Background Treatment selection may confound observational comparisons of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in adults with metabolic dysfunction-associated steatotic liver disease and heart failure (HF). Aims To compare recorded outcomes between treatment groups and examine whether the associations persisted after restricting the analysis by agent and diabetes status and separating early and later outcome windows. Study Design Retrospective, initiation-based, active-comparator cohort study (new-user design not verified). Methods We used the TriNetX US Collaborative Network and a common index eligibility period from January 1, 2018, through June 2, 2026. The revised analyses were performed on September 12, 2026. An additional sensitivity analysis of acute HF excluded patients with this outcome before the start of the day 1-1825 window. The primary analysis compared semaglutide, liraglutide, or dulaglutide with empagliflozin or dapagliflozin using 1:1 propensity score matching and assessed outcomes during days 1-1825. Separate analyses of the broader GLP-1 RA group examined outcomes during days 1-90 and 91-1825 and among patients with type 2 diabetes and no recorded type 1 diabetes. We report endpoint-specific event proportions, risk differences, hazard ratios (HRs), 95% confidence intervals (CIs), and proportionality test results. Results The primary analysis included 8,550 patients per group after matching. Mortality occurred in 599/8,514 (7.0%) versus 861/8,509 (10.1%); the HR was 0.607 (95% CI, 0.546-0.673). Coded acute HF diagnoses occurred in 1,217/8,550 (14.2%) versus 2,525/8,550 (29.5%); the HR was 0.398 (95% CI, 0.372-0.427), with evidence of non-proportional hazards. In separately matched descriptive interval analyses (8,489 patients per group), the HR for coded acute HF was 0.262 (95% CI, 0.236-0.291) during days 1-90 and 0.507 (95% CI, 0.469-0.548) during days 91-1825. The HR for acute kidney injury during the later interval was 0.740 (95% CI, 0.650-0.842). Among 5,709 matched pairs with type 2 diabetes and no recorded type 1 diabetes, the HR for coded acute HF was 0.431 (95% CI, 0.397-0.468), whereas the HR for ketoacidosis was 0.683 (95% CI, 0.455-1.025). No advantage was observed for acute pancreatitis in any analysis. In a separate analysis excluding patients with prior acute HF, the HR was 0.421 (95% CI, 0.362-0.489), with evidence of non-proportional hazards. Albumin and bilirubin remained imbalanced in a direction favoring the GLP-1 RA group; body mass index also remained imbalanced. Conclusion GLP-1 RA exposure was associated with lower observed hazards for several outcomes, and the association with coded acute HF was weaker after day 90. The early concentration and magnitude of this association make treatment channeling a plausible explanation, although this analysis cannot establish that explanation. These exploratory findings do not support causal inferences or treatment-preference conclusions and do not challenge randomized evidence supporting SGLT2i use in HF.
Background The prognostic value of longitudinal single-point insulin sensitivity estimator (SPISE) patterns for stroke, particularly when considered in combination with hypertension (HTN), remains unclear among adults with cardiovascular-kidney-metabolic (CKM) syndrome stages 0-3. Aims This study aimed to examine the association of combined longitudinal SPISE patterns and HTN status with incident stroke among adults with CKM syndrome stages 0-3. Study Design A nationwide prospective cohort study. Methods We included adults aged ≥ 45 years with CKM stages 0-3 from the China Health and Retirement Longitudinal Study. SPISE was calculated at Waves 1 and 3, and incident stroke was ascertained through Wave 5. K-means clustering was used to identify longitudinal SPISE patterns, which were dichotomized as persistently low or non-persistently low. Participants were then cross-classified according to longitudinal SPISE pattern and baseline HTN status. Cumulative SPISE exposure was calculated from repeated SPISE measurements. Cox models were used to examine associations with incident stroke. Dose-response, subgroup, sensitivity, and model-performance analyses were also performed. Results Among 4,443 participants, 348 incident strokes occurred. A persistently low longitudinal SPISE pattern was associated with a higher risk of incident stroke than a persistently high pattern [hazard ratio (HR), 2.29; 95% confidence interval (CI), 1.59-3.29]. Compared with the group with no HTN and a non-persistently low SPISE pattern, stroke risk was higher in the group with no HTN and a persistently low SPISE pattern (HR, 1.48; 95% CI, 1.12-1.95), the group with HTN and a non-persistently low SPISE pattern (HR, 1.57; 95% CI, 1.10-2.23), and the group with HTN and a persistently low SPISE pattern (HR, 2.45; 95% CI, 1.84-3.26). Higher cumulative SPISE exposure was inversely associated with incident stroke (HR per 1-unit increment, 0.95; 95% CI, 0.93-0.97), with an approximately linear dose-response relationship. Incorporating the combined longitudinal SPISE pattern and HTN status increased the apparent C-index from 0.612 to 0.646. However, optimism-corrected discrimination was comparable between the combined model and the HTN-only model. Conclusion The combination of longitudinal SPISE patterns and HTN status identified a subgroup at the highest risk of incident stroke in this CKM population.
