University of Exeter Medical School

CONTEXT:Maternal (vs paternal) type 1 diabetes is associated with a relative reduction in type 1 diabetes risk in offspring during early life. OBJECTIVE:To determine whether this effect extends into later life. To clarify the importance of intrauterine exposure to maternal type 1 diabetes, and baseline genetic susceptibility in this context. METHODS:We compared the proportion of individuals with type 1 diabetes diagnosed aged 0 to 88 years of age with affected mothers and fathers across 5 observational studies (n = 11 475), and used random-effects meta-analyses to generate overall effect estimates. We examined this by age at diagnosis, and timing of parental diagnosis relative to offspring birth. We compared the type 1 diabetes genetic risk score (T1D-GRS2) of individuals with affected mothers and fathers. RESULTS:Almost half as many individuals with type 1 diabetes had an affected mother vs father (odds ratio [OR], 0.55; 95% CI, 0.48-0.64; P < .0001). A lower proportion of individuals with affected mothers than fathers was apparent even among individuals diagnosed as adults (>18 years) (OR, 0.63; 95% CI, 0.43-0.91; P = .01). The lower proportion of individuals with maternal vs paternal type 1 diabetes was only observed if maternal diagnosis preceded offspring birth (OR, 0.51; 95% CI, 0.37-0.70; P < .001 vs OR 0.97; 95% CI, 0.69-1.38; P = .87 after birth). T1D-GRS2 was similar between individuals with affected mothers and fathers (P = .25). CONCLUSION:Our analyses suggest intrauterine exposure to maternal type 1 diabetes is associated with long-lasting relative protection against offspring type 1 diabetes, which is independent of genetic susceptibility as measured by T1D-GRS2.

Human pharmaceuticals are increasingly detected in environments around the world, with growing international calls to mitigate the ecological and human health risks posed by these novel entities. Exposure to pharmaceutical pollutants can negatively affect the behaviour, reproduction, and health of wildlife, contributing towards declining ecological health and global biodiversity loss. Pharmaceuticals in the environment are also driving rising levels of antimicrobial resistance, a major public health threat. Developing strategies to mitigate these public and environmental health risks has been greatly limited by diverse and often conflicting stakeholder interests and the need to retain the major human health and socioeconomic benefits that pharmaceuticals provide. In this Personal View, we propose a multistakeholder, systems-based approach for high-income countries to develop transformational national mitigation strategies. Applying this approach to a UK case study highlighted the growing risks caused by the unsustainability of the current UK health-care pharmaceutical system and enabled us to identify 37 synergistic intervention points that target both the tangible easy wins and the deep-rooted social drivers of the issue. We believe our approach will support high-income countries in minimising the public and environmental health risks associated with pharmaceutical pollution, by driving long-term sustainability across the pharmaceutical lifecycle, for a positive pharmaceutical future.

Saharan Africa is experiencing a rapid increase in the burden of diabetes, accompanied by increasing rates of microvascular, macrovascular, and pregnancy-related complications. This Series paper synthesises current evidence on diabetes-related complications in sub-Saharan Africa and examines shared cardiometabolic risks, mental health comorbidities, and interactions with communicable diseases through a multiple long-term conditions lens. Widespread late diagnosis and inadequate control of key cardiometabolic risk factors (eg, hypertension, dyslipidaemia, obesity, and hyperglycaemia) drive high complication rates—whereas mental health disorders and infectious disease comorbidities further exacerbate susceptibility. Although risk factor reduction is central to preventing diabetes complications in sub-Saharan Africa, progress is impeded by multilevel barriers spanning individual, interpersonal, health system, societal, and policy domains. To address this growing complexity, we identify priorities for research and implementation, including the development of context-specific guidelines, scalable integrated care models, strengthened surveillance systems, and long-term cohorts co-designed with communities, health-care providers, and policy makers.

