Multi-ancestry polygenic mechanisms of type 2 diabetes.

Type 2 diabetes (T2D) is a multifactorial disease with substantial genetic risk, for which the underlying biological mechanisms are not fully understood. In this study, we identified multi-ancestry T2D genetic clusters by analyzing genetic data from diverse populations in 37 published T2D genome-wide association studies representing more than 1.4 million individuals. We implemented soft clustering with 650 T2D-associated genetic variants and 110 T2D-related traits, capturing known and novel T2D clusters with distinct cardiometabolic trait associations across two independent biobanks representing diverse genetic ancestral populations (African, n = 21,906; Admixed American, n = 14,410; East Asian, n =2,422; European, n = 90,093; and South Asian, n = 1,262). The 12 genetic clusters were enriched for specific single-cell regulatory regions. Several of the polygenic scores derived from the clusters differed in distribution among ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a body mass index (BMI) of 30 kg m-2 in the European subpopulation and 24.2 (22.9-25.5) kg m-2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg m-2 in the East Asian group. Thus, these multi-ancestry T2D genetic clusters encompass a broader range of biological mechanisms and provide preliminary insights to explain ancestry-associated differences in T2D risk profiles.

The simultaneous occurrence of gestational diabetes and hypertensive disorders of pregnancy affects fetal growth and neonatal morbidity.

BACKGROUND: Gestational diabetes is associated with increased risk of hypertensive disorders of pregnancy, but there are limited data on fetal growth and neonatal outcomes when both conditions are present. OBJECTIVE: We evaluated the risk of abnormal fetal growth and neonatal morbidity in pregnancies with co-occurrence of gestational diabetes and hypertensive disorders of pregnancy. STUDY DESIGN: In a retrospective study of 47,093 singleton pregnancies, we compared the incidence of appropriate for gestational age birthweight in pregnancies affected by gestational diabetes alone, hypertensive disorders of pregnancy alone, or both gestational diabetes and hypertensive disorders of pregnancy with that in pregnancies affected by neither disorder using generalized estimating equations (covariates: maternal age, nulliparity, body mass index, insurance type, race, marital status, and prenatal care site). Secondary outcomes were large for gestational age birthweight, small for gestational age birthweight, and a neonatal morbidity composite outcome (stillbirth, hypoglycemia, hyperbilirubinemia, respiratory distress, encephalopathy, preterm delivery, neonatal death, and neonatal intensive care unit admission). RESULTS: The median (interquartile range) birthweight percentile in pregnancies with both gestational diabetes and hypertensive disorders of pregnancy (50 [24.0-78.0]; N=179) was similar to that of unaffected pregnancies (50 [27.0-73.0]; N=35,833). However, the absolute rate of appropriate for gestational age birthweight was lower for gestational diabetes/hypertensive disorders of pregnancy co-occurrence (78.2% vs 84.9% for unaffected pregnancies). Adjusted analyses showed decreased odds of appropriate for gestational age birthweight in pregnancies with both gestational diabetes and hypertensive disorders of pregnancy compared with unaffected pregnancies (adjusted odds ratio, 0.72 [95% confidence interval, 0.52-1.00]; P=.049), and in pregnancies complicated by gestational diabetes alone (adjusted odds ratio, 0.78 [0.68-0.89]; P<.001) or hypertensive disorders of pregnancy alone (adjusted odds ratio, 0.73 [0.66-0.81]; P<.001). The absolute risk of large for gestational age birthweight was greater in pregnancies with both gestational diabetes and hypertensive disorders of pregnancy (14.5%) than in unaffected pregnancies (8.2%), without apparent difference in the risk of small for gestational age birthweight (7.3% vs 6.9%). However, in adjusted models comparing pregnancies with gestational diabetes/hypertensive disorders of pregnancy co-occurrence with unaffected pregnancies, neither an association with large for gestational age birthweight (adjusted odds ratio, 1.33 [0.88-2.00]; P=.171) nor small for gestational age birthweight (adjusted odds ratio, 1.32 [0.80-2.19]; P=.293) reached statistical significance. Gestational diabetes/hypertensive disorders of pregnancy co-occurrence carried an increased risk of neonatal morbidity that was greater than that observed with either condition alone (gestational diabetes/hypertensive disorders of pregnancy: adjusted odds ratio, 3.13 [2.35-4.17]; P<.001; gestational diabetes alone: adjusted odds ratio, 2.01 [1.78-2.27]; P<.001; hypertensive disorders of pregnancy alone: adjusted odds ratio, 1.38 [1.26-1.50]; P<.001). CONCLUSION: Although pregnancies with both gestational diabetes and hypertensive disorders of pregnancy have a similar median birthweight percentile to those affected by neither condition, pregnancies concurrently affected by both conditions have a higher risk of abnormal fetal growth and neonatal morbidity.

Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity.

We identified genetic subtypes of type 2 diabetes (T2D) by analyzing genetic data from diverse groups, including non-European populations. We implemented soft clustering with 650 T2D-associated genetic variants, capturing known and novel T2D subtypes with distinct cardiometabolic trait associations. The twelve genetic clusters were distinctively enriched for single-cell regulatory regions. Polygenic scores derived from the clusters differed in distribution between ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a BMI of 30 kg/m2 in the European subpopulation and 24.2 (22.9-25.5) kg/m2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg/m2 in the East Asian group, explaining about 75% of the difference in BMI thresholds. Thus, these multi-ancestry T2D genetic subtypes encompass a broader range of biological mechanisms and help explain ancestry-associated differences in T2D risk profiles.

Multi-ancestry Polygenic Mechanisms of Type 2 Diabetes Elucidate Disease Processes and Clinical Heterogeneity.

We identified genetic subtypes of type 2 diabetes (T2D) by analyzing genetic data from diverse groups, including non-European populations. We implemented soft clustering with 650 T2D-associated genetic variants, capturing known and novel T2D subtypes with distinct cardiometabolic trait associations. The twelve genetic clusters were distinctively enriched for single-cell regulatory regions. Polygenic scores derived from the clusters differed in distribution between ancestry groups, including a significantly higher proportion of lipodystrophy-related polygenic risk in East Asian ancestry. T2D risk was equivalent at a BMI of 30 kg/m2 in the European subpopulation and 24.2 (22.9-25.5) kg/m2 in the East Asian subpopulation; after adjusting for cluster-specific genetic risk, the equivalent BMI threshold increased to 28.5 (27.1-30.0) kg/m2 in the East Asian group, explaining about 75% of the difference in BMI thresholds. Thus, these multi-ancestry T2D genetic subtypes encompass a broader range of biological mechanisms and help explain ancestry-associated differences in T2D risk profiles.

Gestational Glucose Intolerance and Birth Weight-Related Complications.

OBJECTIVE: To evaluate the risks of large-for-gestational-age birth weight (LGA) and birth weight-related complications in pregnant individuals with gestational glucose intolerance, an abnormal screening glucose loading test result without meeting gestational diabetes mellitus (GDM) criteria. METHODS: In a retrospective cohort study of 46,989 individuals with singleton pregnancies who delivered after 28 weeks of gestation, those with glucose loading test results less than 140 mg/dL were classified as having normal glucose tolerance. Those with glucose loading test results of 140 mg/dL or higher and fewer than two abnormal values on a 3-hour 100-g oral glucose tolerance test (OGTT) were classified as having gestational glucose intolerance. Those with two or more abnormal OGTT values were classified as having GDM. We hypothesized that gestational glucose intolerance would be associated with higher odds of LGA (birth weight greater than the 90th percentile for gestational age and sex). We used generalized estimating equations to examine the odds of LGA in pregnant individuals with gestational glucose intolerance compared with those with normal glucose tolerance, after adjustment for age, body mass index, parity, health insurance, race and ethnicity, and marital status. In addition, we investigated differences in birth weight-related adverse pregnancy outcomes. RESULTS: Large for gestational age was present in 7.8% of 39,685 pregnant individuals with normal glucose tolerance, 9.5% of 4,155 pregnant individuals with gestational glucose intolerance and normal OGTT, 14.5% of 1,438 pregnant individuals with gestational glucose intolerance and one abnormal OGTT value, and 16.0% of 1,711 pregnant individuals with GDM. The adjusted odds of LGA were higher in pregnant individuals with gestational glucose intolerance than in those with normal glucose tolerance overall (adjusted odds ratio [aOR] 1.35, 95% CI 1.23-1.49, P <.001). When compared separately with pregnant individuals with normal glucose tolerance, those with either gestational glucose intolerance subtype had higher adjusted LGA odds (gestational glucose intolerance with normal OGTT aOR 1.21, 95% CI 1.08-1.35, P <.001; gestational glucose intolerance with one abnormal OGTT value aOR 1.77, 95% CI 1.52-2.08, P <.001). The odds of birth weight-related adverse outcomes (including cesarean delivery, severe perineal lacerations, and shoulder dystocia or clavicular fracture) were higher in pregnant individuals with gestational glucose intolerance with one abnormal OGTT value than in those with normal glucose tolerance. CONCLUSION: Gestational glucose intolerance in pregnancy is associated with birth weight-related adverse pregnancy outcomes. Glucose lowering should be investigated as a strategy for lowering the risk of these outcomes in this group.

