Cox Proportional Hazards Regression Research Articles

Impact of metabolic abnormalities on the association between normal-range urinary albumin-to-creatinine ratio and cardiovascular mortality: evidence from the NHANES 1999–2018

BackgroundThe urinary albumin to creatinine ratio (UACR) is associated with adverse cardiovascular outcomes, even when within the normal range. However, the potential modification of this effect by metabolic abnormalities remains unclear. This study explored whether metabolic abnormalities modify the association between normal-range UACR and cardiovascular mortality.MethodsThis cohort study included 27,298 U.S. adults from the National Health and Nutrition Examination Survey 1999–2018, with mortality follow-up through December 31, 2019. Normal UACR (< 30 mg/g) was considered. Metabolic abnormalities were categorized into three groups based on the number of metabolic abnormality components: metabolic health (0 components), pre-metabolic syndrome (Pre-MetS, 1–2 components), and metabolic syndrome (MetS, 3–5 components). Multivariable Cox proportional hazards regression was used to estimate the association between normal UACR and cardiovascular mortality, stratified by metabolic abnormality groups.ResultsOver a median follow-up of 9.67 years, 764 cardiovascular deaths occurred. In the fully adjusted model, higher normal UACR was associated with an increased risk of cardiovascular death in metabolically abnormal individuals, but not in metabolically healthy individuals. When UACR was divided into tertiles, the highest tertile was associated with a 60% and 79% higher risk of cardiovascular mortality in the Pre-MetS and MetS groups, respectively, compared with the lowest tertile (Pre-MetS: HR, 1.60 [95% CI: 1.19–2.15]; MetS: HR, 1.79 [95% CI: 1.34–2.41]).ConclusionA higher normal UACR was associated with an increased risk of cardiovascular death in metabolically abnormal individuals, underscoring the need for early renal risk management in this population.

Associations of Depression, Antidepressants with Atrial Fibrillation Risk in HFpEF Patients.

Studies dedicated to exploring the incidence of atrial fibrillation (AF) in patients with concurrent depression and heart failure with preserved ejection fraction (HFpEF) are scarce. The impact of antidepressant therapy on AF risk within this population remains unclear. Our current study aimed to investigate the link between depression and AF risk in HFpEF patients and to assess the influence of antidepressant medication on the development of AF. We utilized Kaplan-Meier estimates to determine the event-free status for AF and applied the Log-rank test for comparative analysis between groups. The associations were quantified using univariate and multivariate Cox proportional hazards regression models, with results expressed as hazard ratios (HR) and 95% confidence intervals (CI). Among the 784 patients in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, 29.1% (228) were identified with major depression. After adjusting for significant confounders, compared with mild depression, major depression at baseline was not linked to the incidence of AF (adjusted HR = 0.82, 95% CI: 0.46-1.49). Additionally, compared with controls, antidepressant use at baseline did not significantly influence the risk of incident AF in patients with HFpEF and major depression (adjusted HR = 0.41, 95% CI: 0.08-2.10). The presence of major depression at baseline did not elevate the risk of incident AF among individuals with HFpEF. Additionally, the use of antidepressants showed no correlation with an increased rate of AF among HFpEF patients with comorbid major depression. URL: https://clinicaltrials.gov/study/NCT00094302. Unique identifier: NCT00094302.

Air pollutants, residential greenspace, and the risk of kidney stone disease: a large prospective cohort study from the UK Biobank.

The epidemiological evidence regarding the correlation between air pollution, residential greenspace, and the risk of kidney stone disease (KSD) is limited, with no large-scale prospective studies conducted on this relationship. We conducted a large-scale prospective study from the UK Biobank to explore the correlation between air pollution, residential greenspace, and the risk of KSD. This study included 419,835 UK Biobank participants who did not have KSD at baseline. An air pollution score was derived through the summation of concentrations for five air pollutants, including particulate matter (PM) with aerodynamic diameter ≤2.5 μm (PM2.5), ranging from 2.5 to 10 μm (PM2.5-10), ≤10 μm (PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx). Various covariates were adjusted for in Cox proportional hazard regression to evaluate the risk of KSD associated with air pollution score, single air pollutant, and residential greenspace. During a follow-up period of 12.7 years, 4503 cases of KSD were diagnosed. Significant associations were found between KSD risk and air pollution score (HR: 1.08, 95% CI: 1.03-1.13), PM2.5 (1.06, 1.02-1.11), PM10 (1.04, 1.01-1.07), NO2 (1.09, 1.02-1.16), NOx (1.08, 1.02-1.11), greenspace buffered at 300 m (0.95, 0.91-0.99), and greenspace buffered at 1000 m (0.92, 0.86-0.98) increase per interquartile range (IQR). PM2.5 and NO2 reductions may be a key mechanism for the protective impact of residential greenspace on KSD (P for indirect path < 0.05). Prolonged exposure to air pollution was correlated with a higher risk of KSD, while residential greenspace exhibits an inverse association with KSD risk, partially mediated by the reduction in air pollutants concentrations. These findings emphasize the significance of mitigating air pollution and maintaining substantial greenspace exposure as preventive measures against KSD.

