The DOHaD theory was originally proposed to explain the link between fetal development and risk for non-communicable disease - NCD. With advancements in human microbiome research, this theory has been extended to consider postnatal development of the infant gut microbiome and how this contributes to NCD trajectories. C. difficile transiently colonizes the gut microbiota of up to 50% of infants without causing symptoms, but has been associated with disease in the longterm. We reviewed and summarized the current literature to identify prenatal, birth and postnatal factors contributing to C. difficile colonization, and subsequent changes in host biology and NCD outcomes. Many early-life factors promote C. difficile colonization, including prenatal overweight, cesarean birth, hospitalization, antibiotic exposure, formula feeding, histamine-2 receptor antagonist treatment, household pets and smoking, and daycare attendance. Whereas, prenatal milk consumption and having siblings seem to protect against colonization. When C. difficile is present in the gut, associated changes to gut microbiota and metabolites are reported in observational studies. Clinical trial evidence suggests that preceding changes like a reduction in Bifidobacterium species, could promote C. difficile colonization. C. difficile colonization during infancy increases the risk for NCD, including obesity and many atopic diseases (asthma, eczema, food and peanut sensitization). Furthermore, its colonization and abundance was found to be a statistical mediator of these health outcomes, pointing to a potential mediating role for C. difficile in NCD onset. Evidence from the current literature supports the inclusion of C. difficile colonization during infancy as an important biomarker in the developmental origins of disease.

To develop and validate a fully automated deep learning-based method for total kidney volume (TKV) measurement from unenhanced computed tomography (CT) images in patients with autosomal dominant polycystic kidney disease (ADPKD).

A fully automated kidney segmentation model based on the nnU-Net framework was developed using unenhanced CT images from 236 patients, including 111 patients with ADPKD. The development dataset was divided into a training cohort and an internal testing cohort. An independent cohort of 70 patients with ADPKD was used for validation, including longitudinal scans from 20 patients. The reference standard consisted of semi-automated kidney segmentation followed by slice-by-slice manual correction performed independently by two experienced radiologists. Automated and reference segmentations were compared using the Dice similarity coefficient (DSC), intraclass correlation coefficient (ICC), linear regression and Bland-Altman analysis.

Automated segmentation exhibited excellent spatial agreement with the reference standard, with a mean DSC of 0.96 ± 0.01 for TKV. Volumetric agreement was near perfect (ICC = 0.999; 95% confidence interval, 0.998-0.999), with minimal bias (-0.14%) and high precision (±2.09%). Longitudinal analysis demonstrated robust agreement for kidney growth assessment (ICC = 0.99; bias, - 0.64%; precision, ± 4.81%). The automated method required approximately 5 s per case, compared with 30 min for expert-assisted reference segmentation.

This automated segmentation method enables fast, accurate, and reproducible TKV quantification from unenhanced CT images in patients with ADPKD, offering a clinically feasible alternative to manual volumetric analysis.

Platelet-rich fibrin (PRF) has emerged as a widely utilized autologous biomaterial in periodontal and peri-implant regenerative therapy owing to its ability to provide a three-dimensional fibrin scaffold enriched with platelets, leukocytes, growth factors, and cytokines. However, persistent hyperglycemia (as observed in patients with poorly controlled diabetes mellitus) induces oxidative stress in oral and systemic tissues and impairs angiogenesis and extracellular matrix remodeling.

To provide an overview of the potential impact of persistent hyperglycemia on PRF-mediated regeneration of periodontal and peri-implant tissues, and to gain an in-depth understanding of the underlying biological mechanisms and their clinical implications.

The research question was "Does a state of persistent hyperglycemia affect PRF-mediated periodontal and peri-implant tissue regeneration?" Indexed databases and Google Scholar were searched without time and language barriers up to and including August 2026. The pattern of the present study was customized to summarize the pertinent studies.

