In non-pregnant adults living with HIV, dolutegravir is associated with weight gain and increased type 2 diabetes risk. In pregnancy, data on the effect of dolutegravir on gestational diabetes (GDM) risk is inconclusive. Data are particularly limited in Asian populations, where diabetes risk is especially high and not always associated with weight gain. We examined the association of dolutegravir with GDM among women living with HIV in India.

We combined data from two cohorts of pregnant women living with HIV conducted at BJ Government Medical College in Pune, India-the PRACHITi study (2016-2019) and the PRAGATHi study (2023-present). Women were screened for GDM with the fasting 2-h 75 g oral glucose tolerance test and diagnosed by World Health Organization criteria. Demographics, anthropometrics, antiretroviral therapy (ART), CD4 count and HIV viral load were collected at screening. Multivariate logistic regression was used to determine the association between current dolutegravir use and GDM.

Of 254 women living with HIV, 99.2% (n = 252) were on ART, of whom 66.3% (n = 167) were on dolutegravir-, 22.6% (n = 57) were on efavirenz- and 6.3% (n = 16) were on protease inhibitor (PI)-based ART. Overall, median CD4 count was 549.5 cells/mm³ (IQR 401-753), and 82.2% (n = 198) had undetectable viral load. Median body-mass index (BMI) was 21.3 kg/m² (IQR 19.4-23.8). The prevalence of GDM was 11.8% (N = 30). Among women on dolutegravir-based ART, the prevalence was 10.8% (N = 18); among women on efavirenz-based ART, the prevalence was 12.3% (N = 7), and the prevalence was 25% (N = 4) among women on PI-based ART. Compared to women not taking dolutegravir, women taking dolutegravir had similar age and BMI but greater weight gain from the second to the third trimester (3.7 vs. 2.9 kg, p <0.01) and infant birthweight percentile (14.2 vs. 6.9, p <0.01). On multivariate logistic regression, dolutegravir use was associated with lower odds of GDM than other ART (aOR 0.2, 95% CI 0.1-1.0) irrespective of viral load and time on ART. Older age (aOR 1.1, 95% CI 1.1-1.2) and second-trimester BMI (aOR 1.2 per kg/m², 95% CI 1.1-1.3) were also associated with GDM.

Women on dolutegravir had lower odds of GDM compared to women taking other ART, despite greater weight gain. Ongoing studies are investigating the possible anti-inflammatory mechanisms.

Type 1 diabetes mellitus (T1DM) increases dementia risk. Understanding clinical modifiers of that effect could inform prevention.

We analyzed data from All of Us. Participants were aged ≥50 years with T1DM (n = 5,442) or no diabetes (n = 226,819).

Among 232,261 participants (mean [SD] age 64.5 [9.0] years; 57.3% women), 2.3% had a T1DM diagnosis. Among those without diabetes, each additional comorbidity corresponded to a dementia hazard ratio (HR) of 1.22 (95% CI: 1.19, 1.26). The dementia HR among participants with both T1DM and depression, compared with having neither, was pronounced (HR: 5.47 [95% CI: 4.23, 7.08]) and consistent with the independent associations of T1DM alone (HR: 2.01 [95% CI:1.38, 2.92]) and depression alone (HR: 2.55 [95% CI: 2.22, 2.95]).

Individuals who have both T1DM and depression are at especially high risk for dementia.

Chronic low-grade inflammation drives the development and progression of type 2 diabetes mellitus (T2DM) and microvascular complications, including diabetic kidney disease. The neutrophil-to-lymphocyte ratio (NLR) is a routine hematological index reflecting systemic inflammatory activity. This study evaluated NLR's association with T2DM, glycemic control, and renal function in a Hodeidah City cohort, assessing renal function via the CKD-EPI creatinine equation.

Continuous variables were expressed as medians (interquartile ranges) and analyzed using nonparametric tests. Associations were evaluated via Spearman correlation and exploratory linear regression.