Differences in setting of initial dementia diagnosis among fee-for-service Medicare beneficiaries.

Accurate and timely diagnosis of dementia is necessary to allow affected individuals to make informed decisions and access appropriate resources. When dementia goes undetected until a hospitalization or nursing home stay, this could reflect delayed diagnosis or misdiagnosis, and may reflect underlying disparities in healthcare access. In this retrospective cohort study, we used 2012-2020 Medicare claims and other administrative data to examine variation in setting of dementia diagnosis among fee-for-service Medicare beneficiaries with an initial claims-based dementia diagnosis in 2016. We used multinomial logistic regression to evaluate the association of person and geographic factors with diagnosis location, and Cox proportional hazards regression to examine 4-year survival relative to diagnosis location. Among 754,204 Medicare beneficiaries newly diagnosed with dementia in 2016, 60.3% were diagnosed in the community, 17.2% in hospitals, and 22.5% in nursing homes. Adjusted 4-year survival rates were significantly lower among those diagnosed in hospitals [-16.1 percentage points (95% CI: -17.0, -15.1)] and nursing homes [-16.8 percentage points (95% CI: -17.7, -15.9)], compared to those diagnosed in the community. Community-diagnosed beneficiaries were more often female, younger, Asian or Pacific Islander, Native American or Alaskan Native, Hispanic, had fewer baseline hospitalizations and higher homecare use, and resided in wealthier ZIP codes. Rural beneficiaries were more likely to be diagnosed in hospitals. Many older adults are diagnosed with dementia in a hospital or nursing home. These individuals have significantly lower survival than those diagnosed in the community, which may indicate diagnosis during an acute illness or care transition, or at a later disease stage, all of which are suboptimal. These results highlight the need for improved dementia screening in the general population, particularly for individuals in rural areas and communities with higher social deprivation.

Prognostic value of interim [68Ga]Ga-DOTA-TOC PET/CT in patients with neuroendocrine tumour who underwent peptide receptor radionuclide therapy.

This study evaluated the prognostic value of basal and interim [68Ga]Ga-DOTA-TOC PET/CT in patients with locally advanced or metastatic neuroendocrine tumour (NET) who received peptide receptor radionuclide therapy (PRRT). Patients with NET who received PRRT with [177Lu]Lu-DOTA-TATE at our institution were retrospectively reviewed. Among them, patients who underwent both basal and interim (after two cycles of PRRT) [68Ga]Ga-DOTA-TOC PET/CT were included. Alongside clinicopathologic parameters, PET parameters of maximum standardised uptake value (SUVmax), tumour-to-liver ratio (TLR), whole tumour volume (WTV) and total receptor expression (TRE: WTV multiplied by mean standardised uptake value) were obtained from basal and interim [68Ga]Ga-DOTA-TOC PET/CT, and their proportional changes (∆) were assessed for associations with progression-free survival (PFS) using Kaplan-Meier analysis, log-rank tests, and a Cox proportional-hazards regression model. Twenty-four patients were finally included (10 men and 14 women, median age of 56.5 years, age range 32-74 years). Among them, 16 patients (66.7%) experienced disease progression. In univariate analysis, high ∆WTV (≥ -10%, hazard ratio [HR] = 3.053 [1.003-9.289], p = 0.049) and high ∆TRE (≥ -21%, HR = 3.567 [1.144-11.122], p = 0.028) were significantly associated with shorter PFS. In multivariate analyses adjusted for WHO grade, high ∆WTV (HR = 3.345 [1.055-10.601], p = 0.043) and high ∆TRE (HR = 3.894 [1.194-12.695], p = 0.024) were significant predictors of shorter PFS. The study demonstrates that basal and interim [68Ga]Ga-DOTA-TOC PET/CT scans, through proportional changes in WTV and TRE, effectively predict PFS in neuroendocrine tumour patients receiving PRRT. Question Peptide receptor radionuclide therapy is utilised for patients with somatostatin receptor-positive well-differentiated neuroendocrine tumours; however, prognostic predictors are not well established. Findings Progression-free survival was significantly associated with the proportional change in whole tumour volume and total receptor expression between basal and interim [68Ga]Ga-DOTA-TOC PET/CT. Clinical relevance Interim [68Ga]Ga-DOTA-TOC PET/CT can serve as a valuable imaging method to predict prognosis of peptide receptor radionuclide therapy.

