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Ophthalmic immune-related adverse events (Eye-irAEs) from immune checkpoint inhibitors can cause visual morbidity. The absence of standardized definitions for Eye-irAEs not only impedes the development of evidence-based treatments but also progress in translational research. The objective of this study was to develop consensus guidance for an approach to Eye-irAEs. Four ophthalmic physicians (uveitis specialists and neuro-ophthalmologists) drafted Eye-irAE consensus guidance and definitions, which were reviewed by the multidisciplinary Eye-irAE definition panel. The panel was divided into Group A (Neuro-ophthalmology/Orbital Disease) and Group B (Uveitis/Ocular Surface Disease). A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. For each disorder, five diagnostic components were evaluated: symptoms, examination findings, laboratory studies/imaging findings, diagnostic criteria, and treatment. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free-text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND Corporation/ University of California Los Angeles Health Services Utilization Study (RAND/UCLA) Appropriateness Method with prespecified definitions. 29 panelists from 25 academic medical centers voted on 114 rating scales (66 neuro-ophthalmic/orbital disease components, 48 uveitis/ocular surface disease components); of these, 86.3% (57/66) in Group A and 89.6% (43/48) in Group B reached first-round consensus. After revisions, all items except 6.1% (4/66) in Group A and 1.6% (1/60) in Group B received second-round consensus. Consensus definitions were achieved for 10/11 neuro-ophthalmic/orbital disorders: optic neuritis, inflammatory optic disc edema, arteritic ischemic optic neuropathy, optic perineuritis, orbital inflammation, thyroid eye disease-like orbital inflammation, cavernous sinus syndrome, oculomotor mononeuritis, trochlear mononeuritis, and abducens mononeuritis. Consensus definitions were achieved for 9/10 uveitis/ocular surface disorders: anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, Vogt-Koyanagi-Harada-like syndrome, sarcoidosis-like syndrome, acute macular neuroretinopathy, dry eye disease, and scleritis. These disease definitions establish a standardized classification for Eye-irAE, highlighting differences between irAEs and other inflammatory disorders. Importantly, diagnostic certainty does not always align directly with the need to treat as an Eye-irAE. Given the consensus from this representative panel group, it is anticipated the definitions will be used broadly across clinical and research settings.

Abstract Aims To investigate the cost‐effectiveness of early initiation of metformin and usual care for gestational diabetes mellitus (GDM). Methods Economic evaluation from a healthcare perspective, based on the EMERGE randomised controlled trial. In total, 535 women with GDM were randomised to placebo in addition to usual care or metformin in addition to usual care. Economic outcomes included incremental healthcare costs and quality adjusted life years ( QALYs ) and expected cost‐effectiveness at cost‐effectiveness threshold values of €20,000, €45,000 and €100,000 per QALY gained. Uncertainty was explored using parametric, non‐parametric, deterministic and probabilistic methods and heterogeneity using subgroup analysis. Results On average, relative to the placebo arm, the early metformin arm was associated with non‐statistically significant mean increases of €193.07 (95% CI : −€789.88, €1176.01; p = 0.700) and 0.002 QALYs (95% CI : −0.009, 0.013; p = 0.771). In terms of expected cost‐effectiveness at threshold values of €20,000, €45,000 and €100,000 per QALY gained, the probability of the early metformin arm being more cost‐effective was estimated at 0.423, 0.452 and 0.524. Exploratory subgroup analyses provided more favourable but not definitive evidence in favour of the early metformin arm for cohorts with previous GDM and previous caesarean section. Conclusions We do not find definitive evidence that early initiation of metformin in addition to usual care for GDM was more cost‐effective than usual care alone. The clinical and economic evidence may be considered equivocal, but worthy of further examination.

