PRDM9 binding localizes almost all meiotic recombination sites in humans and mice. However, most PRDM9-bound loci do not become recombination hotspots. To explore factors that affect binding and subsequent recombination outcomes, we mapped human PRDM9 binding sites in a transfected human cell line and measured PRDM9-induced histone modifications. These data reveal varied DNA-binding modalities of PRDM9. We also find that human PRDM9 frequently binds promoters, despite their low recombination rates, and it can activate expression of a small number of genes including CTCFL and VCX. Furthermore, we identify specific sequence motifs that predict consistent, localized meiotic recombination suppression around a subset of PRDM9 binding sites. These motifs strongly associate with KRAB-ZNF protein binding, TRIM28 recruitment, and specific histone modifications. Finally, we demonstrate that, in addition to binding DNA, PRDM9's zinc fingers also mediate its multimerization, and we show that a pair of highly diverged alleles preferentially form homo-multimers.

The Centers for Disease Control and Prevention states that individuals with diabetes are at higher risk for severe illness with coronavirus disease 2019 (COVID-19) and poorer health outcomes (1). Research suggests the underlying reason for an increased risk of COVID-19 complications in individuals with diabetes may be poor glycemic control or hyperglycemia (2). Information on clinical outcomes for patients with type 1 diabetes who have confirmed cases of COVID-19 is limited. To our knowledge, this is the first U.S.-based multicenter study that addresses these questions in a population with type 1 diabetes. This study aimed to examine patient characteristics and adverse outcomes among patients with type 1 diabetes with confirmed COVID-19. As a secondary objective, we investigated patient attributes and clinical outcomes in people with COVID-19-like symptoms for whom testing was unavailable or results were pending. The T1D Exchange Quality Improvement Collaborative (T1DX-QI) (3) is conducting this study in collaboration with an additional 49 endocrinology clinics (a total of 64 U.S. sites). The study was approved as exempt by a central review board (Western Institutional Review

The pseudoautosomal region (PAR) is a short region of homology between the mammalian X and Y chromosomes, which has undergone rapid evolution. A crossover in the PAR is essential for the proper disjunction of X and Y chromosomes in male meiosis, and PAR deletion results in male sterility. This leads the human PAR with the obligatory crossover, PAR1, to having an exceptionally high male crossover rate, which is 17-fold higher than the genome-wide average. However, the mechanism by which this obligatory crossover occurs remains unknown, as does the fine-scale positioning of crossovers across this region. Recent research in mice has suggested that crossovers in PAR may be mediated independently of the protein PRDM9, which localises virtually all crossovers in the autosomes. To investigate recombination in this region, we construct the most fine-scale genetic map containing directly observed crossovers to date using African-American pedigrees. We leverage recombination rates inferred from the breakdown of linkage disequilibrium in human populations and investigate the signatures of DNA evolution due to recombination. Further, we identify direct PRDM9 binding sites using ChIP-seq in human cells. Using these independent lines of evidence, we show that, in contrast with mouse, PRDM9 does localise peaks of recombination in the human PAR1. We find that recombination is a far more rapid and intense driver of sequence evolution in PAR1 than it is on the autosomes. We also show that PAR1 hotspot activities differ significantly among human populations. Finally, we find evidence that PAR1 hotspot positions have changed between human and chimpanzee, with no evidence of sharing among the hottest hotspots. We anticipate that the genetic maps built and validated in this work will aid research on this vital and fascinating region of the genome.

Objective Studies in other developed countries have suggested that socioeconomic position may be a risk factor for poorer pregnancy outcomes. This analysis aimed to explore the independent impact of socioeconomic position on selected severe maternal morbidities among women in Australia. Design A case–control study using data on severe maternal morbidities associated with direct maternal death collected through the Australasian Maternity Outcomes Surveillance System. Setting Australia. Population 623 cases, 820 controls. Methods Logistic regression analysis to investigate differences in outcomes among different socioeconomic groups, classified by Socio‐Economic Indexes for Areas (SEIFA) quintile. Main outcome measures Severe maternal morbidity (amniotic fluid embolism, placenta accreta, peripartum hysterectomy, eclampsia or pulmonary embolism). Results SEIFA quintile was statistically significantly associated with maternal morbidity, with cases being twice as likely as controls to reside in the most disadvantaged areas (adjusted OR 2.00, 95%CI 1.29–3.10). Maternal age [adjusted odds ratio (aOR) 2.20 for women aged 35 or over compared with women aged 25–29, 95%CI 1.64–3.15] and previous pregnancy complications (aOR 1.30, 95%CI 1.21–1.87) were significantly associated with morbidity. A parity of 1 or 2 was protective (aOR 0.58, 95%CI 0.43–0.79), whereas previous caesarean delivery was associated with maternal morbidity (aOR 2.20 for women with one caesarean delivery, 95%CI 1.44–2.85, compared with women with no caesareans). Conclusion The risk of severe maternal morbidity among women in Australia is significantly increased by social disadvantage. This study suggests that future efforts in improving maternity care provision and maternal outcomes in Australia should include socioeconomic position as an independent risk factor for adverse outcome.