Primary comparisons revealed that T2DM patients possessed a significantly higher NLR than healthy controls, confirming a systemic inflammatory phenotype. Within the T2DM group, NLR did not differ significantly across HbA1c (p = 0.066) or eGFR categories (p = 0.328). However, NLR positively correlated with serum creatinine (Spearman ρ = 0.352, p = 0.022) and demonstrated an inverse, nonsignificant association with eGFR (ρ = -0.275, p = 0.078).

NLR may serve as a practical adjunctive inflammatory biomarker in T2DM. Nevertheless, accurate clinical interpretation requires careful adjustment for renal function, comorbidities, and medication exposure. The absence of comprehensive data regarding the albumin-to-creatinine ratio (ACR), diabetes duration, and specific medication history limited multivariable confounder adjustment and complete nephropathy staging.

Microbiome studies increasingly indicate that disease-associated shifts cannot be understood from compositional changes alone. The functional architecture of microbial communities-encoded in patterns of association among microbial gene families-may reveal how these systems reorganize across biological conditions. Here, we present a network-based framework for characterizing microbiome rewiring across conditions. The approach combines condition-specific network inference, differential network analysis, and pathway-level network analysis to identify associations that are gained, lost, or altered between groups, with a specific focus on sex-dependent differences. We apply the framework to inflammatory bowel disease, type 2 diabetes, and atherosclerotic cardiovascular disease (ACVD), comparing male and female-specific microbial gene family networks within each disease context. Across these settings, differential networks flag large numbers of candidate rewired associations; however, permutation testing (sex labels shuffled, group sizes preserved, 500 permutations for gene-family networks, and 1000 for pathway networks) shows that the global amount of apparent rewiring is not greater than expected under the null at the global or edge level in any cohort, and that most edges exclusive to one group are induced by group-specific feature filtering rather than by a genuine change in association ($\sim $80%-83% in ACVD). We therefore present the method as a rigorously validated framework and a cautionary case study: the differential-network machinery is sound, but the headline biological signal in a naive analysis is largely a property of correlation thresholding and, for the longitudinal inflammatory bowel disease (IBD) cohort, of pseudoreplication. The only non-null result across all validations is a SOHPIE-DNA per-taxon test in the IBD disease arm (15 taxa at FDR $< 0.05$), which we report as a single nominal finding requiring independent replication. Code, data, and supplementary information are available at https://github.com/mmilano87/NetMicrobiome.

Diabetic Cardiomyopathy (DCM) is connected to prolonged systemic glucose metabolism and/or hyperinsulinemia-induced cardiac metaflammation. This study aims to investigate the effects of combined endurance and resistance training on the protein levels of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), caspase-1, and interleukin -1β (IL-1β) in the myocardium of male rats with type 2 diabetes.

In this experimental study, 24 male Wistar rats (8 weeks old, 260±20 g) were randomly divided into three groups: (n=8/groups): Normal Control (NC), Diabetes Control (DC), and Diabetes+Combined Training (DCT). After type 2 diabetes induction, the training group performed the combined training for 8 weeks, five sessions/week, in spring 2024 at AJA University of Medical Sciences. Approximately 48 hours following the end of the training protocol, blood samples and myocardium tissue were taken for subsequent assessment of inflammatory and biochemical markers. Group comparisons were achieved using one-way ANOVA, followed by the Tukey post hoc test using SPSS (version 22).

Chronic implementation of combined training significantly downregulated final weight (P=0.033), protein levels of NLRP3, Caspase-1, and IL-1β (P=0.03, 0.001 and 0.019, respectively) in the cardiac tissue as well as modulation the homeostatic model assessment for insulin resistance (HOMA-IR: P=0.039) via attenuation of serum glucose and insulin levels (P=0.032 and 0.07) of the training group compared to the diabetic group.

The modality of combined training (endurance+resistance) can reduce the risk factors associated with DCM in the myocardium of type 2 diabetic rats.