A comparative retrospective longitudinal study of arthritis risk and cognitive decline in older adults

Arthritis often results in unmet healthcare needs for older adults with cognitive decline, who may struggle to communicate pain or recall symptoms. However, the risk factors for arthritis in this group remain underexplored. We addressed this gap by identifying and comparing arthritis risk factors among older adults with varying cognitive statuses. Data from 334 participants with cognitive decline and 808 participants with normal cognition were analysed using the Korean Longitudinal Study of Aging, tracking arthritis diagnoses over 12 years with Kaplan–Meier curves and Cox proportional hazards regression. Results showed 47.6% of older adults with cognitive decline developed arthritis, compared with 30.1% with normal cognition. Key risk factors for the cognitive decline group included depressive symptoms (hazard ratio [HR]: 1.87), living alone (HR: 1.66), infrequent social interactions (HR: 1.42), and greater dependency in daily activities (HR: 1.41). In the normal cognition group, additional chronic illnesses (HR: 1.41) and higher body mass index (HR: 1.09) were significant risk factors. Understanding these distinct risk factors is crucial for preventing and managing arthritis among at risk groups. Moreover, these findings can assist in developing comprehensive public health strategies integrating mental health and social support to improve health outcomes for older adults with cognitive decline.

Association between reduced hemoglobin-to-red cell distribution width ratio and elevated cardiovascular mortality in patients with diabetes: Insights from the National Health and Nutrition Examination Study, 1999-2018.

The purpose of this research was to examine the relationship between the hemoglobin-to-red blood cell distribution width ratio (HRR) and cardiovascular disease (CVD)-related mortality in people who have diabetes. Data derived from the National Health and Nutrition Examination Survey (NHANES), between the years 1999 to 2018, were meticulously analyzed. Mortality data, encompassing events until December 31, 2019, were systematically collected. A comprehensive group comprising of 8,732 participants were subjected to scrutiny, and subsequently, classified into four distinct groups predicated upon quartiles of baseline HRR levels: Q1 (n = 2,183), Q2 (n = 2,181), Q3 (n = 2,185), and Q4 (n = 2,183). The correlation between HRR and CVD-related mortality was examined through the use of survival curves and Cox proportional hazard regression models, the latter incorporating weights as advised by NHANES. Among the 8,732 participants in the study cohort, CVD-related mortality was identified in 710 cases. The Kaplan-Meier analysis demonstrated a significant association, indicating that a decreased HRR was correlated with a reduction in survival in cases with CVD. Both univariate and multivariable Cox proportional hazard regression analyses consistently indicated that patients exhibiting a lower HRR exhibited a markedly elevated risk of CVD-related mortality in comparison to those with higher HRR. Notably, the correlation between HRR and decreasing CVD-related mortality was discerned to be non-linear. In patients with diabetes, a decreased HRR was associated with an increased risk of CVD-related mortality.

Senescence-related genes as prognostic indicators in breast cancer survival.

Breast cancer is a leading cause of cancer-related mortality among women worldwide, particularly affecting those in their later years. As the incidence of breast cancer increases with age, understanding the biological mechanisms that link aging and cancer becomes crucial. Cellular senescence, a hallmark of aging, plays a dual role in cancer by inhibiting tumorigenesis while also contributing to tumor progression through the senescence-associated secretory phenotype (SASP). This study aims to investigate the prognostic significance of senescence-related genes in breast cancer. We utilized the SenMayo gene list, a comprehensive set of senescence-related genes, to analyze gene expression data from a large cohort of breast cancer samples. The data was sourced from the Kaplan-Meier plotter, an integrated database that compiles gene expression information from multiple independent cohorts. Cox proportional hazards regression and false discovery rate (FDR) corrections were employed to evaluate the correlation between gene expression and survival outcomes, aiming to establish a prognostic signature. Our findings demonstrate that higher expression levels of senescence-related genes are significantly associated with improved survival, while lower expression levels correlate with shorter survival outcomes. These results suggest that senescence-related pathways play a protective role in breast cancer, potentially serving as valuable prognostic indicators. The identification of a prognostic signature based on senescence-related genes underscores the importance of cellular senescence in breast cancer progression and survival. Our study highlights the potential of senescence-related biomarkers in enhancing patient stratification and informing treatment strategies, contributing to the growing body of literature on the intersection of aging and cancer.

