A map of human PRDM9 binding provides evidence for novel behaviors of PRDM9 and other zinc-finger proteins in meiosis.

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 Impact of Climate Change on People Living with Diabetes: A Scoping Review

Objective: There is substantial literature detailing the interaction between climate change and diabetes incidence, prevalence, and development. However, there is limited understanding on the impact of climate change on People Living with Diabetes (PWD). This scoping review describes the impact of climate change on morbidity and mortality for PWD.Materials and methods: The scoping review was conducted between November 2022 and February 2023, using articles published in PubMed Central and Google Scholar databases. Articles published from 1970 to 2022 with the following key terms “diabetes”, “type 1 diabetes”, “type 2 diabetes”, “climate change”, “global warming”, and “natural disaster” were reviewed. Results: A total of 13,838 articles were identified and reviewed. After applying the review criteria, 42 applicable articles were included in the scoping review. PWD are impacted directly by climate change-induced events including extreme temperatures, air pollution, and natural disasters. Difficulty in storing insulin, maintaining special diets, and accessing diabetes supplies are indirect results of the climate crisis on people with diabetes leading to adverse outcomessuch as increased risk of hospitalizations, morbidity, and mortality. Conclusions: Environmental hazards due to climate change increase morbidity and mortality for PWD. Policies that address the interconnection between the two phenomena would improve global diabetes population health. Future research should explore potential solutions to addressing this crisis across multiple populations and settings

Differences in COVID-19 Outcomes Among Patients With Type 1 Diabetes: First vs Later Surges

Background Outcomes of the novel coronavirus SARS-CoV-2 (COVID-19) have improved throughout the pandemic. However, whether outcomes of COVID-19 in the type 1 diabetes (T1D) population improved over time is unknown. Therefore, we aim to investigate differences in COVID-19 outcomes for patients with T1D in the US. Method We analyzed data collected via a registry of patients with T1D and COVID-19 from 56 sites between April 2020 and January 2021. First, we grouped cases into First Surge (04/09/2020 - 07/31/2020, n=188) and Late Surge (08/01/2020 - 01/31/2021, n=410). Then, we compared outcomes between both groups using descriptive statistics and logistic regression models. Results Adverse outcomes were more frequent during the first surge including Diabetic Ketoacidosis (32% versus 15%, p<0.001), severe hypoglycemia (4% versus 1%, p=0.04) and hospitalization (52% versus 22%, p<0.001). The First surge cases were older (28 +/- 18.8 years versus 18.8 +/- 11.1 years, p<0.001), had higher hemoglobin A1c (HbA1c) levels (Median (IQR): 9.3 (4.0) versus 8.4(2.8), <0.001) and use public insurance (n(%): 107 (57) versus 154 (38), p <0.001). There were five times increased odds of hospitalization for adults (OR 5.01 (2.11,12.63) in the first surge compared to the late surge. Conclusion COVID-19 cases among patients with T1D reported during the first surge had a higher proportion of adverse outcomes than those presented in a later surge

Impact of special GP training on adherence to antihypertensive medication : a cluster randomized controlled trial

Hypertension is a major public health challenge and a modifiable risk factor for many chronic diseases. Non-adherence to antihypertensive treatment is an important reason for uncontrolled levels of blood pressure. The importance of physician related interventions on adherence to such treatment has not yet been explored. The objective of this study was to determine the impact of special general practitioner (GP) training in management of hypertension (special care) on adherence to antihypertensive medication versus usual care provided by GPs in the community. We hypothesized that medication adherence of individuals seeking special care is higher compared to those seeking usual care from GPs. This study was a sub-study built into a cluster randomized controlled trial conducted in 6 urban clusters of Karachi. Clusters were randomized to special care vs. usual care. In special care intervention clusters, GPs were trained intensively over one day in the management of hypertension, including use of non-pharmacological interventions and low cost generic drug. Eligible subjects were hypertensive individuals taking antihypertensive medication, aged 40 years or above and visiting GPs in the selected clusters. Subjects were blinded to intervention assignment. Adherence was measured using the Medication Event Monitoring System (MEMS), an electronic bottle that records the date and time of cap opening and pill intake. Data were downloaded on the computer using an electronic communicator . Primary adherence outcome was correct dosing, defined as percentage of prescribed doses taken. Secondary adherence outcome was timing compliance, defined as the percentage of prescribed number of doses taken within a correct interval. A linear regression analysis was conducted and multivariable models were built to study factors associated with the primary and secondary outcomes. A total of 217 eligible individuals were approached in selected clusters and 200 (92.1%) consented to participate. 178 (89%) successfully completed six weeks of follow-up. The mean age (SD) of study participants in both the randomized groups was 55 years (+ 11). Correct dosing of medication (SD) was seen in 43.6% (16.9) of subjects in special care group as opposed to 38.3% (19.0) in the usual care group (p=0.05). Timing compliance to medicine was seen in 42.6% (20.6) of subjects in special care group as opposed to 36.4% (16.8) in usual care (p=0.03). For subjects seeking special care there was a relative improvement of 13% (95% CI: 9.0-17.9) and 17% (95% CI: 12.0- 22.0) for dosing and timing compliance, respectively. In the multivariable model, special GP care (% adherence=6.0, 95% CI: 1.1-10.9) and family encouragement was associated with both adherence outcomes. GP factors independently associated with correct dosing were explaining medication purpose to patient (% adherence=19.0, 95% CI: 13.7-24.3) and self reported consultation time of \u3e10 minutes compared to \u3c=10 minutes (% adherence=6.5, 95% CI: 1.9-11.1). GP factors associated with timing compliance were explaining medication purpose (% adherence=10.8, 95% CI: 4.5-17.1) and prescribing once compared to twice or over daily dose of medication (% adherence=6.4, 95% CI: 0.9-11.8). A supplementary analysis done on a subset of study population reveals hypertension control rates were 49% in special care and 29% in the usual care group (p=0.04). In conclusion, special care by GPs had a positive impact on improving patients\u27 medication adherence. Based on our findings, we recommend that rigorous training of GPs in management of hypertension should be incorporated in hypertension control programs in urban Pakistan. Our results need further confirmation in long term studies