Evidence evaluating the impact of persistent hyperglycemia on PRF remains limited and is largely confined to ex vivo, in vitro, and observational studies. Nevertheless, the available data consistently suggest that poorly controlled diabetes mellitus is associated with alterations in PRF architecture, including increased porosity, reduced clot dimensions, diminished PRF yield, and a less organized fibrin meshwork. Limited evidence also indicates that although growth factor release from PRF may be preserved under hyperglycemic conditions, PRF obtained from individuals with well-controlled diabetes mellitus shows structural and biological characteristics that closely resemble those observed in systemically healthy individuals. This suggests that regenerative capacity may be preserved when glycemic levels are adequately controlled. This supports the idea that the regenerative capacity of PRF may be preserved when glycemic levels are adequately maintained.

Glycemic control appears to be a key determinant of PRF quality and regenerative outcomes. Nevertheless, the lack of prospective clinical studies evaluating direct regenerative outcomes highlights the need for well-designed clinical trials to clarify the influence of persistent hyperglycemia on PRF-mediated periodontal and peri-implant regeneration.

Persistent hyperglycemia may compromise the regenerative potential of PRF primarily through alterations in fibrin architecture, which may further lead to faster clot breakdown and impairment of biological responsiveness within a chronically inflammatory environment. However, limited data to date suggest that effective glycemic control and patient education may help preserve PRF characteristics favorable for periodontal and peri-implant tissue regeneration.

The C-reactive protein-triglyceride-glucose index (CTI) has been identified as a potential new biomarker for insulin resistance and inflammation. However, the association between CTI and osteoarthritis (OA) risk in prediabetic (Pre-DM) individuals from different populations remains unclear. This population-based cohort study included 3043 participants from the China Health and Retirement Longitudinal Study across Waves 1 to 5. The primary endpoint was the incidence of OA events. The associations between the CTI and incident OA incidence were evaluated by competing risk models and Cox regression models, with restricted cubic splines applied to investigate potential nonlinear relationships. To ensure the robustness of the findings, subgroup analyses, multiple imputation, and propensity score methods were also applied. During the 9-year follow-up, 946 (31.09%) participants developed OA. The highest OA risk was observed in the highest CTI quartile (Q4) (HR, 1.376; 95% CI, 1.12, 1.692) in Model 3. A nonlinear relationship between the CTI and OA risk was identified (P for nonlinearity = .012). Subgroup analysis revealed that individuals with a body mass index <24 years and those with a body mass index between 24 and 28 years were more sensitive to the adverse effects of the CTI on OA risk (P for interaction = .012). Furthermore, the association between elevated CTI and OA risk remained consistent across various sensitivity analyses. The CTI can serve as an independent risk marker for predicting the onset of incident OA in middle-aged and older individuals with Pre-DM. Addressing insulin resistance and inflammation may play a crucial role in enhancing primary prevention strategies for OA.

Nutrient deficiencies associated with progression from obesity to metabolic dysfunction are poorly characterized. Using electronic health records (TriNetX Research Network), we evaluated the association between key nutritional deficiencies and metabolic outcomes among patients with obesity.

Deficiencies assessed included protein-energy malnutrition, deficiencies in vitamin D, calcium, magnesium, and vitamin B12, and prior underweight status. Outcomes included severe obesity, prediabetes, type 2 diabetes, metabolic syndrome, metabolic dysfunction-associated steatotic liver disease (MASLD), and metabolic dysfunction-associated steatohepatitis (MASH). After matching propensity scores, cohorts with the double burden of malnutrition (DBM) were compared with a reference cohort of patients with obesity but no history of nutritional deficiencies.

The most prevalent types of DBM were vitamin D deficiency (10.6%), protein deficiency (8.9%) and calcium deficiency (7.5%). Incidence rates of obesity and all types of DBM increased from 2023 to 2025. Although middle-aged White and Black/African American patients represented the largest demographic groups, adults aged >70 years exhibited higher incidence rates of protein, calcium, magnesium, and B12 deficiencies. Vitamin D deficiency (median hazard ratio [HR] 3.09; IQR 2.32-5.66), vitamin B12 deficiency (median HR 2.49; IQR 2.16-6.08), and prior underweight (median HR 2.23; IQR 1.76-3.98) were associated with the highest burden of metabolic diseases.

