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Abstract Background Preexisting diabetes (PDM) increases the risk of maternal and perinatal mortality and morbidity. Reduction of maternal hyperglycemia prior to and during pregnancy can reduce these risks. Despite compelling evidence that preconception care (PCC), which includes achieving strict glycemic goals, reduces the risk of congenital malformations and other adverse pregnancy outcomes, only a minority of individuals receive PCC. Suboptimal pregnancy outcomes demonstrated in real-world data highlight the need to further optimize prenatal glycemia. New evolving technology shows promise in helping to achieve that goal. Dysglycemia is not the only driver of poor pregnancy outcomes in PDM. The increasing impact of obesity on pregnancy outcomes underscores the importance of optimal nutrition and management of insulin sensitizing medications during prenatal care for PDM. Objective To provide recommendations for the care of individuals with PDM that lead to a reduction in maternal and neonatal adverse outcomes. Methods The Guideline Development Panel (GDP) composed of a multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 10 clinically relevant questions related to the care of individuals with diabetes before, during and after pregnancy. The GDP prioritized randomized controlled trials (RCTs) evaluating the effects of different interventions (eg, PCC, nutrition, treatment options, delivery) during the reproductive life cycle of individuals with diabetes, including type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Systematic reviews queried electronic databases for publications related to these 10 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and develop recommendations. The approach incorporated perspectives from 2 patient representatives and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. Results In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest asking a screening question about pregnancy intention at every reproductive, diabetes, and primary care visit. Screening for pregnancy intent is also suggested at urgent care/emergency room visits when clinically appropriate (2 | ⊕OOO). This was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced glycated hemoglobin (HbA1c) at the first prenatal visit and congenital malformations. In individuals with diabetes mellitus who have the possibility of becoming pregnant, we suggest use of contraception when pregnancy is not desired (2 | ⊕⊕OO). This was suggested based on indirect evidence in women with diabetes, where PCC—including contraception as a key component—showed a clinically significant association with improvements in first-trimester HbA1c and the rate of congenital malformations, together with indirect evidence from the general population regarding the reduction of unplanned pregnancies and pregnancy terminations with the use of contraception. In individuals with T2DM, we suggest discontinuation of glucagon-like peptide-1 receptor agonist (GLP-1RA) before conception rather than discontinuation between the start of pregnancy and the end of the first trimester (2 | ⊕OOO). This was suggested based on limited data on risk of exposure to GLP-1RA receptor agonists during pregnancy. In pregnant individuals with T2DM already on insulin, we suggest against routine addition of metformin (2 | ⊕OOO). This was suggested based on the GDP judgment that the benefit of adding metformin to insulin to achieve decrease in rates of large for gestational age infants did not outweigh the potential harm of increasing the risk of small for gestational age infants or adverse childhood outcomes related to changes in body composition. In individuals with PDM, we suggest either a carbohydrate-restricted diet (<175 g/day) or usual diet (>175 g/day) during pregnancy (2 | ⊕OOO). This was suggested based on the GDP judgment that the available evidence was limited and very indirect, resulting in significant uncertainty about the net benefits or harms. As such, the evidence was insufficient to support a recommendation either for or against a carbohydrate intake cutoff of 175 g/day. In pregnant individuals with T2DM, we suggest either the use of a continuous glucose monitor (CGM) or self-monitoring of blood glucose (SMBG) (2 | ⊕OOO). There is lack of direct evidence supporting superiority of CGM use over SMBG for T2DM during pregnancy. There is indirect evidence supporting improved glucometrics with the use of CGM for individuals with T2DM outside of pregnancy, substantial improvements in neonatal outcomes for individuals with T1DM using CGM during pregnancy and the potential for decreasing adverse pregnancy outcomes with improved glucometrics in individuals with T2DM. In individuals with PDM using a CGM, we suggest against the use of a single 24-hour CGM target <140 mg/dL (7.8 mmol/L) in place of standard-of-care pregnancy glucose targets of fasting <95 mg/dL (5.3 mmol/L), 1-hour postprandial <140 mg/dL (7.8 mmol/L), and 2-hour postprandial < 120 mg/dL (6.7 mmol/L) (2 | ⊕OOO). This was suggested based on