Abstract Metformin is well‐established as a treatment for type 2 diabetes in non‐pregnant individuals. The low cost, acceptability and broad tolerability of metformin have also made it an attractive option for research into the treatment of other conditions associated with insulin resistance. Despite almost 50 years of clinical experience with the use of metformin to treat diabetes in pregnancy, many questions remain regarding its precise effectiveness in different maternal subgroups, as well as potential short‐term and long‐term effects on the offspring. In this narrative review, we present the current evidence for the use of metformin during pregnancy in various maternal subgroups, including women living with overweight and obesity, women at risk of gestational diabetes, women diagnosed with gestational diabetes and women with pregestational diabetes, including type 2 diabetes. Our specific focus is on the impact of metformin on short‐term maternal, fetal and neonatal outcomes. We also consider the evidence for other emerging indications for metformin in pregnancy, such as the prevention and management of pre‐eclampsia. Plain Language Summary This article looks at research on how metformin use in pregnancy affects mothers and newborns in the short term. Doctors have prescribed metformin since the 1970s for the treatment of diabetes in pregnancy. Despite years of use, there are still questions about how safe and effective metformin is for mothers and their children. Metformin taken during pregnancy moves through the placenta into the foetus's bloodstream. The short‐term and long‐term effects of metformin on offspring need careful attention. The studies that have looked at the link between metformin use and birth defects have not found any strong link between taking metformin in pregnancy and birth defects, however close attention will continue to be paid in this area. Some large studies have examined the use of metformin in pregnant women who do not have diabetes, but who do live with overweight or obesity. The studies are difficult to compare. Some, but not all, of these studies have shown less weight gain for the mother if metformin is taken by these women during pregnancy. Other large studies have looked at whether metformin can prevent gestational diabetes. The results are mostly disappointing. They suggest that metformin does not stop gestational diabetes from developing. However, the participants in these studies were mostly from white backgrounds and metformin may help prevent gestational diabetes in women of different ethnic backgrounds. However, more research is needed. Metformin has been widely studied as an alternative to insulin for the treatment of gestational diabetes. Because different countries diagnose and treat GDM differently, this makes comparing study results difficult. Women with gestational diabetes seem to gain less weight during pregnancy if they use metformin rather than insulin. Using metformin instead of insulin may result in lower average birth weights for babies from these pregnancies. Also, the use of metformin may lead to fewer babies being born abnormally large. Similarly, large trials have examined the use of metformin in pregnant women who are living with type 2 diabetes. These studies show that metformin can lower a mother's insulin needs. It can also help control weight gain and reduce the risk of having a large baby. One study found that metformin use in women living with Type 2 diabetes might increase the risk of having smaller babies. This was especially true if the mother had high blood pressure or kidney disease. This finding requires further investigation. Metformin might help prevent pre‐eclampsia, but this is still unclear. Research is ongoing into a potential role for metformin in the treatment of pre‐eclampsia. In conclusion, metformin has been studied in many groups of pregnant women. Women with gestational diabetes or type 2 diabetes may see benefits like less weight gain and better blood sugar/glucose control. Current evidence suggests that metformin shouldn't be used if there are foetal growth issues. It is also not recommended for mothers with high blood pressure or kidney disease. Future studies might find specific groups of pregnant women who would benefit the most from metformin.

In this study, we propose a new mathematical model able to quantify C-peptide secretion and β-cell responsivity in response to a glucagon bolus in individuals without and with type 2 diabetes. We show that individuals with type 2 diabetes exhibit reduced β-cell responsivity to glucagon.

Introduction: The lack of understanding about the genetic and molecular basis of young stroke (<55 years of age) has hindered development of diagnostic, management, and therapeutic approaches. Whole exome sequencing (WES) can be leveraged as a tool for studying etiological processes underlying stroke. At the time of study inception, this is the single largest WES study in this unique young stroke population to uncover elusive stroke etiologies. Methods: The Mayo Clinic TAPESTRY database is a research program conducting whole exome sequencing of 100,000 participants. Of these, 406 participants met the criteria for young stroke (18-54 years of age) based on ICD-9 and ICD-10 diagnostic codes. Controls were TAPESTRY participants without a stroke-related ICD diagnosis. Cases were matched for age, gender, and race for a 1:4 case-control ratio. Ischemic stroke etiology was classified using TOAST classification. To uncover genetic mechanisms, a gene centric approach was used to identify variants in our cohort. A list of 66 genes known to be associated with young stroke was curated based on existing genetic databases. Various filtration strategies were used to identify potentially damaging variants (graphic 1). Results: There were 406 cases (363 ischemic and 43 hemorrhagic; 291 female; age at stroke onset 39.8±10.4; 368 were White) and 3,857 controls. TOAST classification yielded 20 patients with large artery atherosclerosis, 58 cardioembolic, 10 small vessel disease, 148 other determined (58 patent foramen ovale, 50 dissection, 48 hypercoagulable state, 11 Moyamoya, 11 vasculitis, 10 fibromuscular dysplasia), and 165 undetermined etiologies. Several individuals had multiple competing etiologies. Of cerebral hemorrhages, there were 6 aneurysmal, 6 arteriovenous malformation, 5 hypertensive, 2 substance abuse, 3 trauma, and 21 other etiologies. Across the entire cohort, 35,054 variants were found within the 66 genes identified from the literature. Filtration identified 48 potentially damaging variants across 30 genes in 44 patients (20 cryptogenic and 21 other: 12 patent foramen ovale, 5 vasculitis, 4 dissection, 4 cardioembolic) that were absent in controls. Conclusion: WES is a powerful tool that can be used to uncover potential genetic mechanisms in the young stroke population. An improved understanding of etiologies would improve diagnostics and pave the way for new preventive and therapeutic approaches, thus improving the overall care of young stroke patients.