These findings underscore the interplay between nutritional deficiencies and metabolic disease risk in obesity and support targeted interventions for populations affected by DBM, especially older adults, and in the context of racial and socioeconomic disparities.

The skeletal muscle plays a central role in glucose metabolism, but absolute muscle mass is strongly influenced by both body size and adiposity. Herein, we investigated whether residual appendicular lean mass (ALM), a body-size-adjusted measure of the skeletal muscle reserve, was associated with insulin resistance and whether this association differed according to the obesity status of Korean adults.

This cross-sectional study included 14,647 adults extracted from the Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2010. Residual ALM was derived as the standardized (z-score) residual from a linear regression model including the age, sex, and body mass index (BMI). Associations between residual ALM and log-transformed homeostasis model assessment of insulin resistance (HOMA-IR) were examined using complex survey-weighted linear regression models. Metabolic syndrome was evaluated as a secondary clinical outcome.

In the unadjusted analyses, residual ALM was positively associated with HOMA-IR (β = 0.041, 95% confidence interval [CI] 0.030-0.052; P < 0.001). After adjusting for age, sex, and BMI, higher residual ALM was associated with lower HOMA-IR (β = -0.060, 95% CI -0.070 to -0.049; P < 0.001); this association remained significant after further adjustment for hypertension, dyslipidemia, diabetes mellitus, chronic kidney disease, smoking status, and hepatic steatosis index (β = -0.043, 95% CI -0.053 to -0.033; P < 0.001). The magnitude of the inverse association differed according to obesity status (P for interaction = 0.007), and was more pronounced among individuals without obesity. Higher residual ALM was further associated with lower odds of metabolic syndrome after adjusting for BMI and hepatic steatosis index (odds ratio 0.86, 95% CI 0.81-0.92; P < 0.001).

Higher residual ALM was independently associated with lower insulin resistance and lower odds of metabolic syndrome in Korean adults. Higher body-size-adjusted skeletal muscle reserve was associated with a more favorable metabolic profile, particularly among non-obese adults.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are an established treatment for management of type 2 diabetes mellitus (T2DM) and obesity. While these agents provide clinical benefits, chronic rodent bioassays have shown a consistent increase in thyroid C-cell tumors, raising regulatory concerns for human carcinogenicity risk and resulting in a boxed warning for medullary thyroid carcinoma (MTC). However, the human relevance of the rodent tumors is unclear due to species differences in GLP-1 receptor (GLP-1R) biology. Carcinogenicity testing of pharmaceuticals is described in ICH S1 guidelines. ICH S1B(R1) outlines experimental approaches to carcinogenicity evaluation including a weight-of-evidence (WoE) framework to determine whether long-term rat carcinogenicity studies add value to human cancer risk assessments. This manuscript applies that framework across seven approved GLP-1RAs: lixisenatide, exenatide, liraglutide, dulaglutide, semaglutide, tirzepatide, and albiglutide, to evaluate the relevance of rodent thyroid tumors and the utility of 2-year bioassays for this drug class. Across all six WoE domains, the evidence supports concluding that GLP1-RAs are tumorigenic in rats via a known human-irrelevant mechanism. Thus, within the S1B(R1) WoE framework, future carcinogenicity testing in rats is unlikely to provide additional value for regulatory decision-making for this class of pharmaceuticals.