indirect evidence that associated adverse pregnancy outcomes with a fasting glucose > 126 mg/dL (7 mmol/L). In individuals with T1DM who are pregnant, we suggest the use of a hybrid closed-loop pump (pump adjusting automatically based on CGM) rather than an insulin pump with CGM (without an algorithm) or multiple daily insulin injections with CGM (2 | ⊕OOO). This was suggested based on a meta-analysis of RCTs which demonstrated improvement in glucometrics with increased time in range (MD +3.81%; CI −4.24 to 11.86) and reduced time below range (MD −0.88%; 95% CI: −2.04 to 0.27) with the use of hybrid closed-loop pump technology. In individuals with PDM, we suggest early delivery based on risk assessment rather than expectant management (2 | ⊕OOO). This was suggested based on indirect evidence that risks may outweigh benefits of expectant management beyond 38 weeks gestation and that risk assessment criteria may be useful to inform ideal delivery timing. In individuals with PDM (including those with pregnancy loss or termination), we suggest postpartum endocrine care (diabetes management), in addition to usual obstetric care (2 | ⊕OOO). As the postpartum period frequently overlaps with preconception, this was suggested based on indirect evidence demonstrating a strong association between PCC and both reduced HbA1c at the first prenatal visit and congenital malformations. Conclusion The data supporting these recommendations were of very low to low certainty, highlighting the urgent need for research designed to provide high certainty evidence to support the care of individuals with diabetes before, during, and after pregnancy. Investment in implementation science for PCC is crucial to prevent significant mortality and morbidity for individuals with PDM and their children. RCTs to further define glycemic targets in pregnancy and refinement of emerging technology to achieve those targets can lead to significant reduction of harm and in the burden of diabetes care. Data on optimal nutrition and obesity management in pregnancy are lacking. More research on timing of delivery in women with PDM is also needed.

Abstract Rationale: Chronic lung diseases, such as COPD and bronchiectasis (BE), may manifest differently by gender in symptom presentation, time to diagnosis, and overall disease burden. This study aimed to assess perceptions of individuals with self-reported COPD, BE, or non-tuberculous mycobacteria (NTM) regarding healthcare experiences and disease-related symptoms. Methods: This cross-sectional study analyzed data from US-based and international participants with self-reported COPD, BE, or NTM using an online survey. Participants were recruited through the COPD Foundation (COPDF) social media channels and completed a questionnaire developed with input from a steering committee that included COPDF leadership, physician-researchers, and patient stakeholders. The survey explored participants’ experiences with healthcare, disease burden, and self-reported symptoms. A subset of women answered additional questions regarding menopause-related symptom changes. Descriptive statistics were calculated and analyzed across self-identified genders and two disease groups: COPD (with or without BE or NTM) and BE (with or without NTM or COPD). Continuous variables were compared using ANOVA, while categorical variables were analyzed using chi-square or Fisher's exact test. Results: Of 632 respondents included in these analyses (mean age 70±9 years, 74% women), 68% reported COPD and 32% BE (both groups included individuals with or without additional diagnoses). Women with COPD were younger than men (p=0.048) and had a shorter duration between symptom onset and initial healthcare visit (< 6 months) (p<0.01). Compared to men, a higher proportion of women with COPD reported that their diagnosis was not explained by a healthcare provider (p=0.0381) and that they experienced anxiety, depression, or fear related to their diagnosis (p=0.0074). Among participants with BE, men and women were similar in age, though a higher proportion of men had shorter intervals (<6 months) between initial healthcare visit and confirmed diagnosis (p=0.0244) and received their diagnosis during hospitalization (p=0.0244). Both men and women across diagnoses reported similar levels of disease management burden, pulmonologist visit frequency, CAAT scores, numbers of comorbidities, and financial difficulties related to their lung condition. Over 75% of women identified as post-menopausal, with approximately one-third reporting worsening pulmonary symptoms associated with menopause. Conclusions: Despite similarities in disease management and comorbidity burden, women with BE and men with COPD reported longer times to initial healthcare visits and diagnostic delays, respectively. Additionally, over one-third of post-menopausal women experienced symptom exacerbation since menopause. These findings underscore the need to further explore gender-based differences and disparities in healthcare access and pulmonary care to enhance lung health outcomes across genders.