Assessment of the Validity of Administrative Data for Gestational Diabetes Ascertainment.

BACKGROUND: Administrative data, including International Classification of Diseases codes and birth certificate records, are often used for retrospective gestational diabetes research investigations to describe associations of gestational diabetes with perinatal complications and long-term outcomes, and to determine gestational diabetes prevalence. Research investigating the validity of using International Classification of Diseases codes and birth certificates for gestational diabetes ascertainment shows varying degrees of reliability. OBJECTIVE: This study aimed to evaluate the accuracy of both International Classification of Diseases codes and birth certificate diagnosis for gestational diabetes ascertainment in a large hospital-based cohort of pregnant individuals, using laboratory criteria for gestational diabetes mellitus as the reference. STUDY DESIGN: We studied individuals who received prenatal care at an academic hospital and affiliated community health centers between 1998 and 2016. In the setting of universal 2-step screening for gestational diabetes, pregnant individuals were classified as having gestational diabetes if ≥2 oral glucose tolerance test values met or exceeded National Diabetes Data Group thresholds. We calculated the sensitivity, specificity, positive predictive value, and negative predictive value for International Classification of Diseases code and birth certificate ascertainment of gestational diabetes, and their exact binomial 95% confidence intervals. RESULTS: In a cohort of 51,059 pregnancies with complete glucose screening, 1303 (2.6%) met National Diabetes Data Group laboratory criteria for gestational diabetes. Gestational diabetes International Classification of Diseases codes had moderate sensitivity of 70.5% (95% confidence interval, 67.9-72.9), high specificity of 99.3% (95% confidence interval, 99.3-99.4), a positive predictive value of 73.3% (95% confidence interval, 70.8-75.8), and a negative predictive value of 99.2% (95% confidence interval, 99.1-99.3). In the 46,512 pregnancies linked to birth certificate data, birth certificate diagnosis had moderate sensitivity (66.3% [95% confidence interval, 63.6-69.0]), high specificity (98.9% [95% confidence interval, 98.8-99.0]), moderate positive predictive value (62.1% [95% confidence interval, 59.8-64.4]), and high negative predictive value (99.1% [95% confidence interval, 99.0-99.2]). CONCLUSION: Ascertainment of gestational diabetes using administrative data, including International Classification of Diseases codes or birth certificates, has moderate sensitivity, moderate positive predictive value, high specificity, and high negative predictive value. Our findings provide context for interpreting the validity of studies that depend on administrative data for ascertainment of gestational diabetes and comparing them with prospective studies that use laboratory-based gestational diabetes criteria.

Gestational Glucose Intolerance and Risk of Future Diabetes.

