The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the consensus statement on the management of type 2 diabetes in nonpregnant adults, published since 2006 and last updated in 2022. The target audience is the multidisciplinary health care team providing diabetes care in the U.S. and Europe. A systematic examination of publications since 2022 informed new recommendations. This update has broadened the focus from the management of hyperglycemia to the holistic management of type 2 diabetes and its risk of associated multiple long-term conditions. Fundamental aspects of diabetes care include promoting healthy lifestyle behaviors (healthy eating, 24-h physical behaviors including sleep, and avoiding tobacco and substance use), alongside the provision of psychological support and weight management interventions. For the management of people living with type 2 diabetes, earlier use, potentially from diagnosis, of sodium-glucose cotransporter 2 (SGLT2) inhibitors and/or glucagon-like peptide 1 (GLP-1)-based therapies to offer organ protection and improve long-term outcomes in type 2 diabetes is advocated. Furthermore, earlier combination use of SGLT2 inhibitors and GLP-1-based therapies should be considered in people with concomitant cardiovascular disease, chronic kidney disease, and heart failure. Finally, the ability to transform outcomes for people living with type 2 diabetes is within our grasp through the consistent, equitable, and systematic implementation of strategies and therapies that are already available.

Noonan syndrome (NS) is a multisystem RASopathy marked by characteristic facies, congenital heart disease, short stature, and variable neurodevelopmental and systemic complications. Although molecular and clinical knowledge has advanced, evidence-based clinical guidance in Japan has been limited. A multidisciplinary committee in pediatric endocrinology, clinical genetics, and pediatric cardiology developed consensus guidelines on diagnosis, comorbidity assessment, treatment, and transitional care. Clinical questions were defined, and the literature published through March 2024 was systematically reviewed. Evidence was graded in partial accordance with the Minds Clinical Practice Guideline Development Manual 2020 and the GRADE framework, with expert consensus supplementing areas of limited evidence. External review included patient groups and academic societies, and the guideline was approved in 2025. The guideline recommends expanding diagnostic panels to include LZTR1, SOS2, MRAS, RRAS, and RRAS2 in addition to established genes. It advises comprehensive childhood assessment for tumor predisposition, coagulation abnormalities, hearing and ophthalmologic problems, neurodevelopmental features, and endocrine and cardiovascular complications, with strong emphasis on cardiac evaluation. Growth hormone therapy is recommended for short stature with careful monitoring for malignancy risk. MEK inhibitors may help selected patients with refractory hypertrophic cardiomyopathy or lymphatic abnormalities. Lifelong multidisciplinary surveillance and structured transition to adult care are strongly emphasized.

A steady increase in the number of grandparent caregivers - accelerated by recent trends such as children orphaned by the COVID-19 pandemic or the opioid crisis - magnifies the importance of addressing cardiovascular disease (CVD) risk in that already at high-risk group. However, few efforts have directly addressed the specific cardiac health needs of grandparent primary caregivers (or custodial grandparents). In this paper, we describe the research protocol for the Rural Caregiver Heart Health Education (RICHH) intervention for implementation with grandparent caregivers (RICHH-GP) study funded by the National Institute of Heart, Lung, and Blood. This study will tailor an existing CVD risk reduction intervention (RICHH) for implementation with grandparent primary caregivers and then test the modified design for feasibility, acceptability, and preliminary efficacy. The expected outcome of RICHH-GP is to establish the groundwork for an expanded future clinical trial in which we will test effectiveness with a longer follow-up and with increased inclusivity of participants from marginalized populations. The specific aims are: 1) modify the RICHH intervention to target custodial grandparents from a variety of backgrounds; 2) employ the tailored intervention and assess its feasibility and acceptability via a 2-arm randomized controlled trial; 3) test the preliminary efficacy of RICHH-GP based on measures of CVD risk (physical activity, dietary intake, nicotine exposure, sleep, body mass index, lipids, blood pressure, and HbA1c), self-management behaviors, and depressive symptoms at 4- and 6-months compared to baseline and; 4) (exploratory) examine the proximal impact of the RICHH-GP intervention on CVD risk and depressive symptoms on a subsample of grandchildren of the grandparent participants. The ultimate objectives of this work are to prevent CVD-related morbidity and mortality and overall physical decline, improve psychological well-being among grandparent caregivers, and foster a more heart-healthy environment in grandfamilies.