Heart failure with preserved ejection fraction (HFpEF) is a systemic disease in which metabolic comorbidities obesity, type 2 diabetes (T2D), and chronic kidney disease (CKD) converge to drive systemic inflammation, endothelial dysfunction, and myocardial fibrosis. Microvascular dysfunction represents an important link between these comorbidities and abnormalities within and beyond the heart, although its causal contribution to HFpEF remains incompletely established. In addition to promoting myocardial stiffness and diastolic dysfunction, impaired microvascular function across the pulmonary and peripheral circulations may contribute to reduced tissue perfusion, exercise intolerance, and dyspnoea. CKD may further aggravate this process through volume and neurohormonal pathways as well as circulating uraemic and inflammatory factors that impair endothelial function, through a kidney-microvascular axis. Despite its high prevalence and poor prognosis, therapeutic options for HFpEF have historically been limited. Recent advances, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 (GLP-1) receptor agonists and dual incretin therapies (GLP-1/GIP RAs), and (non-steroidal) mineralocorticoid receptor antagonists, have reshaped the therapeutic landscape by improving cardiovascular and renal outcomes in patients with HFpEF. These agents exert complementary effects on hemodynamic stress, metabolic dysregulation, inflammation, and fibrosis, and may also improve microvascular function across multiple vascular beds. In this narrative review, we provide an organ-by-organ synthesis of the pathophysiological interactions among the heart, kidney, systemic microvasculature, pulmonary circulation, and skeletal muscle in CKMS-related HFpEF. We further map the clinical and mechanistic effects of aforementioned therapies across these interconnected organ systems and highlight areas in which mechanistic and clinical evidence gaps remain.

Identifying clinical findings that are distinct between inflammatory bowel disease (IBD) and intestinal lymphoma could be helpful for providing preliminary guidance for clients regarding their horse's prognosis while awaiting histopathologic results.

To describe and compare the clinical findings of horses with a final histopathologic diagnosis of IBD vs intestinal lymphoma.

Forty-six adult (≥1-year-old) horses with a final histopathologic diagnosis of IBD or intestinal lymphoma on endoscopic duodenal biopsy, surgical biopsy, or necropsy.

Retrospective single-center case series via electronic medical record review of histopathology.

Eighteen horses had a final diagnosis of lymphoma (11 intestinal only, 7 multicentric including the intestinal tract) and 28 had IBD (22 lymphoplasmacytic IBD, 5 eosinophilic IBD, 1 mixed lymphoplasmacytic and eosinophilic IBD). Acute colic (54%) and recurrent colic (39%) were more common in horses with IBD than in horses with lymphoma (11% and 5%; P = .004 and P = .01, respectively). Ultrasonographic evidence of abdominal mesenteric lymphadenopathy was more commonly identified in horses with lymphoma than horses with IBD (60% vs 0%; P < .001). Clinicopathologic values were largely indistinguishable between groups.

Clinical findings of IBD and intestinal lymphoma were largely indistinguishable in this cohort, although recurrent or acute colic might be more commonly seen in horses with IBD than those with lymphoma.

Fruquintinib is a highly selective, oral inhibitor of all three vascular endothelial growth factor receptors (-1, -2, and -3) that was approved, including in China, the United States, and the European Union, for the treatment of previously treated metastatic colorectal cancer (mCRC). The efficacy of fruquintinib for mCRC has been consistently demonstrated in randomized, double-blind, Phase 3 clinical studies, including FRESCO (NCT02314819), which enrolled patients in China, and FRESCO-2 (NCT04322539), which enrolled patients across 14 countries in North America, Europe, Asia, and Australia. In both studies, patients were randomized 2:1 to receive oral fruquintinib 5 mg or a matching placebo once daily, 3 weeks on, 1 week off, in 28-day cycles, plus best supportive care, until progression or unacceptable toxicity. Both FRESCO and FRESCO-2 met their primary endpoints, demonstrating significant improvements in overall survival (OS) with fruquintinib versus placebo: in FRESCO (fruquintinib: n = 278; placebo: n = 138), median OS was 9.3 with fruquintinib versus 6.6 months with placebo (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.51-0.83; p < 0.001); in FRESCO-2 (fruquintinib: n = 461; placebo: n = 230), median OS was 7.4 with fruquintinib versus 4.8 months with placebo (HR, 0.66; 95% CI, 0.55-0.80; p < 0.001). The most common any-grade treatment-emergent adverse events with fruquintinib (incidence ≥ 20% in either study, excluding laboratory abnormalities) were hypertension, palmar-plantar erythrodysesthesia, proteinuria, dysphonia, diarrhea, asthenia, decreased appetite, hypothyroidism, and fatigue. This mini-review summarizes the mechanism of action, pharmacokinetics, key clinical trials, and clinical efficacy and safety data for fruquintinib.