Abstract Introduction: Endobronchial optical coherence tomography (EB-OCT) imaging has unique potential to diagnose and quantify early, microscopic disease changes and assess therapeutic responsivity in interstitial lung disease (ILD). However, training and time requirements for interpretation and quantitative evaluation of large volumetric EB-OCT datasets need to be optimized to facilitate clinical adoption. We develop and validate a computationally-efficient, rapid EB-OCT quantitative image analysis framework using artificial intelligence (AI) with deep learning architecture for 2D feature segmentation, 3D feature burden and spatial distribution mapping, and computer-aided diagnosis in early ILD subjects. Methods: Volumetric EB-OCT datasets, consisting of 2D cross-sectional images, were acquired from multiple locations in the bilateral lungs of ILD and healthy control subjects. EB-OCT features were manually segmented from cross-sectional images by an expert EB-OCT reader, including fibrosis, microscopic honeycombing, traction bronchiolectasis, normal parenchyma, and emphysema. EB-OCT images with corresponding feature segmentations were used to train and validate a multiclass convolutional neural network. The 2D AI-based segmentation model was subsequently evaluated against manual ‘ground truth’ segmentations for each feature in a de novo ‘test’ dataset of independent subjects using dice similarity score, precision, recall/sensitivity, specificity, and balanced accuracy. To generate 3D AI-based quantitative feature burden and spatial distribution maps, AI-based feature segmentation was performed on each EB-OCT 2D cross-sectional image within a volumetric imaging site. Three external pathologist readers independently interpreted 3D AI-based features maps for each EB-OCT imaging site acquired for a subject (without access to EB-OCT images) and provided a single diagnosis of usual interstitial pneumonia (UIP) or non-UIP ILD. Performance of computer-aided ILD diagnosis was compared against independently evaluated histopathology, clinical diagnosis, and prior EB-OCT image interpretation. Results: EB-OCT was acquired in 51 subjects: 30 in vivo early ILD, 5 in vivo non-ILD controls, and 16 ex vivo end-stage ILD. Overall pixel similarity between 2D manual and AI-based segmentation demonstrated high accuracy for each ILD feature (mean balanced accuracy 0.9). 3D quantitative AI-based feature maps demonstrated strong agreement (Spearman ρ0.87, p<0.001) between manual and AI-based segmentation. AI-based computer-aided diagnosis demonstrated 100% sensitivity/specificity for histologic UIP and clinical IPF for all pathologist readers, with improved diagnostic accuracy and significantly reduced training (45-minute training, 75% reduction) and interpretation time (<1 minute per subject for computer-aided diagnosis, 88% reduction) compared to EB-OCT image interpretation. Conclusion: The AI-based EB-OCT image analysis framework could expedite computer-aided diagnosis of early ILD and robust, quantitative assessment of microscopic disease burden, progression, and therapeutic responsivity.

Objectives: To determine associations between physician sex and use of postoperative healthcare resources among patients undergoing common surgeries in Ontario, Canada. Background: Prior studies have shown that patients of female physicians experience better outcomes and have lower healthcare costs compared with patients of male physicians. Understanding differences in resource utilization may offer insights into the care pathways and practice patterns contributing to these differences. Methods: We conducted a population-based, retrospective cohort study of adults (≥18 years of age) undergoing 1 of 25 common surgeries, between January 1, 2007, and December 31, 2019, in Ontario, Canada. The primary outcome was the utilization of one of the following: intensive care unit admission, other medical interventions (eg, tracheostomy, new dialysis starts, and home oxygen), and discharge care needs (eg inpatient rehab, long-term care, and home care use) within 30 days. The data were summarized using descriptive statistics and adjusted using multivariable generalized estimating equations. Results: This population-based study included 1,100,193 patients (61.8% female). Patients treated by male surgeons had higher use of postoperative resources versus those with female surgeons within 30 days (adjusted rate 33.1; 95% confidence interval [CI]: 28.0–39.2 versus 31.2; 95% CI: 25.8–37.7), 90 days, and 1 year. Consistent with these findings, following adjustment for patient, surgeon, procedural, and hospital characteristics, patients treated by male surgeons were significantly more likely to utilize postoperative resources within 30 days (adjusted odds ratio: 1.14; 95% CI: 1.03–1.27; P = 0.010) and at other time points. This difference was primarily driven by the higher use of home care among patients with a male versus female surgeon at all time points (30 days: adjusted odds ratio, 1.13; 95% CI: 1.05–1.21; P = 0.002). Conclusions: Patients with male surgeons had higher postoperative resource utilization when compared with those treated by female surgeons, which was almost entirely driven by the higher use of home care. Further mixed-methods investigation is needed to better understand other potentially relevant factors including surgical outcomes, individual patient preferences, and surgical team decision-making.