Cardiac valve tissue obtained during the surgical management of infective endocarditis (IE) and sent for culture may influence postoperative antibiotic therapy. We sought to identify clinical and microbiologic risk factors associated with positive valve cultures (PVCs) and IE relapses in a cohort of patients undergoing surgical management.

This is a retrospective, multicenter study of patients with surgical management during the acute course (<42 days) of IE-directed antibiotic therapy. The rate of PVC, IE relapse, and mortality were collected. Univariate and multivariable logistic regressions were performed to identify risk factors associated with PVC.

Of 113 patients included, 36 (31.9%) had PVCs. Univariate and multivariable analyses showed that preoperative antibiotic duration and pathogens were associated with PVC. The median number of days of preoperative antibiotics was 6.5 (interquartile range [IQR], 4.0-11.0) for patients with PVCs compared to 13.0 (IQR, 8.0-21.0) for those with negative valve cultures (NVCs). In a multivariable model, preoperative antibiotic administration decreased the risk of PVC (odds ratio [OR], 0.85 per day [95% CI, .77-.91]). Enterococcal IE increased the risk of PVC compared to streptococcal IE (OR, 4.16 [95% CI, 1.07-17.48]). Of note, 33 (63.2%) patients with NVCs received a median of 8 (IQR, 5-18.5) days of avoidable intravenous antibiotics per patient. Only 1 IE relapse was identified and occurred in a patient with NVCs.

Both preoperative antibiotic duration and causative pathogen were associated with PVC. IE relapses were rare and unrelated to PVC. There may be an opportunity to shorten postoperative antibiotic durations following surgical management in patients with IE.

Subarachnoid hemorrhage (SAH) remains a devastating cerebrovascular emergency with high mortality and long-term neurological morbidity, yet the mechanisms driving secondary brain injury remain incompletely understood. The glymphatic system, a glial-dependent perivascular clearance pathway, promotes convective exchange of cerebrospinal fluid and interstitial fluid through aquaporin-4 water channels on astrocytic endfeet to remove neurotoxic solutes. Emerging evidence implicates glymphatic dysfunction as a key mediator of brain injury after SAH. This review synthesizes current knowledge on the anatomical and physiological foundations of the glymphatic system, examines the multifaceted mechanisms by which SAH disrupts this clearance network, and discusses the pathophysiological consequences linking glymphatic impairment to neurological outcomes. Understanding the glymphatic dimension of SAH pathophysiology may illuminate novel therapeutic targets and ultimately improve the clinical management of this devastating condition.

The diagnosis of Fabry disease (FD) in heterozygous females remains clinically challenging, as random X-chromosome inactivation frequently leads to preserved α-galactosidase A (α-Gal A) activity and absence of classic clinical stigmata. While concurrent FD and IgA nephropathy (IgAN) is a rare comorbidity predominantly reported in East Asian females, its overlap with systemic autoimmune conditions such as undifferentiated connective tissue disease (UCTD) has not been documented. The shared immunopathogenic mechanisms linking lysosomal sphingolipid storage, immune-mediated glomerular injury, and systemic autoimmunity remain poorly understood.

A 44-year-old Chinese woman presented with facial and lower limb edema, proteinuria (2.772 g/24h), and microscopic hematuria. She lacked classic FD manifestations, and both plasma α-Gal A activity (4.31 μmol/L/h) and lyso-Gb3 (0.52 ng/mL) were normal. Renal biopsy confirmed IgAN (Lee grade III, M1E1S1T0-C0) but electron microscopy incidentally identified pathognomonic lamellated zebra bodies in podocytes. GLA gene sequencing identified a heterozygous c.593T>C (p.Ile198Thr) mutation, confirming FD. Serologic workup revealed high-titer ANA (1:1000) and anti-SSA positivity, fulfilling UCTD criteria.

The patient declined enzyme replacement therapy and received renoprotective regimens combined with hydroxychloroquine. At 6-month follow-up, renal function remained stable and no new UCTD manifestations occurred. Family screening identified her son as a hemizygous GLA carrier.