Clinical Correlates and Prognostic Impact of Cognitive Dysfunction in Patients With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). At baseline, cognitive function was normal (MMSE score 28-30) in 1809 of 2895 patients (62.5%), borderline (score 24-27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemia attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first HF hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06-1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21-2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

Association of novel dietary and lifestyle inflammation scores with incidence and progression of coronary artery calcification in middle-late adulthood: a longitudinal cohort study

BackgroundDietary patterns and lifestyle factors can influence the intensity of systemic inflammation and, consequently, the development and progression of coronary artery calcification (CAC). This study aimed to explore the relationship between the inflammatory potentials of diet and lifestyle, as captured by novel dietary and lifestyle inflammation scores (DIS and LIS), with CAC incidence and progression.MethodsWe analyzed data on 5949 Black and White men and women ≥ 45 years old participating in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Baseline data on diet and lifestyle factors were collected from 2000 to 2002 and used to construct the DIS and LIS, which reflect the overall inflammatory potential of diet and lifestyle. Cox proportional hazard regression was used to calculate the hazard ratios (HR) and 95% confidence intervals (95% CI) for CAC incidence and progression across quartiles of DIS and LIS, adjusting for potential confounders.ResultsOver a median follow-up of 8.0 years, among 2638 participants with zero CAC score at baseline, 977 individuals developed positive scores, and 1681 out of 2561 participants showed CAC progression. For individuals in the highest (more pro-inflammatory) compared to the lowest (more anti-inflammatory) quartiles of the LIS, the multivariable-adjusted HR for CAC incidence was 1.35 (95% CI, 1.10–1.65; P trend < 0.002). This association was stronger among younger adults aged < 60 years compared to those aged ≥ 60 years, with respective values of 1.76 (1.34–2.30) and 1.02 (0.78–1.35) (P interaction < 0.001). However, the LIS was not significantly associated with the progression of existing CAC. Among the components of the LIS, a body mas index (BMI) ≥ 25 kg/m2 and current smoking were significant predictors for the incidence and progression of CAC, respectively. No significant association was found between DIS and CAC incidence and progression.ConclusionsLifestyle factors, through their impact on systemic inflammation, may be associated with a higher risk of CAC incidence in middle and late adulthood.

Clinical usefulness of C-reactive protein-albumin-lymphocyte (CALLY) index as a prognostic biomarker in patients undergoing surgical resection of pancreatic cancer.

The C-reactive protein-albumin-lymphocyte (CALLY) index, which simultaneously evaluates the nutritional, immunological, and inflammatory statuses, is a new prognostic biomarker in patients with various cancers; however, no study has reported the clinical significance of the CALLY index in patients with pancreatic cancer. This study aimed to investigate whether the preoperative CALLY index is a prognostic biomarker in patients undergoing surgical resection of pancreatic cancer. We retrospectively enrolled 461 patients with pancreatic cancer who underwent surgical resection between January 2013 and December 2022. The overall survival (OS) and relapse-free survival (RFS) rates were calculated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional hazards regression models. The optimal cut-off value for the preoperative CALLY index was 1.9. In the low CALLY group, patients were older (p = 0.012), more patients underwent pancreaticoduodenectomy (p = 0.002), the median tumor size was larger (p < 0.001), more patients had pathologically confirmed metastatic lymph nodes (p = 0.015) and worse pathological stage (p = 0.015), and fewer patients received adjuvant chemotherapy (p = 0.003). A low CALLY index was associated with decreased OS (22.1 vs. 37.9months) and RFS (12.4 vs. 16.4months). Univariate and multivariate analyses showed that the preoperative CALLY index was an independent prognostic factor for OS (p < 0.001) and RFS (p = 0.045). The preoperative CALLY index is a prognostic biomarker for both OS and RFS in patients undergoing surgery for pancreatic cancer.