PURPOSE Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We analyze the role of germline DICER1 status in outcomes of ovarian SLCT. METHODS Patients with SLCT were enrolled in the International Pleuropulmonary Blastoma/ DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and those with known germline DICER1 status were selected for analysis. RESULTS Of 162 patients with SLCT, 60% had a germline DICER1 pathogenic or likely pathogenic (P/LP) variant. The adjusted 3-year recurrence-free survival (RFS) was 87.2% (95% CI, 79.4 to 95.8) for patients with a germline DICER1 P/LP variant compared with 78.1% (95% CI, 66.4 to 91.9) for those without a germline DICER1 P/LP variant ( P = .043). The adjusted 3-year and 5-year overall survival (OS) was 93.9% (95% CI, 87.3 to 100.0) for those with a germline DICER1 P/LP variant compared with the 3-year OS of 91.3% (95% CI, 83.4 to 100.0) and the 5-year OS of 78.2% (95% CI, 63.8 to 95.9) for those without a germline DICER1 P/LP variant ( P = .021). Among patients with a germline DICER1 P/LP variant, the risk of a subsequent, nonrecurrent event was 36.2% (95% CI, 21.4 to 48.1) within 10 years. Previous/concurrent and subsequent neoplasms were rare among those without a germline DICER1 P/LP variant. CONCLUSION This cohort study of patients with SLCT demonstrated that those with germline DICER1 P/LP variants had superior RFS and OS even when adjusting for other prognostic factors. Beyond prognostic implications of a germline DICER1 P/LP variant, germline testing helps identify patients at risk of subsequent neoplasms, including metachronous SLCT.

AbstractBackgroundOvarian juvenile granulosa cell tumors (juvGCT) are rare sex cord‐stromal tumors that occur primarily in children and adolescents. This study summarizes the clinical presentation and outcomes of patients with juvGCT.MethodsPatients were enrolled in the International Ovarian and Testicular Stromal Tumor and/or International Pleuropulmonary Blastoma/DICER1 Registries. Available medical records were abstracted, and pathology was centrally reviewed. Surgical staging was classified using the 2014 International Federation of Gynecology and Obstetrics (FIGO) criteria.ResultsIn total, 70 patients with juvGCT enrolled and were diagnosed between 2001 and 2024; most patients (81%, 57 of 70) presented with FIGO stage I disease. Adjuvant chemotherapy was given in 30% (21 of 70); all regimens were platinum‐based. Three‐year event‐free survival among patients with stage IA tumors was 80.2% (95% confidence interval [CI], 62.4%–100.0%), IC1 was 87.4 (95% CI, 72.4%–100.0%), IC2‐IC3 was 63.6% (95% CI, 40.7%–99.5%), and II‐IV was 48% (95% CI, 24.6%–93.8%). Of the patients with recurrent juvGCT with known mitotic index (MI), all had MI greater than 19 mitoses per 10 high power fields (HPF) at diagnosis.ConclusionOutcomes were worse for patients with FIGO stage ≥IC2 disease and for tumors with >19 mitoses per 10 HPF. Given the prognostic significance of MI, the authors strongly recommend the assessment of MI for all juvGCTs. More information about tumor biology is critical to identify which patients may benefit from adjuvant chemotherapy and to facilitate the development of novel therapies.

Abstract Aims To evaluate whether the effect of inclisiran to lower LDL-C varied by background lipid-lowering therapy (LLT). Methods and results In ORION-10 and ORION-11 Phase 3 trials, patients (N = 3178) with atherosclerotic cardiovascular disease (ASCVD) or ASCVD risk equivalents were randomized 1:1 to receive inclisiran or placebo on Day 1, Day 90, and 6-monthly thereafter. In this pooled post hoc analysis, patients were stratified by baseline combination therapy [statin plus ezetimibe (n = 214; 6.7%)], monotherapy [statin (n = 2711; 85.3%) or ezetimibe (n = 54; 1.7%)], or neither LLT [none (n = 199; 6.3%)] into therapy groups with/without other LLT. Stratification by baseline statin intensity was also performed (N = 3155). Relative and absolute changes in LDL-C were assessed. Mean (±SD) baseline LDL-C was 2.7 mmol/L (±1.0), 2.6 mmol/L (±0.9), 3.7 mmol/L (±1.7), and 4.1 mmol/L (±1.5) among patients receiving combination, statin, ezetimibe, or neither LLT, respectively. In these categories, mean (95% confidence interval) time-adjusted, placebo-corrected percentage change in LDL-C after Day 90 to Day 540 with inclisiran were −57.0% (−63.8, −50.1), −51.5.% (−53.4, −49.7), −50.5.% (−59.6, −41.5), and −43.1% (−48.7, −37.6); corresponding absolute changes were −1.5 mmol/L (−1.7, −1.3), −1.3 mmol/L (−1.4, −1.3), −1.7 mmol/L (−2.0, −1.4), and −1.7 mmol/L (−1.9, −1.5). Conclusion Sustained and effective LDL-C lowering with inclisiran was observed irrespective of background LLT treatment. Inclisiran was overall well tolerated with all background LLT treatments, consistent with its established safety profile.