Molecular mechanisms of recombination hotspots in humans

Meiotic recombination involves the exchange of DNA between two homologous chromosomes, forming cross-overs and gene conversion events. The cross-over process is important for the proper segregation of chromosomes during meiosis, and drives genetic diversity. Human hotspots are enriched for a 13-bp motif, CCNCCNTNNCCNC; a close match to this motif occurs in about 40% of our cross-over hotspots. A DNA binding protein called PRDM9, having histone trimethyltransferase (H3K4me3) activity, binds the motif and is becoming established as a major determinant of recombination hotspots (narrow regions with high cross-over activity). This research aimed to understand the mechanisms involved in promoting PRDM9 binding to its target sites, and subsequently, initiating cross-over hotspot activity. We first explored the relationship between PRDM9 binding and DNA sequence, to directly confirm whether PRDM9 binds to the 13-bp hotspot motif using in-vitro gel-shift assays, and found that it does bind sequence specifically to the canonical 13-mer motif. PRDM9 is able to bind the motif in a highly selective manner, with certain single base pair changes abolishing binding. However, we observe that it is also able to tolerate degeneracy in its binding sites, as demonstrated by strong in-vitro binding to degenerate versions of the 13-bp motif. Hence, these results confirmed that PRDM9 is able to directly bind to the 13-bp hotspot motifs, and given that it can also tolerate degeneracy, this raised the question of why PRDM9 is able to bind only a subset of all such potential binding sites in the genome. To address this, a ChIP-seq analysis was performed to identify genome wide binding sites for PRDM9. This information also helped us to characterise binding sites and investigate if factors such as the local chromatin environment play a role in specifying PRDM9 binding tar- gets and hotspot formation. We were able to identify over 170,000 PRDM9 binding sites in the genome. Surprisingly, these binding sites were also enriched in promoter regions, however, bound sites in these regulatory regions showed low recombination activity. We found that PRDM9 is able to confer the H3K4me3 mark on all bound sites, even those without a pre-existing H3K4me2 mark. We also investigated the role of other chromatin related marks on PRDM9 binding and found that binding occurs in chromatin accessible, but nucleosome rich regions, whereas heterochromatin regions tend to inhibit binding. Further, for hotspot formation, it was seen that less chromatin accessible, nucleosome dense regions away from transcribed sites, are preferred. Hotspots tend to avoid regions marked by transcription activating histone modifications, however, these regions do not appear to inhibit PRDM9 binding itself. These results show how PRDM9 binding in the genome is dependent on both primary DNA sequence and the surrounding epigenetic factors. Together these factors promote binding and, with additional downstream factors, positioning of hotspot locations in the human genome.This thesis is not currently available in ORA

Effect of general practitioner education on adherence to antihypertensive drugs: cluster randomised controlled trial

Objective To determine the impact of a simple educational package for general practitioners on adherence to antihypertensive drugs

Results of predicting divergence rate of different types of substitutions from human recombination rate, after regressing out effects of GC content, CpG content and the divergence rate of other types of substitutions in unique DNA.

<p>Mutations potentially due to the deamination of 5-methyl Cytosine in a CpG context in either species were excluded. Only transitions are significantly correlated with human recombination rate.</p