OBJECTIVE: Pregnant individuals are universally screened for gestational diabetes mellitus (GDM). Gestational glucose intolerance (GGI) (an abnormal initial GDM screening test without a GDM diagnosis) is not a recognized diabetes risk factor. We tested for an association between GGI and diabetes after pregnancy. RESEARCH DESIGN AND METHODS: We conducted a retrospective cohort study of individuals followed for prenatal and primary care. We defined GGI as an abnormal screening glucose-loading test result at ≥24 weeks' gestation with an oral glucose tolerance test (OGTT) that did not meet GDM criteria. The primary outcome was incident diabetes. We used Cox proportional hazards models with time-varying exposures and covariates to compare incident diabetes risk in individuals with GGI and normal glucose tolerance. RESULTS: Among 16,836 individuals, there were 20,359 pregnancies with normal glucose tolerance, 2,943 with GGI, and 909 with GDM. Over a median of 8.4 years of follow-up, 428 individuals developed diabetes. Individuals with GGI had increased diabetes risk compared to those with normal glucose tolerance in pregnancy (adjusted hazard ratio [aHR] 2.01 [95% CI 1.54-2.62], P < 0.001). Diabetes risk increased with the number of abnormal OGTT values (zero, aHR 1.54 [1.09-2.16], P = 0.01; one, aHR 2.97 [2.07-4.27], P < 0.001; GDM, aHR 8.26 [6.49-10.51], P < 0.001 for each compared with normal glucose tolerance). The fraction of cases of diabetes 10 years after delivery attributable to GGI and GDM was 8.5% and 28.1%, respectively. CONCLUSIONS: GGI confers an increased risk of future diabetes. Routinely available clinical data identify an unrecognized group who may benefit from enhanced diabetes screening and prevention.

First Trimester Cardiac Biomarkers among Women with Peripartum Cardiomyopathy: Are There Early Clues to This Late-Pregnancy Phenomenon?

OBJECTIVE: Whether biomarkers may enable early identification of women who develop peripartum cardiomyopathy (PPCM) prior to disease onset remains a question of interest. STUDY DESIGN: A retrospective nested case-control study was conducted to determine whether first trimester N-terminal pro-B type natriuretic peptide (NT-proBNP) or high sensitivity cardiac troponin I (hs-cTnI) differed among women who developed PPCM versus unaffected pregnancies. Cases were matched to unaffected women by age, race, parity, and gestational age of sample (control A) and then further by blood pressure and pregnancy weight gain (control B). RESULTS: First trimester NT-proBNP concentrations were numerically higher among women who subsequently developed PPCM (116 pg/mL [83-177]) as compared with women in control A (56.1 pg/mL [38.7-118.7], p = 0.3) or control B (37.6 [23.3 - 53.8], p <0.05). A higher proportion of women who subsequently developed PPCM (50%) had detectable levels of hs-cTnI as compared with control A (0%, p = 0.03) or control B (18.8%, p = 0.52). Among both cases and controls, hs-cTnI values were low and often below the limit of detection. CONCLUSION: There were differences in first trimester NT-proBNP and hs-cTnI concentrations between women who subsequently developed PPCM and those who did not, raising the possibility the early pregnancy subclinical myocardial dysfunction may be associated with this late-pregnancy disease. KEY POINTS: · First trimester NT-proBNP is numerically higher among women who subsequently develop PPCM.. · First trimester hs-cTnI was nominally higher among women who developed PPCM versus those who did not.. · A significant proportion of normal pregnant women have undetectable hs-cTnI..

Waste audits in healthcare: A systematic review and description of best practices.

Healthcare generates large amounts of waste, harming both environmental and human health. Waste audits are the standard method for measuring and characterizing waste. This is a systematic review of healthcare waste audits, describing their methods and informing more standardized auditing and reporting. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we searched MEDLINE, Embase, Inspec, Scopus and Web of Science Core Collection databases for published studies involving direct measurement of waste in medical facilities. We screened 2398 studies, identifying 156 studies for inclusion from 37 countries. Most were conducted to improve local waste sorting policies or practices, with fewer to inform policy development, increase waste diversion or reduce costs. Measurement was quantified mostly by weighing waste, with many also counting items or using interviews or surveys to compile data. Studies spanned single procedures, departments and hospitals, and multiple hospitals or health systems. Waste categories varied, with most including municipal solid waste or biohazardous waste, and others including sharps, recycling and other wastes. There were significant differences in methods and results between high- and low-income countries. The number of healthcare waste audits published has been increasing, with variable quality and general methodologic inconsistency. A greater emphasis on consistent performance and reporting standards would improve the quality, comparability and usefulness of healthcare waste audits.