Desmoid disease is a major cause of morbidity and mortality in familial adenomatous polyposis (FAP), particularly after prophylactic colorectal surgery. Although APC genotype and family history are recognized risk factors, previous sizeable studies report relative rather than absolute risks. This study aimed to quantify absolute postoperative desmoid risk in FAP patients undergoing risk-reducing colectomy, stratified by APC genotype, and to assess the modifying effect of family history.

This retrospective observational study used records from a prospectively maintained registry. Patients with an APC pathogenic variant (PV) 3' of codon 1399 were classified as high risk, and those with an APC PV 5' of (or at) codon 1399 were classified as low risk. Patients who had not undergone prophylactic colectomy, with < 5 years of postoperative follow-up, or those with a desmoid diagnosed before or at the time of surgery were excluded. Clinical records were reviewed for details of surgery, desmoid diagnosis, and family history. A positive family history was defined as a first-degree relative with genetically confirmed FAP and a diagnosis of desmoid disease (clinical and/or radiological).

Among 48 high-risk patients, 30 (63%) developed desmoid, with no significant difference between colectomy and proctocolectomy (54% versus 70%, respectively; χ2 = 1.42; P = 0.233). Family history was present in 35 of the 48 patients (73%) and increased desmoid risk relative to no family history (80% versus 15%, respectively; P < 0.01). Among the 1213 low-risk patients, 154 (12.7%) developed desmoids, with no significant effect of surgical procedure (13.9% versus 12.1% for proctocolectomy and total/partial colectomy, respectively; χ² = 0.77; P = 0.380). Family history increased desmoid risk relative to no family history (30% versus 10%, respectively; P < 0.01).

A family history of desmoid disease appears to be an important determinant of postoperative desmoid risk in FAP. Although APC PV 3' of codon 1399 does confer a high overall risk, this is largely confined to individuals with first-degree relatives with desmoid. In the absence of a family history, postoperative desmoid risk appeared relatively low regardless of genotype. This supports a more individualized approach to perioperative counselling and surgical decision-making in patients with FAP. In addition, these data highlight that patients with both a 3' APC PV and a positive family history are a particularly high-risk subgroup who may represent an appropriate target population for future chemoprevention trials.

Surgical randomized clinical trials (RCTs) have structural features that differ fundamentally from those of non-surgical trials, which may complicate appraisal using standard assessment frameworks. This methodological systematic review used rectal cancer surgery RCTs as a high-complexity exemplar to identify surgically specific methodological challenges and to examine their interaction with established tools for assessing risk of bias and certainty of evidence.

A systematic literature search was conducted in PubMed, Embase, and the Cochrane Library on 1 November 2025. Eligible studies were RCTs evaluating surgery-related interventions for rectal cancer in adult patients, published in English from 2020 onward, with sufficient methodological detail. Included trials were categorized into predefined, mutually exclusive surgical RCT types. Methodological features were descriptively summarized and conceptually mapped to the domains of the revised Cochrane Risk of Bias (RoB 2) tool and the GRADE framework using both quantitative tabulation and narrative synthesis.

Of 1529 records identified, 45 publications reporting on 35 RCTs were included. Trials were classified into five surgical RCT categories. Surgically specific methodological challenges were most frequently observed in RoB 2 domains D2 (bias due to deviations from intended interventions) and D4 (bias in measurement of the outcome), as well as in the GRADE domain of indirectness.

This review suggests that several challenges encountered when applying RoB 2 and GRADE to surgical RCTs arise from structural characteristics of surgical trial design rather than obvious methodological shortcomings. Contextualizing standard appraisal frameworks within the realities of surgical research may allow for a more nuanced interpretation of existing evidence, inform future trial design, and support more appropriate evidence synthesis.