This study aimed to investigate the mechanism by which the sodium-glucose cotransporter-2 (SGLT2) inhibitor dapagliflozin improves immune imbalance in sepsis with diabetes, focusing on its regulation of macrophage M2 polarization through the APOC1/HMGB1/TLR4 axis. A mouse model of type 2 diabetes was established through intraperitoneal injection of streptozotocin, after which sepsis was induced by cecal ligation and puncture. For in vitro studies, RAW264.7 macrophages and bone marrow-derived macrophages were exposed to high glucose and lipopolysaccharide. Molecular docking was employed to examine potential binding between dapagliflozin and APOC1. Organ pathology in lung, liver, and kidney was evaluated using hematoxylin and eosin staining and biochemical assay kits. Expression levels of APOC1, HMGB1, TLR4, and macrophage M1/M2 markers were analyzed via immunohistochemistry and immunofluorescence. Inflammatory cytokine levels were quantified with enzyme-linked immunosorbent assay. The SGLT2 inhibitor dapagliflozin effectively alleviated lung, liver, kidney injury and dysfunction and reduced inflammatory responses in diabetic mice with sepsis. The treatment also decreased inflammatory cytokine levels in the high glucose/lipopolysaccharide-stimulated cellular model. Furthermore, dapagliflozin treatment significantly increased the levels of M2 macrophage markers in both in vivo and in vitro models. Mechanistically, dapagliflozin was found to target, bind to, and downregulate APOC1 expression. Further investigations revealed that APOC1 promotes macrophage M1 polarization via the APOC1/HMGB1/TLR4 axis, an effect reversed by dapagliflozin. The SGLT2 inhibitor dapagliflozin ameliorates organ damage and inflammation in sepsis with diabetes by promoting macrophage M2 polarization through inhibition of the APOC1/HMGB1/TLR4 axis.

The gut microbiota influences host metabolism through diverse metabolites, many of which have been linked to glucose homeostasis and type 2 diabetes (T2D). Understanding microbial contributions to metabolite biosynthesis is essential for developing dietary and microbiota-targeted T2D prevention and treatment strategies. We performed targeted plasma metabolomics in individuals with T2D and healthy controls, all receiving histidine supplementation, before and after gut microbiota suppression using 7-day broad-spectrum antibiotic treatment. Associations between pre-antibiotic metabolite levels and fecal metagenomics-derived gut microbiota composition were examined using co-abundance network analysis and Random Forest modeling. Indole-3-propionic acid (IPA) was the only gut-derived metabolite differing between groups before antibiotics, with lower levels in T2D and higher levels associated with reduced T2D odds. Antibiotic treatment reduced IPA to near-undetectable levels in both groups, confirming its predominantly microbial origin. Beyond established inverse associations with BMI and glycemic markers, we found a novel inverse correlation between IPA and glycemic variability, consistent with a protective association with T2D. Plasma IPA was associated with gut microbiota beta diversity. IPA-associated species clustered within a single co-abundance module, but did not include known IPA producers, suggesting plasma IPA is influenced by broader microbial community composition rather than IPA-producing capacity of individual taxa alone. This study provides direct human evidence that plasma IPA is virtually exclusively gut microbiota-derived in individuals with T2D, extending prior findings in healthy populations. It highlights IPA's relevance to metabolic health and T2D, and guides future research on dietary and microbiota-targeted strategies to modulate IPA, advancing T2D prevention and treatment.

Although the association between erectile dysfunction (ED) and cardiovascular disease is well established, its prevalence in patients with atherosclerosis remains poorly defined.

To evaluate ED prevalence, severity, and associated risk factors (RFs) in patients with atherosclerotic disease.

This single-centre, cross-sectional, non-randomised observational study included male patients referred to a vascular surgery service with documented atherosclerotic disease. Erectile function was assessed using the International Index of Erectile Function-15 questionnaire, and RFs were analysed using univariable and multivariable regression models.

A total of 162 patients were enrolled (mean age, 70.1 ± 8.6 years); ED was present in 93.8%, with severe ED observed in 62.3%. Multivariable analysis confirmed age as a significant RF for ED, particularly > 75 years, while age, diabetes mellitus, and subjective ED duration were significantly associated with greater severity.

The high prevalence of ED supports its role as a manifestation of systemic vascular disease linked to endothelial dysfunction and diffuse atherosclerosis.

ED is highly prevalent among patients with clinically overt atherosclerotic disease requiring vascular surgery referral, and may represent a marker of systemic vascular pathology. Routine assessment of sexual function may improve cardiovascular risk stratification and preventive management.