Cohort Study of Maternal Gestational Weight Gain, Gestational Diabetes, and Childhood Asthma.

Data on the association of maternal gestational weight gain (GWG) and gestational diabetes mellitus (GDM) with childhood asthma are limited and inconsistent. We aimed to investigate these associations in a U.S. pre-birth cohort. Analyses included 16,351 mother-child pairs enrolled in the Massachusetts General Hospital Maternal-Child Cohort (1998-2010). Data were obtained by linking electronic health records for prenatal visits/delivery to determine BMI, GWG, and GDM (National Diabetes Data Group criteria) and to determine asthma incidence and allergies (atopic dermatitis or allergic rhinitis) for children. The associations of prenatal exposures with asthma were evaluated using logistic regression adjusted for maternal characteristics. A total of 2306 children (14%) developed asthma by age 5 years. Overall, no association was found between GWG and asthma. GDM was positively associated with offspring asthma (OR 1.46, 95% CI 1.14-1.88). Associations between GDM and asthma were observed only among mothers with early pregnancy BMI between 20 and 24.9 kg/m2 (OR 2.31, CI 1.46-3.65, p-interaction 0.02). We report novel findings on the impact of prenatal exposures on asthma, including increased risk among mothers with GDM, particularly those with a normal BMI. These findings support the strengthening of interventions targeted toward a healthier pregnancy, which may also be helpful for childhood asthma prevention.

Breast cancer polygenic risk scores are associated with short-term risk of poor prognosis breast cancer.

PURPOSE: Polygenic risk scores (PRS) for breast cancer may help guide screening decisions. However, few studies have examined whether PRS are associated with risk of short-term or poor prognosis breast cancers. The study purpose was to evaluate the association of the 313 SNP breast cancer PRS with 2-year risk of poor prognosis breast cancer. METHODS: We evaluated the association of breast cancer PRS with breast cancer overall, ER + and ER- breast cancer, and poor prognosis breast cancer diagnosed within 2 years of a negative mammogram among a cohort of 3657 women using logistic regression adjusted for age, breast density, race/ethnicity, year of screening, and genetic ancestry principal components. Breast cancers were considered poor prognosis if they were metastatic, positive lymph nodes, ER/PR + HER2- and > 2 cm, ER/PR/HER2-, or HER2 + and > 1 cm. RESULTS: Of the 308 breast cancers, 137 (44%) were poor prognosis. The overall breast cancer PRS was significantly associated with breast cancer diagnosis within 2 years (OR 1.39, 95% CI 1.23-1.57, p < 0.001). The breast cancer PRS was also associated specifically with diagnosis of poor prognosis disease (OR 1.24, 95% CI 1.03-1.49, p = 0.018), but was more strongly associated with good prognosis cancer (OR 1.52 95% CI 1.29-1.80 p = 3.60 × 10-7) The ER + PRS was significantly associated with ER/PR + breast cancer (OR 1.41, 95% CI 1.24-1.61, p < 0.001) and the ER- PRS was significantly associated with ER- breast cancer (OR 1.48, 95% CI 1.08-2.02, p = 0.015). CONCLUSION: Breast cancer PRS was independently and significantly associated with diagnosis of both breast cancer overall and poor prognosis breast cancer within 2 years of a negative mammogram, suggesting PRS may help guide decisions about screening intervals and supplemental screening.

Genetic Loci and Physiologic Pathways Involved in Gestational Diabetes Mellitus Implicated Through Clustering.

