted hazard ratio, 0.81; 95% confidence interval, 0.66 to 0.98). Conclusions The risk of death or congestive heart failure was not higher in older adults with CKD starting sitagliptin at \u3e50 versus ≤50 mg/d

Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer.

To identify common alleles associated with different histotypes of epithelial ovarian cancer (EOC), we pooled data from multiple genome-wide genotyping projects totaling 25,509 EOC cases and 40,941 controls. We identified nine new susceptibility loci for different EOC histotypes: six for serous EOC histotypes (3q28, 4q32.3, 8q21.11, 10q24.33, 18q11.2 and 22q12.1), two for mucinous EOC (3q22.3 and 9q31.1) and one for endometrioid EOC (5q12.3). We then performed meta-analysis on the results for high-grade serous ovarian cancer with the results from analysis of 31,448 BRCA1 and BRCA2 mutation carriers, including 3,887 mutation carriers with EOC. This identified three additional susceptibility loci at 2q13, 8q24.1 and 12q24.31. Integrated analyses of genes and regulatory biofeatures at each locus predicted candidate susceptibility genes, including OBFC1, a new candidate susceptibility gene for low-grade and borderline serous EOC

Discovery of common and rare genetic risk variants for colorectal cancer.

To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.Goncalo R Abecasis has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. Heather Hampel performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, Inc., is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. Rachel Pearlman has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest

T cell phenotypes in COVID-19 - a living review

COVID-19 is characterized by profound lymphopenia in the peripheral blood, and the remaining T cells display altered phenotypes, characterized by a spectrum of activation and exhaustion. However, antigen-specific T cell responses are emerging as a crucial mechanism for both clearance of the virus and as the most likely route to long-lasting immune memory that would protect against re-infection. Therefore, T cell responses are also of considerable interest in vaccine development. Furthermore, persistent alterations in T cell subset composition and function post-infection have important implications for patients’ long-term immune function. In this review, we examine T cell phenotypes, including those of innate T cells, in both peripheral blood and lungs, and consider how key markers of activation and exhaustion correlate with, and may be able to predict, disease severity. We focus on SARS-CoV-2-specific T cells to elucidate markers that may indicate formation of antigen-specific T cell memory. We also examine peripheral T cell phenotypes in recovery and the likelihood of long-lasting immune disruption. Finally, we discuss T cell phenotypes in the lung as important drivers of both virus clearance and tissue damage. As our knowledge of the adaptive immune response to COVID-19 rapidly evolves, it has become clear that while some areas of the T cell response have been investigated in some detail, others, such as the T cell response in children remain largely unexplored. Therefore, this review will also highlight areas where T cell phenotypes require urgent characterisation

The role and uses of antibodies in COVID-19 infections: a living review

Coronavirus disease 2019 has generated a rapidly evolving field of research, with the global scientific community striving for solutions to the current pandemic. Characterizing humoral responses towards SARS-CoV-2, as well as closely related strains, will help determine whether antibodies are central to infection control, and aid the design of therapeutics and vaccine candidates. This review outlines the major aspects of SARS-CoV-2-specific antibody research to date, with a focus on the various prophylactic and therapeutic uses of antibodies to alleviate disease in addition to the potential of cross-reactive therapies and the implications of long-term immunity