IMPORTANCE Rates of thyroid hormone prescribing in the United States and the United Kingdom have increased substantially. If some of the increase is due to lowering the thyrotropin threshold for treatment, this may result in less benefit and greater harm. OBJECTIVE To define trends in thyrotropin levels at the initiation of levothyroxine sodium therapy and the risk of developing a suppressed thyrotropin level following treatment. DESIGN, SETTING, PARTICIPANTS, AND EXPOSURE Retrospective cohort study using data from the United Kingdom Clinical Practice Research Datalink. Among 52 298 individuals who received a prescription for levothyroxine between January 1, 2001, and October 30, 2009, we extracted data about the thyrotropin level before levothyroxine therapy initiation, clinical symptoms, and thyrotropin levels up to 5 years after levothyroxine was initiated. We excluded persons who had a history of hyperthyroidism, pituitary disease, or thyroid surgery; those who were taking thyroid-altering medication or if the levothyroxine prescription was related to pregnancy; and those who did not have a thyrotropin level measured within 3 months before the initiation of levothyroxine. MAIN OUTCOMES AND MEASURES The median thyrotropin level at the time of the index levothyroxine prescription, the odds of initiation of levothyroxine therapy at thyrotropin levels of 10.0 mIU/L or less, and the age-stratified odds of developing a low or suppressed thyrotropin level after levothyroxine therapy. RESULTS Between 2001 and 2009, the median thyrotropin level at the initiation of levothyroxine therapy fell from 8.7 to 7.9 mIU/L. The odds ratio for prescribing levothyroxine at thyrotropin levels of 10.0 mIU/L or less in 2009 compared with 2001 (adjusted for changes in population demographics) was 1.30 (95% CI, 1.19-1.42; P < .001). Older individuals and individuals with cardiac risk factors had higher odds of initiation of levothyroxine therapy with a thyrotropin level 10.0 mIU/L or less. At 5 years after levothyroxine initiation, 5.8% of individuals had a thyrotropin level of <0.1 mIU/L. Individuals with depression or tiredness at baseline had increased odds of developing a suppressed thyrotropin level, whereas individuals with cardiac risk factors (eg, atrial fibrillation, diabetes mellitus, hypertension, and raised lipid levels) did not. CONCLUSIONS AND RELEVANCE We observed a trend toward levothyroxine treatment of more marginal degrees of hypothyroidism and a substantial risk of developing a suppressed thyrotropin level following therapy. Large-scale prospective studies are required to assess the risk-benefit ratio of current practice.

Summary Background We assessed whether overnight home use of automated closed loop insulin delivery (artificial pancreas) improves glucose control. Methods We studied 24 adults with type 1 diabetes in a multicentre crossover study design comparing four weeks of overnight closed loop using a model predictive control algorithm to direct insulin delivery, with four weeks of insulin pump therapy in which participants used real-time display of continuous glucose monitoring independent of their pumps as control. Primary outcome was time when glucose was in the target range of 3·9 and 8·0mmol/l between midnight to 07:00. Analyses were by intention to treat. Trial registration ClinicalTrials.gov NCT01440140. Findings Closed loop was utilised over median 8·3 (interquartile range 6·0, 9·6)hours on 555nights (86%). Proportion of time when overnight glucose was in target range was significantly higher during closed loop compared to control by 13·5% (95% CI, 7·3–19·7; p<0·001). Mean overnight glucose (8·2±0·9 vs. 9·0±1·3mmol/l; p=0·005) and time spent above target (44·3%±11·9 vs. 57·1%±15·6; p=0·001) were significantly lower during closed loop. Time spent below target was low and comparable [1·8%(0·6, 3·6) vs. 2·1%(0·7, 3·9); p=0·28]. Lower mean overnight glucose was brought about by increased overnight insulin delivery [6·4 (4·5, 8·1) vs. 4·9 (3·7, 6·3)units; p<0·001) without changing the total daily insulin amount [34·5 (29·3, 48·4) vs. 35·4 (29·7, 45·2)units; p=0·32]. No severe hypoglycaemia episodes occurred during control period and two during closed loop not related to algorithm instructions. Interpretation Unsupervised overnight closed loop at home is feasible and may improve glucose control in adults with type 1 diabetes.