Survival and Treatment Patterns in Stage II to III Esophageal Cancer

Existing clinical trials favor neoadjuvant chemoradiation therapy (NCRT) followed by surgery alone for locally advanced esophageal cancer (EC) and perioperative chemotherapy as the preferred modality for esophageal adenocarcinoma (EAC). However, it is unclear whether these trial findings are reflected in the patterns of care and survival outcomes among patients in the clinical setting. To investigate survival outcomes in the clinical setting among patients with EC after various treatment modalities. This retrospective cohort study examined data from the National Cancer Database maintained by the American College of Surgeons and focused on patients with clinical stage II or III EC, excluding those with gastroesophageal junction cancer, who underwent trimodality therapy (NCRT followed by esophagectomy), definitive chemoradiation therapy (DCRT), radiotherapy (RT) alone, or perioperative chemotherapy from January 2006 to December 2020. Analyses were conducted from December 2023 to August 2024. Perioperative chemotherapy, trimodality therapy, DCRT, and single-modality RT. A Cox proportional hazards regression model was used to compare overall survival (OS) between treatment groups in the entire cohort, among patients with squamous cell carcinoma or adenocarcinoma, and among those older than 65 years. Landmark survival analysis at 6 months was performed to reduce survivorship bias. The study included 57 116 patients (median age, 64 [IQR, 57-72] years; 45 410 [79.5%] male); 21 619 patients (37.9%) received trimodality therapy, 32 493 (57.1%) received DCRT, 2692 (4.7%) received single-modality RT, and 312 (0.5%) received perioperative chemotherapy. In the overall study population, 37 698 patients (66.0%) had EAC, and of the 312 patients that received perioperative chemotherapy, 283 (90.7%) had EAC. In adjusted survival analysis, perioperative chemotherapy (adjusted hazard ratio [AHR], 0.33; 95% CI, 0.28-0.39; P <.001) and trimodality therapy (AHR, 0.45; 95% CI, 0.44-0.46; P < .001) were associated with improved OS compared with DCRT. In contrast, RT alone was associated with worse outcomes compared with DCRT (AHR, 1.37; 95% CI, 1.30-1.45; P < .001). The median OS for perioperative chemotherapy of 66.2 months (95% CI, 43.1-111.9 months; P < .001) was longer compared with that for DCRT alone (18.1 months; 95% CI, 17.8-18.4 months; P < .001). Trimodality therapy was associated with a median OS of 43.9 months (95% CI, 42.8-45.5 months; P < .001), which was shorter than that for perioperative chemotherapy but improved compared with DCRT and RT alone, which was associated with a median OS of 13.5 months (95% CI, 12.8-14.0 months; P < .001). In the subgroup of patients older than 65 years, those who received perioperative chemotherapy had longer median OS (56.7 months; 95% CI, 36.4-115.2 months; P < .001) compared with those receiving other treatment modalities (eg, trimodality therapy: 40.1 months; 95% CI, 38.1-42.0 months; P < .001). Patients who received RT alone had the worst median OS (13.6 months; 95% CI, 12.8-14.4 months; P < .001). In this cohort study of patients with stage II to III EC, trimodality therapy was associated with improved OS compared with DCRT or RT alone for locally advanced EC and perioperative chemotherapy was associated with improved OS for adenocarcinoma.

Comprehensive Evaluation of the Cardiovascular Protective Effects of SGLT2 Inhibitors in Patients with Advanced Chronic Kidney Disease: A Real-World Evidence.

Introduction Diabetes, kidney disease, and cardiovascular disease have complex interactions and coexistences that significantly worsen a patient's overall health. Previous research results have shown that SGLT2i hypoglycemic drugs can not only effectively control blood sugar in diabetic patients, but also protect the kidneys and heart. This study further focuses on diabetic patients with kidney disease to explore the effectiveness of using SGLT2i hypoglycemic drugs in avoiding heart-related complications or death. Methods This is a multi-center retrospective cohort study using the Taipei Medical University Clinical Research Database (TMUCRD) as the data source. This study selected patients who suffered from both type 2 diabetes and chronic kidney disease from 2008/01/01 to 2020/12/31 as the research team. Integrated or separate 4P-MACE (4-point major adverse cardiovascular events) and mortality were the outcomes of this study. The Kaplan Meier curves method and Cox proportional hazard regression analysis were used to explore the association between each influencing factor and the outcome. Results A total of 5,005 patients with type 2 diabetes and CKD were included in this study, of which 524 patients were stably treated with SGLT2i, 3,952 patients were treated with DPP4i, and 529 patients were treated with TZD. The results showed that the SGLT2i user group had a significantly lower risk of 4P-MACE compared with the SGLT2i non-user group (HR: 0.68, 95% CI [0.49, 0.95], p=0.024). The SGLT2i group had a significantly lower risk of cardiovascular mortality compared with the DPP4i and TZD groups (HR: 0.37, 95% CI [0.21, 0.65], p&lt;0.001; HR: 0.42, 95% CI [0.20, 0.90], p=0.025). Conclusion This study found that for patients with both diabetes and kidney disease, SGLT2i is a better option than other oral hypoglycemic medications because it can significantly avoid the occurrence of heart-related complications. The results of this study can be used as a reference for clinical medication selection practice.