Hundreds of common genetic variants acting through distinguishable physiologic pathways influence the risk of type 2 diabetes (T2D). It is unknown to what extent the physiology underlying gestational diabetes mellitus (GDM) is distinct from that underlying T2D. In this study of >5,000 pregnant women from three cohorts, we aimed to identify physiologically related groups of maternal variants associated with GDM using two complementary approaches that were based on Bayesian nonnegative matrix factorization (bNMF) clustering. First, we tested five bNMF clusters of maternal T2D-associated variants grouped on the basis of physiology outside of pregnancy for association with GDM. We found that cluster polygenic scores representing genetic determinants of reduced ß-cell function and abnormal hepatic lipid metabolism were associated with GDM; these clusters were not associated with infant birth weight. Second, we derived bNMF clusters of maternal variants on the basis of pregnancy physiology and tested these clusters for association with GDM. We identified a cluster that was strongly associated with GDM as well as associated with higher infant birth weight. The effect size for this cluster's association with GDM appeared greater than that for T2D. Our findings imply that the genetic and physiologic pathways that lead to GDM differ, at least in part, from those that lead to T2D.

Dumpster Diving in the Emergency Department.

INTRODUCTION: Healthcare contributes 10% of greenhouse gases in the United States and generates two milion tons of waste each year. Reducing healthcare waste can reduce the environmental impact of healthcare and lower hospitals' waste disposal costs. However, no literature to date has examined US emergency department (ED) waste management. The purpose of this study was to quantify and describe the amount of waste generated by an ED, identify deviations from waste policy, and explore areas for waste reduction. METHODS: We conducted a 24-hour (weekday) ED waste audit in an urban, tertiary-care academic medical center. All waste generated in the ED during the study period was collected, manually sorted into separate categories based on its predominant material, and weighed. We tracked deviations from hospital waste policy using the hospital's Infection Control Manual, state regulations, and Health Insurance Portability and Accountability Act standards. Lastly, we calculated direct pollutant emissions from ED waste disposal activities using the M+WasteCare Calculator. RESULTS: The ED generated 671.8 kilograms (kg) total waste during a 24-hour collection period. On a per-patient basis, the ED generated 1.99 kg of total waste per encounter. The majority was plastic (64.6%), with paper-derived products (18.4%) the next largest category. Only 14.9% of waste disposed of in red bags met the criteria for regulated medical waste. We identified several deviations from waste policy, including loose sharps not placed in sharps containers, as well as re-processable items and protected health information thrown in medical and solid waste. We also identified over 200 unused items. Pollutant emissions resulting per day from ED waste disposal include 3110 kg carbon dioxide equivalent and 576 grams of other criteria pollutants, heavy metals, and toxins. CONCLUSION: The ED generates significant amounts of waste. Current ED waste disposal practices reveal several opportunities to reduce total waste generated, increase adherence to waste policy, and reduce environmental impact. While our results will likely be similar to other urban tertiary EDs that serve as Level I trauma centers, future studies are needed to compare results across EDs with different patient volumes or waste generation rates.

Botulinum Toxin Injections for Leg Contouring in East Asians.

BACKGROUND: A common aesthetic concern among East Asian women is enlarged calves. Although surgical resection has been a traditional treatment option, botulinum toxin injections into the gastrocnemius muscle are an emerging, noninvasive alternative. OBJECTIVE: To perform a literature review on botulinum toxin injections for leg contouring. MATERIALS AND METHODS: A literature review was conducted using PubMed, Web of Science, Embase, and Cochrane's CENTRAL database to identify articles relating to combinations of the terms botulinum toxin, gastrocnemius, calves, and leg contouring. RESULTS: Based on the limited publications to date, the authors prepared a review on how to treat an enlarged calf with botulinum toxin including injection techniques, anticipated efficacy, outcome monitoring, and potential side effects. CONCLUSION: Botulinum toxin injections for calf reduction are an emerging, noninvasive treatment option. Studies to date suggest that it is an efficacious method with few immediate side effects. Future areas for investigation include defining the criteria for calf hypertrophy, minimum effective dosage of botulinum toxin, and the potential long-term effects of injections.