Atypical diabetes subtypes and presentations are disproportionately prevalent in populations of African and Asian ancestry. This review discusses the epidemiology, clinical presentation, aetiopathogenesis and management of four atypical diabetes subtypes commonly reported in Black African populations. These are ketosis-prone diabetes (KPD), fibrocalculous pancreatic diabetes (FCPD), type 2 diabetes in individuals without overweight or obesity, and malnutrition-related diabetes (MRD). The review summarises current insights into these atypical diabetes subtypes in Black African populations and provides practical recommendations to guide their precision diagnosis and management in the African region. These four atypical diabetes subtypes exhibit phenotypic features that diverge from those of classical type 1 and type 2 diabetes. KPD is characterised by unprovoked, transient, index episodes of diabetic ketoacidosis, often in the absence of markers of islet cell autoimmunity, with frequent subsequent insulin independence and diabetes remission. FCPD typically presents in young lean individuals, with a strong male preponderance and with radiological evidence of pancreatic calcifications, reduced beta cell reserve and severe hyperglycaemia without ketosis. Type 2 diabetes in individuals without overweight or obesity is characterised by normal BMI with a trend towards low levels of markers of visceral adiposity, insulin resistance and an exaggerated beta cell secretory dysfunction. MRD is associated with a previous and persistent history of undernutrition, with features of undernutrition such as stunting and BMI <18.5 kg/m2, resistance to diabetic ketoacidosis, no evidence of visceral or ectopic adiposity, and severe beta cell secretory dysfunction. The high prevalence and heterogeneous presentation of these atypical forms of diabetes in African populations highlight the urgent need for enhanced collaborative research to better define their epidemiology, improve diagnostic accuracy and develop context-appropriate management strategies tailored to diverse African populations.

BACKGROUND:Randomized trials have demonstrated that early anticoagulation after acute atrial fibrillation-associated ischemic stroke is safe and non-inferior to delayed initiation. Whether anticoagulation should be delayed in people with larger infarcts is uncertain. AIMS:To investigate whether ischemic stroke infarct volume, measured precisely by segmentation, modifies the treatment effect of early anticoagulation with a direct oral anticoagulant (DOAC). METHODS:We did a prespecified secondary analysis of OPTIMAS (NCT: 03759938), a randomized, parallel-group, open-label trial with blinded outcome assessment which randomized people with acute ischemic stroke and atrial fibrillation to early initiation of any licensed DOAC, within 4 days of onset, or delayed initiation 7-14 days from onset. The primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage (ICH), and systemic arterial embolism within 90 days. A central neuroimaging laboratory determined infarct volume using diffusion-weighted magnetic resonance imaging (MRI) using a validated deep learning segmentation model; on computed tomography (CT), infarcts were segmented manually. We modeled infarct volume as a continuous variable using restricted cubic splines and tested for an interaction with treatment allocation in mixed effects logistic regression. RESULTS:We included 3572 participants (mean age = 78 ± 10 years, 45% female), 98.6% of the main trial population. The effect of early versus delayed anticoagulation did not vary with infarct volume (pinteraction = 0.18). Rates of the primary outcome were 17/568 (3.0%) and 12/599 (2.0%) for early versus delayed initiation with infarcts of 0-5 mL; 6/220 (2.7%) and 11/229 (4.8%) with infarcts of 5-10 mL; 13/258 (4.6%) and 10/283 (3.5%) with infarcts of 10-25 mL; 6/145 (4.1%) and 8/145 (5.5%) with infarcts of 25-50 mL; 1/93 (1.1%) and 7/94 (7.4%) with infarcts of >50 mL; and 14/481 (2.9%) and 10/430 (2.2%) in participants with no infarct visible on clinically acquired brain imaging. Corresponding odds ratios and 95% confidence intervals were 1.52 (0.71-3.20), 0.55 (0.20-1.51), 1.29 (0.55-3.00), 0.74 (0.25-2.21), 0.13 (0.02-1.11), and 1.25 (0.55-2.86), respectively. There were no increased rates of symptomatic ICH with respect to anticoagulation timing for those with large infarcts (>25 mL); there were 3/238 (1.3%) events in the early group and 5/239 (2.1%) in the delayed group. CONCLUSION:The treatment effect of early anticoagulation with a DOAC in acute ischemic stroke associated with atrial fibrillation was not modified by infarct volume. Adverse outcomes were not increased with early anticoagulation in people with larger infarcts. Our results provide no evidence that anticoagulation initiation should be delayed beyond 4 days on the basis of infarct size.