This case highlights that routine electron microscopy during renal biopsy is critical for detecting occult FD in females with normal enzyme activity, and is consistent with a biologically plausible hypothesis of Gb3-driven immune dysregulation as a potential shared link among FD, IgAN, and systemic autoimmunity, which requires further validation in larger cohorts and functional studies.

Pregnancy loss remains a significant challenge in obstetric care, with traditional risk assessment methods, such as clinical history and radiological investigations, often lacking precision in predicting outcomes. This study applied machine learning (ML) to develop a robust model for identifying factors associated with pregnancy loss, with the goal of highlighting candidate predictors for further investigation and validation in future studies in African populations.

The study utilized sociodemographic, clinical and laboratory variables collected at baseline from an ongoing cohort study titled "Future maternal cardiovascular health after pre-eclampsia in an indigenous African population". A total of 1,017 pregnant women attending Mulago National Referral Hospital in Kampala, Uganda were enrolled between 2019 and 2021. However, the outcome question was not administered to women on their first pregnancy, limiting the modeling population to multigravid women (n = 655). Advanced ML tools in R and Python were employed to process the de-identified data, including rigorous data cleaning, feature selection, and handling of missing values. Several ML classifiers were trained and evaluated using cross-validation techniques and the training-test split approach, with performance assessed using Matthew's Correlation Coefficient (MCC), precision, recall and F1 score.

Random Forest achieved the highest discrimination (MCC 0.36, 95% CI 0.25-0.47; ROC-AUC 0.74, 95% CI 0.63-0.83), followed closely by CatBoost (MCC 0.35, 95% CI 0.18-0.46; ROC-AUC 0.71, 95% CI 0.61-0.77); confidence intervals for the two ensemble models overlapped substantially. Both outperformed logistic regression (MCC 0.22, 95% CI 0.08-0.35). Across both tree-based models and both SHAP and permutation-based importance methods, the number of pregnancies carried past seven months, maternal age, and maternal education ranked as the leading correlates. Subgroup analysis showed broadly consistent discrimination across reliable age, education, and maternal tribe.

A few sociodemographic and obstetric history factors are statistically associated with a documented history of pregnancy loss among multigravid women in this Ugandan cohort. Because the outcome reflects reproductive history rather than the result of an observed pregnancy, these findings should be read as hypothesis-generating groundwork for future prospective, externally validated risk-prediction research rather than as a clinical tool for identifying women at risk of a future miscarriage.

Poststroke dysphagia (PSD) is a common, debilitating consequence of stroke that affects up to 50% of patients and leads to multiple medical complications. Transcranial direct current stimulation (tDCS) therapeutic efficacy depends on the electrode montage and interindividual anatomical differences. The use of the standard C5/C6 placement based on 10-20 electroencephalography (EEG) coordinates to guide electrode placements may result in misalignment with the target position.

To investigate whether computational modeling leads to improved electric field (EF) parameters compared with those generated with standard electrode placement methods, and whether smaller sized electrodes can yield more focal results, we compared EF values across three tDCS montages targeting the cortical swallowing area (CSA): (i) optimized circular (Opt-C, 1.5 cm radius), (ii) EEG-based, conventional circular (Conv-C, 1.5 cm radius), and (iii) conventional square (Conv-S, 5 × 5 cm) electrode montages.

Structural MRI data from 50 PSD patients were analyzed. EF distributions were simulated using finite element method (FEM) analysis based on three-dimensional tetrahedral head models generated with the tES LAB 4.0 platform. Across montages, we compared EF strength, defined as the mean L2 norm of the EF (E_norm) across nodes within the target ROI, and target-specific focality, defined as the summed volume of target-ROI elements with E_norm values at or above the 75th percentile of the corresponding whole-brain gray and white matter E_norm distribution.

Significant differences in EF strength (p < 0.001) and target-specific focality (p < 0.001) were identified across the three tDCS montages. The Opt-C montage produced the highest EF strength (median: 0.3525 V/m; IQR: 0.306-0.455) and target-specific focality (median: 104.69 mm³; IQR: 88.17-120.31). Additionally, small circular electrodes resulted in significantly greater EF strength and target-specific focality than square electrodes (p < 0.001).