Background Human papillomavirus 16 (HPV16) plays a major role in the development of cervical cancer (CC). Programmed cell death ligand 1 (PD-L1) expression in tumor-infiltrating lymphocytes (TILs) is an important feature of the tumor immune microenvironment and may affect responses to immune checkpoint blockade. However, the relationship between the HPV16 E7 oncoprotein and PD-L1 expression in TILs remains unclear. Aim To investigate the presence of HPV16 E7 protein in exosomes from CC tissues and plasma, determine the association between exosomal E7 and PD-L1 expression in TILs, and explore whether E7-rich tumor-derived exosomes contribute to increased PD-L1 expression in TILs. Study Design This study combined clinical observational analyses and in vitro experiments. Three CC single-cell RNA sequencing datasets, a 30-patient HPV16-positive cohort, and a 104-patient tissue microarray cohort were analyzed. In vitro experiments were conducted to further examine the potential relationship between exosomal E7 and PD-L1 expression in TILs. Methods Blood and pathological samples from 30 patients with HPV16-positive CC, as well as culture fluid from the C33A and SiHa CC cell lines, were collected. Exosomes were isolated, and E7 protein expression was assessed. Bioinformatics analyses of CC single-cell RNA sequencing datasets were performed to evaluate CD274 mRNA expression in TILs. Immunohistochemistry (IHC) was used to assess PD-L1 protein expression in TILs in the 30-patient cohort, while multiplex immunofluorescence was used to evaluate E7 and PD-L1 expression in TILs in a 104-patient tissue microarray. Exosome uptake by TILs was assessed using confocal microscopy. TILs were co-cultured with exosomes, and HPV16 E7 and PD-L1 expression was evaluated by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blotting in the TIL blank control, co-culture blank control, co-culture empty vector, and co-culture E7-overexpression groups. Results E7 protein was detected in exosomes from the peripheral blood of 28 of 30 patients (93.3%) and in exosomes from SiHa cell culture. PD-L1 was expressed in TILs, with a positive rate of 43.3% (13/30). In the tissue microarray cohort (n = 103; 28 events), higher CD3+PD-L1+/CD3+ expression was associated with poorer survival (HR = 2.97, p = 0.009). CD3+E7+/CD3+ expression showed a borderline association with poorer survival in the dichotomized analysis (HR = 2.15, p = 0.052) but was significantly associated with survival when modeled as a continuous variable (per 10%: HR = 1.28, p = 0.002). In the 30-patient cohort, exosomal E7 protein content was significantly associated with PD-L1 expression in TILs (Cramér's V = 0.728, p = 0.0001). qRT-PCR and western blotting demonstrated increased PD-L1 mRNA and protein expression in TILs exposed to exosomes from E7-overexpressing cells. Conclusion HPV16 E7 protein is present in exosomes from patients with CC and HPV16-positive CC cells. Higher exosomal E7 levels are associated with increased PD-L1 expression in TILs, and exposure to E7-rich exosomes is associated with upregulated PD-L1 expression in TILs. These findings suggest that exosomal E7 may contribute to PD-L1 regulation in TILs and may be associated with poorer prognosis in patients with CC. Further studies are needed to determine whether E7 directly mediates this effect and to clarify its functional and clinical significance.
