Introduction: Overall survival (OS) is often considered gold standard outcome in clinical trials for oncology treatments in patients with locally advanced (LA) head and neck squamous cell carcinoma (HNSCC). However, the need for long-term follow-up significantly increases the duration of the trials and thereby delaying patient access to new treatments. Using event-free survival (EFS) as an early clinical endpoint would potentially be more efficient than OS. Therefore, there is a need to evaluate the relationship between EFS and OS.
Aims: To describe and compare the EFS and OS patterns of LA HNSCC by different stages at diagnosis and by resectable/unresectable diseases, and to evaluate the correlations between EFS and OS using patient-level real-world clinical data.
Methods: This is a retrospective cohort study using electronic health records in Hong Kong. Patients with LA HNSCC and started primary treatment between 2006 and 2017 were included. The patients were followed for 5 years. Events for OS included all-cause deaths, while events for EFS included locoregional progression, recurrent, distal metastasis, and all-cause deaths. Patterns for EFS and OS were evaluated using Kaplan–Meier curves, and correlations between EFS and OS (in days) were measured by correlation coefficient, R.
Results: A total of 1,811 eligible patients was included. EFS and OS showed similar survival patterns: better survival was observed in patients with lower stages at diagnosis, or with resectable tumours (log-rank test p<0.05). EFS showed good correlation with OS (R=0.86). Subgroup analysis considering only either locoregional progression, recurrent, or distal metastasis events showed good correlation between distal metastasis-free survival and OS, but moderate correlations for the other two.
Conclusions: EFS showed good correlation with OS, suggesting that it could potentially be used as an early endpoint in trials for LA HNSCC.
Keywords: locally advanced head and neck squamous cell carcinoma, event-free survival, overall survival

Introduction: RCTs suggest that angiotensin-receptor blockers (ARB) may limit the onset and the progression of nephropathy and retinopathy in patients with type 2 diabetes (T2DM). However, high-dose Olmesartan may be linked to increased cardiovascular risk. Real-world evidence remains limited, and results are inconsistent.
Aims: This study aimed to conduct a target trial emulation study to evaluate the effect of ARB initiation on chronic complications in T2DM patients with hypertension.
Methods: We used a Chinese regional health care database OMOP CDM to emulate a sequence of target trials including T2DM patients with hypertension who initiated ARB or not between 2012 and 2022. The effects of ARB initiation on new onset of diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), and cardiovascular mortality and morbidity were analysed in both intention-to-treat (ITT) and per-protocol (PP) approaches. A time-discrete dataset was constructed by month for each eligible person-trial, where the marginal structural model was adopted to estimate the causal effect accounting for time-varying variables. Pooled logistic regression approximated hazard ratios (HR).
Results: A total of 8,682 person-trial initiators (8,682 individuals) and 941,073 person-trial non-initiators (19,987 individuals) were included. In ITT analysis, ARB initiation was associated with a reduced risk of DR (adjusted HR: 0.81; 95% CI: 0.51–1.27) and cardiovascular death (adjusted HR: 0.97; 95% CI: 0.79–1.19), though not statistically significant. No association was found for DPN (adjusted HR: 1.27; 95% CI: 0.94–1.72). However, a significantly increased risk of cardiovascular morbidity was observed (adjusted HR: 1.32; 95% CI: 1.26–1.39). PP analysis results were consistent.
Conclusions: ARB initiation may offer modest protection against DR and cardiovascular mortality in T2DM patients with hypertension, but these associations were not statistically significant. Importantly, ARB use was associated with higher cardiovascular morbidity risk, highlighting the need for vigilant CV monitoring in clinical practice.