MRI-guided personalized tDCS planning improved modeled EF delivery to the cortical swallowing target and revealed significant deviations from conventional C5/C6 placement in patients with severe PSD. These findings support image-guided target engagement as a framework for precision neuromodulation in PSD, while prospective physiological and clinical validation is required before therapeutic efficacy can be inferred.

Mitochondrial dysfunction is increasingly recognized as a driver of maladaptive macrophage polarization in atherosclerosis (AS), but the mitochondrial genes that shape disease-relevant macrophage states remain poorly defined.

We integrated weighted gene co-expression network analysis (WGCNA), machine learning, two-sample Mendelian randomization (two-sample MR), bulk transcriptomics, single-cell analysis, disease-level validation, single-cell mediation, and in vitro perturbation to identify macrophage-relevant mitochondrial regulators in AS.

Eight candidate genes were consistently prioritized by WGCNA and machine learning; among them, microsomal glutathione S-transferase 3 (MGST3) showed the strongest protective genetic signal. Two-sample MR supported a protective association between genetically predicted MGST3 expression and coronary artery disease/coronary heart disease risk (training set OR = 0.989, 95% CI 0.978-0.999, P = 0.042; test set OR = 0.977, 95% CI 0.960-0.995, P = 0.013). Human carotid plaque validation confirmed reduced MGST3 at both mRNA and protein levels in AS lesions. Notably, despite this whole-plaque downregulation, single-cell and disease-level analyses revealed an expanded MGST3-high M2-like macrophage state in AS, suggesting a compensatory protective macrophage program within diseased plaques. MGST3-high M2-like cells displayed an OXPHOS-oriented, antioxidant, and less inflammatory transcriptional state, acted as an active signaling population, and showed higher composite MitoHealth scores. Single-cell mediation analysis further indicated that MitoHealth statistically links higher MGST3 expression to lower inflammatory activity, lower M1-like polarization, and lower atherogenic macrophage programming. In M2-polarized macrophages, MGST3 knockdown reduced M2-associated and mitochondrial/antioxidant transcripts while increasing pro-inflammatory transcripts, providing transcript-level functional support. PheWAS analysis detected no significant phenotype associations at the predefined threshold.

These findings define MGST3 as a marker of a mitochondrial-health-associated M2-like macrophage state that appears expanded within AS plaques despite reduced whole-plaque MGST3 expression. The MGST3-MitoHealth axis may represent a compensatory macrophage program linked to mitochondrial preservation and lower pro-atherogenic activation, warranting further diagnostic and therapeutic investigation in AS.

Incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual GIP/GLP-1 receptor agonists, have transformed obesity treatment by producing substantial weight loss and improving cardiometabolic outcomes. However, their therapeutic effects are accompanied by nutritional challenges, including reduced energy intake, gastrointestinal adverse effects, loss of lean mass or fat-free mass, and the risk of inadequate protein and micronutrient intake. This scientific statement of the Polish Society of Dietetics (PTD) summarizes current evidence and provides clinical guidance on nutritional care during incretin-based therapy for obesity. The statements were developed through multidisciplinary expert synthesis and consensus; direct nutrition-specific evidence remains limited, and no formal evidence-grading system was applied. The main features of evidence-informed nutritional care during incretin-based therapy include: 1) structured baseline nutritional assessment and ongoing monitoring of dietary intake, appetite, gastrointestinal tolerance, and body composition; 2) early identification of nutritional risk, including inadequate protein intake, micronutrient insufficiency, dehydration, and excessive loss of lean mass or fat-free mass; 3) individualized dietary strategies supporting adequate nutrient intake and treatment tolerance; 4) preservation of lean mass and muscle function through appropriate protein intake and regular resistance exercise; 5) use of Mediterranean, Dietary Approaches to Stop Hypertension (DASH), or appropriately planned plant-based dietary patterns adapted to individual clinical needs; 6) targeted rather than routine nutritional supplementation based on documented deficiency or increased clinical risk; and 7) integration of registered dietitians within multidisciplinary obesity care pathways. Future research should evaluate the effects of structured dietitian-led interventions on body composition, nutritional status, treatment adherence, and long-term clinical outcomes during incretin-based therapy.