Health care inequities among racial and ethnic groups remain prevalent. For people with type 1 diabetes who require increased medical access and care, disparities are seen in access to care and health outcomes. This article reports on a study by the T1D Exchange Quality Improvement Collaborative evaluating differences in A1C, diabetic ketoacidosis (DKA), severe hypoglycemia, and technology use among racial and ethnic groups. In a diverse cohort of nearly 20,000 children and adults with type 1 diabetes, A1C was found to differ significantly among racial and ethnic groups. Non-Hispanic Blacks had higher rates of DKA and severe hypoglycemia and the lowest rate of technology use. These results underscore the crucial need to study and overcome the barriers that lead to inequities in the care and outcomes of people with type 1 diabetes.Health inequities among racial and ethnic groups persist in both children and adults. Individuals with chronic conditions such as type 1 diabetes require increased medical access and care. Yet, there are disparities in access to care and health outcomes (1). The incidence of type 1 diabetes is increasing in the United States across all populations, and most significantly among Hispanic youths, but despite the higher incidence, health disparities continue to worsen among specific racial and ethnic groups (2,3). Mean A1C levels were found to be higher in Hispanics and non-Hispanic Blacks with type 1 diabetes compared with non-Hispanic Whites in the largest U.S. study to date, which included $11,000 youths and young adults in the T1D Exchange clinic network and registry (4). Non-Hispanic Blacks and Hispanics have been reported to perform fewer blood glucose checks per day than Non-Hispanic Whites (5,6). One study evaluating A1C trajectories over time in $16,000 youths from Australia, Europe, and the United States found that minority groups were more likely to have increasing A1C levels over time compared with Non-Hispanic Whites, specifically in the T1D Exchange and Diabetes-Patienten-Verlaufsdokumentation registries (7).

Objective We examined whether diabetic ketoacidosis (DKA), a serious complication of type 1 diabetes (T1D) was more prevalent among Non-Hispanic (NH) Black and Hispanic patients with T1D and laboratory-confirmed coronavirus disease 2019 (COVID-19) compared with NH Whites. Method This is a cross-sectional study of patients with T1D and laboratory-confirmed COVID-19 from 52 clinical sites in the United States, data were collected from April to August 2020. We examined the distribution of patient factors and DKA events across NH White, NH Black, and Hispanic race/ethnicity groups. Multivariable logistic regression analysis was performed to examine the odds of DKA among NH Black and Hispanic patients with T1D as compared with NH White patients, adjusting for potential confounders, such as age, sex, insurance, and last glycated hemoglobin A1c (HbA1c) level. Results We included 180 patients with T1D and laboratory-confirmed COVID-19 in the analysis. Forty-four percent (n = 79) were NH White, 31% (n = 55) NH Black, 26% (n = 46) Hispanic. NH Blacks and Hispanics had higher median HbA1c than Whites (%-points [IQR]: 11.7 [4.7], P < 0.001, and 9.7 [3.1] vs 8.3 [2.4], P = 0.01, respectively). We found that more NH Black and Hispanic presented with DKA compared to Whites (55% and 33% vs 13%, P < 0.001 and P = 0.008, respectively). After adjusting for potential confounders, NH Black patients continued to have greater odds of presenting with DKA compared with NH Whites (OR [95% CI]: 3.7 [1.4, 10.6]). Conclusion We found that among T1D patients with COVID-19 infection, NH Black patients were more likely to present in DKA compared with NH White patients. Our findings demonstrate additional risk among NH Black patients with T1D and COVID-19.

Context Diabetes mellitus is associated with increased COVID-19 morbidity and mortality, but there is little data focusing on outcomes in people with type 1 diabetes. Objective The objective of this study was to analyze characteristics of adults with type 1 diabetes for associations with COVID-19 hospitalization. Design An observational multi-site cross-sectional study was performed. Diabetes providers answered a 33-item questionnaire regarding demographics, symptoms, and diabetes- and COVID-19-related care and outcomes. Descriptive statistics were used to describe the study population, and multivariate logistic regression models were used to analyze the relationship between HbA1c, age, and comorbidities and hospitalization. Setting Cases were submitted from 52 US sites between March and August 2020. Patients or Other Participants Adults over the age of 19 with type 1 diabetes and confirmed COVID-19 infection were included. Interventions None. Main Outcome Measures Hospitalization for COVID-19 infection. Results A total of 113 cases were analyzed. Fifty-eight patients were hospitalized, and five patients died. Patients who were hospitalized were more likely to be older, to identify as non-Hispanic Black, to use public insurance, or to have hypertension, and less likely to use continuous glucose monitoring or insulin pumps. Median HbA1c was 8.6% (70 mmol/mol) and was positively associated with hospitalization (OR 1.42, 95% CI 1.18-1.76), which persisted after adjustment for age, sex, race, and obesity. Conclusions Baseline glycemic control and access to care are important modifiable risk factors which need to be addressed to optimize care of people with type 1 diabetes during the worldwide COVID-19 pandemic.

Background: The benefits of Continuous Glucose Monitoring (CGM) on glycemic management have been demonstrated in numerous studies; however, widespread uptake remians limited. The aim of this study was to provide real-world evidence of patient attributes and clinical outcomes associated with CGM use across clinics in the U.S. based T1D Exchange Quality Improvement (T1DX-QI) Collaborative. Method: We examined electronic Health Record data from eight endocrinology clinics participating in the T1DX-QI Collaborative during the years 2017-2019. Results: Among 11,469 type 1 diabetes patients, 48% were CGM users. CGM use varied by race/ethnicity with Non-Hispanic Whites having higher rates of CGM use (50%) compared to Non-Hispanic Blacks (18%) or Hispanics (38%). Patients with private insurance were more likely to use CGM (57.2%) than those with public insurance (33.3%) including Medicaid or Medicare. CGM users had lower median HbA1c (7.7%) compared to nonusers (8.4%). Rates of diabetic ketoacidosis (DKA) and severe hypoglycemia were significantly higher in nonusers compared to CGM users. Conclusion: In this real-world study of patients in the T1DX-QI Collaborative, CGM users had better glycemic control and lower rates of DKA and severe hypoglycemia (SH) events, compared to nonusers; however, there were significant sociodemographic disparities in CGM use. Quality improvement and advocacy measures to promote widespread and equitable CGM uptake have the potential to improve clinical outcomes.