Keywords: ARB; T2DM complication; Target trial emulation

Introduction: QTc prolongation is a significant concern in hospitalized patients due to its association with life-threatening arrhythmias. Accurate risk prediction is essential for early intervention. However, existing QTc risk models often lack generalizability across diverse populations and clinical settings.
Aims: This study aimed to develop and validate a machine learning model that integrates both structured and unstructured EHR data to predict QTc prolongation and derive a simplified risk score (QTc Risk Index for Hospitalized Patients, QTRISK-H) for clinical use.
Methods: We conducted a nested case-control study using data from a tertiary hospital, including patients aged ≥45 years with at least two electrocardiograms (ECGs) recorded on different days during hospitalization. Structured data included demographics, comorbidities, medications, QTc values, and laboratory results . Unstructured data from ECG and echocardiography reports were extracted using rule-based natural language processing. Six machine learning models were developed , and performance was assessed using the area under the receiver operating characteristic curve (AUROC) and Brier scores.
Results: A total of 17,081 patients were included in the final analytic cohort, with 13,426 assigned to the training/testing set and 3,655 to the temporal validation set. Among the testing set, the extreme gradient boosting (XGBoost) model achieved the highest AUROC (0.772). QTRISK-H was developed using a logistic regression model, which achieved comparable performance (AUROC 0.758). Key predictors included hypokalemia, number of QT-prolonging medications, myocardial ischemia, and intensive care unit stay. QTRISK-H outperformed existing risk scores in temporal validation.
Conclusion: The XGBoost model demonstrated the best performance, and QTRISK-H offers a clinically practical and interpretable tool for predicting QTc prolongation. Nevertheless, external validation in independent cohorts is warranted to confirm whether it can support risk-informed monitoring and prescribing decisions, thereby helping to prevent QTc prolongation and reduce the risk of serious arrhythmias.
Keywords: QTc prolongation, predicted model, machine learning

Introduction: Depression is a common comorbidity in patients with rheumatoid arthritis (RA), affecting treatment prognosis and quality of life. Janus kinase inhibitors (JAKi) and tumor necrosis factor inhibitors (TNFi) are widely used in moderate-to-severe RA and have been suggested to offer psychiatric benefits. However, direct comparisons of their effects on depression remain scarce.

Aims: To compare the risk of depression among RA patients initiating JAKi versus TNFi.

Methods: We conducted a population-based cohort study using 2017–2023 Korean National Health Insurance claims data, applying a target trial emulation framework. Eligible participants were RA patients aged ≥20 years who newly initiated JAKi or TNFi. The outcome was incident depression occurring ≥6 months after treatment initiation. Patients were followed from drug initiation until the earliest of outcome occurrence, treatment discontinuation, switching, death, or December 2023. Stabilized inverse probability of treatment weighting based on baseline propensity scores was used to adjust for confounding. Weighted Cox models estimated adjusted hazard ratios (aHRs).

Results: Among 8,181 patients (3,847 JAKi users; 4,334 TNFi users), most were female and aged 45–64 years. The incidence rate of depression per 1,000 person-years was 13.1 for JAKi users and 9.9 for TNFi users. JAKi use was not significantly associated with depression compared to TNFi (aHR 1.27, 95% CI 0.92–1.76). However, subgroup analyses revealed higher risks among patients without prior statin use (aHR 1.46, 95% CI 1.02–2.10), without benzodiazepine use (aHR 1.79, 95% CI 1.15–2.80), with intermediate RA-related visit frequency (aHR 1.72, 95% CI 1.01–2.93), and among upadacitinib users (aHR 1.70, 95% CI 1.04–2.77).

Conclusions: Overall, depression risk did not differ significantly between JAKi and TNFi, but JAKi may be less favorable in certain subgroups. These findings highlight the importance of considering psychiatric benefits in clinical decision-making.

Keywords: rheumatoid arthritis, JAKi vs TNFi, depression

Introduction:
Live zoster vaccination (LZV) reduces the incidence of herpes zoster and its complications. Recent evidence suggests additional benefits, including lower risks of cardiovascular disease and dementia. However, its effect on chronic respiratory diseases remains unclear. Given that herpes zoster induces strong immune activation, potentially exacerbating chronic inflammation, evaluating whether vaccination mitigates respiratory disease risk is warranted.

Aims:
We evaluated whether LZV is associated with reduced risk of chronic respiratory diseases, including COPD, asthma, and interstitial lung disease (ILD).

Methods:
We conducted a target trial emulation using a nationwide, population-based cohort of 2,207,784 individuals aged ≥50 years in South Korea. Health insurance claims, national health screening data, and immunization records were integrated to identify exposure to LZV between January 1, 2012, and December 31, 2021. The outcomes were newly diagnosed and hospitalized cases of COPD, asthma, and ILD. After 1:1 exposure-driven propensity score matching, we used Cox proportional hazards models to estimate adjusted hazard ratios (aHRs).

Results:
The matched cohort included 431,266 individuals per group (mean age, 61.13 years; 47.70% male). LZV was associated with significantly reduced risks of COPD (aHR, 0.67 [95% CI, 0.67–0.68]), hospitalized COPD (0.65[0.61–0.68]), asthma (0.68[0.67–0.69]), hospitalized asthma (0.58[0.53–0.64]), ILD (0.80[0.74–0.87]), and hospitalized ILD (0.67[0.55–0.83]). The protective effects were more pronounced in non-smokers and were strongest within 1–3 years post-vaccination, persisting up to 7 years.