OBJECTIVEHypoglycemia may exert proarrhythmogenic effects on the heart via sympathoadrenal stimulation and hypokalemia. Hypoglycemia-induced cardiac dysrhythmias are linked to the "dead-in-bed syndrome," a rare but devastating condition. We examined the effect of nocturnal and daytime clinical hypoglycemia on electrocardiogram (ECG) in young people with type 1 diabetes. RESEARCH DESIGN AND METHODSThirty-seven individuals with type 1 diabetes underwent 96 h of simultaneous ambulatory ECG and blinded continuous interstitial glucose monitoring (CGM) while symptomatic hypoglycemia was recorded. Frequency of arrhythmias, heart rate variability, and cardiac repolarization were measured during hypoglycemia and compared with time-matched euglycemia during night and day. RESULTSA total of 2,395 h of simultaneous ECG and CGM recordings were obtained; 159 h were designated hypoglycemia and 1,355 h euglycemia. A median duration of nocturnal hypoglycemia of 60 min (interquartile range 40-135) was longer than daytime hypoglycemia of 44 min (30-70) (P = 0.020). Only 24.1% of nocturnal and 51.0% of daytime episodes were symptomatic. Bradycardia was more frequent during nocturnal hypoglycemia compared with matched euglycemia (incident rate ratio [IRR] 6.44 [95% CI 6.26, 6.63], P < 0.001). During daytime hypoglycemia, bradycardia was less frequent (IRR 0.023 [95% CI 0.002, 0.26], P = 0.002) and atrial ectopics more frequent (IRR 2.29 [95% CI 1.19,4.39], P = 0.013). Prolonged QTc, T-peak to T-end interval duration, and decreased T-wave symmetry were detected during nocturnal and daytime hypoglycemia. CONCLUSIONSAsymptomatic hypoglycemia was common. We identified differences in arrhythmic risk and cardiac repolarization during nocturnal versus daytime hypoglycemia in young adults with type 1 diabetes. Our data provide further evidence that hypoglycemia is proarrhythmogenic.Hypoglycemia is an inevitable consequence of the current management of type 1 diabetes (1). Improved glycemic control is frequently accompanied by an increased risk of inducing iatrogenic hypoglycemia (2). Observational studies indicate that rates of severe hypoglycemia have generally not fallen despite the introduction of insulin

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The majority of levothyroxine-treated women have early gestational TSH levels above the recommended targets (>2.5 mU/L) with a strong risk of miscarriage at levels exceeding 4.5 mU/L. There is an urgent need to improve the adequacy of thyroid hormone replacement in early pregnancy.

Chronic and recurrent infections occur commonly in both type 1 and type 2 diabetes (T1D, T2D) and increase patient morbidity and mortality. Neutrophils are professional phagocytes of the innate immune system that are critical in pathogen handling. Neutrophil responses to infection are dysregulated in diabetes, predominantly mediated by persistent hyperglycaemia; the chief biochemical abnormality in T1D and T2D. Therapeutically enhancing host immunity in diabetes to improve infection resolution is an expanding area of research. Individuals with diabetes are also at an increased risk of severe coronavirus disease 2019 (COVID-19), highlighting the need for re-invigorated and urgent focus on this field. The aim of this review is to explore the breadth of previous literature investigating neutrophil function in both T1D and T2D, in order to understand the complex neutrophil phenotype present in this disease and also to focus on the development of new therapies to improve aberrant neutrophil function in diabetes. Existing literature illustrates a dual neutrophil dysfunction in diabetes. Key pathogen handling mechanisms of neutrophil recruitment, chemotaxis, phagocytosis and intracellular reactive oxygen species (ROS) production are decreased in diabetes, weakening the immune response to infection. However, pro-inflammatory neutrophil pathways, mainly neutrophil extracellular trap (NET) formation, extracellular ROS generation and pro-inflammatory cytokine generation, are significantly upregulated, causing damage to the host and perpetuating inflammation. Reducing these proinflammatory outputs therapeutically is emerging as a credible strategy to improve infection resolution in diabetes, and also more recently COVID-19. Future research needs to drive forward the exploration of novel treatments to improve infection resolution in T1D and T2D to improve patient morbidity and mortality.