ImportanceUnderstanding the interplay between diabetes risk factors and diabetes development is important to develop individual, practice, and population-level prevention strategies.ObjectiveTo evaluate the progression from normal and impaired fasting glucose levels to diabetes among adults.Design, Setting, and ParticipantsThis retrospective community-based cohort study used data from the Rochester Epidemiology Project, in Olmsted County, Minnesota, on 44 992 individuals with at least 2 fasting plasma glucose (FPG) measurements from January 1, 2005, to December 31, 2017. People who met criteria for diabetes on or before their first FPG measurement were excluded. Data were electronically retrieved in December 2019 with analyses finalized in November 2024.ExposuresThe exposure was baseline FPG level, with covariates including the following measures that are consistently recorded in the electronic health record: body mass index (BMI), age, and sex.Main Outcomes and MeasuresThe cumulative probability of freedom from diabetes was estimated and presented graphically using a Kaplan-Meier curve. Multivariable Cox proportional hazards regression modeling was used to estimate the partial hazard ratios (HRs) for variables of interest. Diabetes was defined as an FPG level greater than 125 mg/dL.ResultsA total of 44 992 individuals (mean [SD] age at baseline, 43.7 [11.8] years; 26 025 women [57.8%]) were included. The baseline mean (SD) BMI was 28.9 (6.6). Over a median follow-up of 6.8 years (IQR, 3.6-9.7 years), 3879 individuals (8.6%) developed diabetes. The Kaplan-Meier 10-year cumulative risk of incident diabetes was 12.8% (95% CI, 12.4%-13.2%). All initial FPG levels outside a range of 80 to 94 mg/dL were associated with increased risk for diabetes (ie, FPG &amp;lt;70 mg/dL: HR, 3.49 [95% CI, 2.19-5.57]; FPG 120-125 mg/dL: HR, 12.47 [10.84-14.34]). Other independent risk factors were male sex (HR, 1.31 [95% CI, 1.22-1.40]), older age (≥60 years: HR, 1.97 [95% CI, 1.71-2.28]), and any abnormal category of BMI, including underweight (BMI &amp;lt;18.5: HR, 2.42 [95% CI, 1.77-3.29]; BMI ≥40: HR, 4.03 [95% CI, 3.56-4.56]). There was a significant additive association of variables, particularly FPG level and BMI. For instance, a woman aged 55 to 59 years with a BMI of 18.5 to 24.9 and an FPG level of 95 to 99 mg/dL had an estimated 10-year diabetes risk of 7.0%. However, an almost doubling of risk to 13.0% was observed if the BMI was 30.0 to 34.9, and risk more than doubled again to 28.0% if FPG level also increased to 105 to 109 mg/dL. A nomogram was generated to facilitate individual classification into one of four 10-year risk categories.Conclusions and RelevanceThis retrospective cohort study of 44 992 individuals suggests that FPG level, age, BMI, and male sex were all associated with development of diabetes, with significant interaction between these variables. These data contribute to understanding the clinical course of diabetes and highlight the substantial individual variation in diabetes risk according to commonly measured clinical variables. The findings facilitate lifestyle and pharmacologic interventions to treat those at highest risk of diabetes to reduce future morbidity and mortality. Further work is needed to validate this risk categorization tool for different populations.

Abstract Context Defects in insulin secretion and action contribute to the progression of prediabetes to diabetes. However, the contribution of α-cell dysfunction to this process has been unclear. Objective This work aimed to understand the relative contributions of α-cell and β-cell dysfunction to declining glucose tolerance. Methods A longitudinal, community-based observational study was conducted at a clinical research unit at an academic medical center. We studied 96 individuals without diabetes (age 55 ± 1 years; body mass index 27.7 ± 0.4) on 2 occasions, 3 years apart using an oral 75-g glucose challenge. Indices for insulin secretion and action were estimated using the oral minimal model. Glucagon secretion rate (GSR) was estimated by deconvolution from peripheral glucagon concentrations. Main outcome measures included glucose tolerance status (categorical variable) and then symmetrical percentage change in peak and 120-minute glucose (post oral glucose tolerance test) concentrations (continuous variables). Results A total of 32 individuals progressed from normal to impaired glucose tolerance (IGT) or from IGT to type 2 diabetes. The disposition index (DI) declined in the progressors (568 ± 98 vs 403 ± 65 10−4 dL/kg/min per μU/mL, baseline vs 3 years; P = .04). α-Cell suppression by glucose (δGSR/δglucose) did not change in the nonprogressors (1.5 ± 0.1 vs 1.3 ± 0.1 nmol/min/L; P = .37) but decreased (1.0 ± 0.2 vs 0.8 ± 0.2 nmol/min/L; P &lt; .01) in those who progressed. Analysis of the entire cohort showed that DI and δGSR/δglucose were independently and inversely correlated with an increase in glycemic excursion. Conclusion These data show that α-cell dysfunction accompanies a decline in β-cell function as IGT or overt type 2 diabetes develops.