Conclusions:
LZV was associated with a reduced incidence of chronic respiratory diseases and related hospitalizations. These findings support broader implementation of zoster vaccination in older adults and highlight potential benefits beyond herpes zoster prevention. Although our study focused exclusively on the live attenuated vaccine, both live and recombinant zoster vaccines may modulate systemic inflammation. Therefore, Further research is needed on the respiratory benefits of recombinant zoster vaccination.

Keywords: chronic respiratory disease; herpes zoster; LZV, target trial emulation, vaccine effectiveness.

Introduction: Gallbladder cancer (GBC) incidence varies significantly by geography, with Northeast India being a high-risk region. The relevance of globally identified risk factors within this distinct population is underexplored.
Aim: To delineate the GBC epidemiological profile in Northeast India by integrating regional patient data with an umbrella review of global evidence.
Methods: A mixed-methods sequential explanatory study was conducted. For the quantitative phase, we collected risk factor data from confirmed GBC patients (N=445) from a tertiary care cancer hospital in Assam, India, following ethical permission. For the qualitative synthesis, a systematic search was conducted in PubMed, Embase, Scopus, and Epistemonikos from inception to 30th June 2025 to identify global risk factors, and the quality of the included meta-analyses was assessed using the AMSTAR-2 tool. To ensure robust triangulation, consistency between regional findings and global evidence was compared with our effect sizes to the prediction intervals derived from the meta-analyses.
Results: Our global evidence synthesis identified over 120 risk associations from 51 meta-analyses, with strong links to gallstones, infections, and certain genetic polymorphisms. Triangulation with our regional cohort confirmed the risk of high parity (mean: 3.38 births), consistent with global data. However, critical divergences emerged: while smoking was rare (80.5% never-smokers), use of smokeless tobacco (58.6%) and betel nut (58.6%) were highly prevalent regional risk factors. Unique regional exposures included the near-universal use of mustard oil (96%), reliance on underground water (68.6%), and proximity to rivers (77.3%). In line with global findings on genetic susceptibility, the absence of Rh-negative blood groups suggests a regional genetic predisposition.
Conclusion: In Northeast India, GBC is influenced by both global risk factors and distinct regional exposures, including specific oral habits and environmental contaminants. Future research should prioritize molecular validation of genetic polymorphisms and toxicological analysis of regional water and food sources.

Introduction: The impact of pneumococcal vaccination on the risk of dementia has not been thoroughly evaluated in large-scale prospective populations.
Aims: We aimed to assess whether pneumococcal vaccination is associated with a reduced incidence of dementia.
Methods: We emulated a target trial with a sequential trial design using data from participants aged 50 years or older in the UK Biobank. Propensity score matching was applied to match vaccine recipients and unvaccinated individuals in a 1:1 ratio for emulating random assignment. A Cox model was used to estimate the hazard ratio (HR), along with the 95% confidence interval (CI), of the association between the use of pneumococcal vaccination and incident dementia.
Results: Overall, the cohort included 13073611 eligible person-trials in the general practice data. We emulated a total of 120 trials between October 2007 and September 2017, during which 30671 pairs of vaccinated participants and matched controls were included. In a median follow-up of 8.0 (IQR, 6.6~10.3) years, a total of 1130 incident dementia cases occurred. In the primary analysis, the incidence of dementia was 23.8 per 10,000 person-years (PYs) in unvaccinated participants and 20.1 per 10,000 PYs in those who received pneumococcal vaccination. After adjusting for potential confounders using PSM, pneumococcal vaccination use was associated with a 15% lower dementia risk (HR=0.85; 95% CI, 0.76~0.96). Specifically, the HRs for the association between pneumococcal vaccination and Alzheimer’s disease, vascular dementia, and other dementias were 0.89 (95% CI, 0.73~1.10), 0.84 (95% CI, 0.61~1.16), and 0.83 (95% CI, 0.70~0.98), respectively. Our findings remained consistent in subgroup and sensitivity analyses.
Conclusions: In this prospective population-based study of adults within the UK Biobank, pneumococcal vaccination was significantly associated with a lower risk of incident dementia. These results support the broader promotion of pneumococcal vaccination to potentially mitigate the burden of dementia among older adults.