This is one of the largest community-based studies of the prevalence of epilepsy in adults conducted in sub-Saharan Africa to date. We identified a lower prevalence than has previously been described in this region. The high proportion of focal onset seizures points to a large burden of acquired, and possibly preventable, epilepsy in this population. A treatment gap of 68.4% confirms that interventions to raise awareness of the treatable nature of epilepsy are warranted in this and similar populations.

Context Hypoglycemia is emerging as a risk for cardiovascular events in diabetes. We hypothesized that hypoglycemia activates the innate immune system, which is known to increase cardiovascular risk. Objective To determine whether hypoglycemia modifies subsequent innate immune system responses. Design and Setting Single-blinded, prospective study of three independent parallel groups. Participants and Interventions Twenty-four healthy participants underwent either a hyperinsulinemic-hypoglycemic (2.5 mmol/L), euglycemic (6.0 mmol/L), or sham-saline clamp (n = 8 for each group). After 48 hours, all participants received low-dose (0.3 ng/kg) intravenous endotoxin. Main Outcome Measures We studied in-vivo monocyte mobilization and monocyte-platelet interactions. Results Hypoglycemia increased total leukocytes (9.98 ± 1.14 × 109/L vs euglycemia 4.38 ± 0.53 × 109/L, P &lt; 0.001; vs sham-saline 4.76 ± 0.36 × 109/L, P &lt; 0.001) (mean ± SEM), mobilized proinflammatory intermediate monocytes (42.20 ± 7.52/μL vs euglycemia 20.66 ± 3.43/μL, P &lt; 0.01; vs sham-saline 26.20 ± 3.86/μL, P &lt; 0.05), and nonclassic monocytes (36.16 ± 4.66/μL vs euglycemia 12.72 ± 2.42/μL, P &lt; 0.001; vs sham-saline 19.05 ± 3.81/μL, P &lt; 0.001). Following hypoglycemia vs euglycemia, platelet aggregation to agonist (area under the curve) increased (73.87 ± 7.30 vs 52.50 ± 4.04, P &lt; 0.05) and formation of monocyte-platelet aggregates increased (96.05 ± 14.51/μL vs 49.32 ± 6.41/μL, P &lt; 0.05). Within monocyte subsets, hypoglycemia increased aggregation of intermediate monocytes (10.51 ± 1.42/μL vs euglycemia 4.19 ± 1.08/μL, P &lt; 0.05; vs sham-saline 3.81± 1.42/μL, P &lt; 0.05) and nonclassic monocytes (9.53 ± 1.08/μL vs euglycemia 2.86 ± 0.72/μL, P &lt; 0.01; vs sham-saline 3.08 ± 1.01/μL, P &lt; 0.05), with platelets compared with controls. Hypoglycemia led to greater leukocyte mobilization in response to subsequent low-dose endotoxin challenge (10.96 ± 0.97 vs euglycemia 8.21 ± 0.85 × 109/L, P &lt; 0.05). Conclusions Hypoglycemia mobilizes monocytes, increases platelet reactivity, promotes interaction between platelets and proinflammatory monocytes, and potentiates the subsequent immune response to endotoxin. These changes may contribute to increased cardiovascular risk observed in people with diabetes.