Exploring the association between chronic prostatitis and the risk of herpes zoster in a cohort study in Taiwan.

The aim of the cohort research was to study the association between chronic prostatitis and the probability of herpes zoster in Taiwan. Using the National Health Insurance Research Database (NHIRD) of Taiwan, we selected male persons newly diagnosed with chronic prostatitis aged 20-84 years between 2013 and 2020. These male persons were then matched with a non-prostatitis group who did not have a diagnosis of prostatitis by using 1:1 propensity score matching on age and relevant comorbidities. All participants were observed either until a new diagnosis of herpes zoster was noted or until the completion of the study period in 2020. Cox proportional hazards regression analysis was employed to study the hazard ratio (HR) and 95% confidence interval (CI) for the risk of herpes zoster associated with chronic prostatitis. A total of 69 239 participants with chronic prostatitis and 69 239 participants with non-prostatitis were included in the analysis. The incidence rate of herpes zoster was higher in participants with chronic prostatitis compared to the non-prostatitis group (8.03 per 1000 person-years for chronic prostatitis group versus 4.74 per 1000 person-years for non-prostatitis group, incidence rate ratio = 1.69, and 95%CI = 1.59-1.81). After adjusting for co-variables, participants with chronic prostatitis were found to have a higher risk of developing herpes zoster compared to the non-prostatitis group (adjusted HR = 1.69, 95%CI = 1.59-1.81, and p < 0.001). This cohort research suggests that people with chronic prostatitis may have a greater risk of developing herpes zoster compared to the non-prostatitis group in Taiwan. Preventive strategies, such as the administration of the herpes zoster vaccine, might be beneficial in people with chronic prostatitis.

Clinical features and long-term prognostic analysis of relapsed pediatric acute lymphoblastic leukemia

Objective: To investigate the clinical characteristics and long-term prognostic factors of relapsed pediatric acute lymphoblastic leukemia (ALL). Methods: Clinical data including the age, time from initial diagnosis to relapse, relapse site, and molecular biological features of 217 relapsed ALL children primarily treated by the Chinese Children's Leukemia Group (CCLG)-ALL 2008 protocol in Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences between April 2008 and April 2015 were collected and analyzed in this retrospective cohort study. Kaplan-Meier analysis was used to evaluate the overall survival (OS) rate and event free survival (EFS) rate for univariate analysis, and Cox proportional-hazards regression model was used to evaluate the influencing factors of OS rate and EFS rate for multivariate analysis. Results: The age at initial diagnosis of 217 relapsed patients was 5 (3, 7) years. There were 135 males and 82 females. The time from initial diagnosis to relapse of 217 children was 22 (10, 39) months. After relapse, 136 out of 217 children (62.7%) received treatment and the follow-up time was 65 (47, 90) months. The 5-year OS rate and EFS rate of the 136 relapsed children were (37±4) % and (26±4) %, respectively. The predicted 10-year OS rate and EFS rate were (35±5) % and (20±4) %, respectively. Univariate analysis showed that the 5-year OS rate in the group of patients with late relapse (43 cases) was significantly higher than those with very early (54 cases) and early relapse (39 cases) ((72±7)% vs. (16±5)%, (28±8)%, χ2=35.91, P<0.05), 5-year OS rate of the isolated extramedullary relapse group (20 cases) was significantly higher than isolated bone marrow relapse group (102 cases) and combined relapse group (14 cases) ((69±11)% vs. (31±5)%, (29±12)%, χ2=9.14, P<0.05), 5-year OS rate of high-risk group (80 cases) was significantly lower than standard-risk group (10 cases) and intermediate-risk group (46 cases) ((20±5)% vs. (90±10)%, (54±8)%, χ2=32.88, P<0.05). ETV6::RUNX1 was the most common fusion gene (13.2%, 18/136). The predicted 10-year OS rate of relapsed children with positive ETV6::RUNX1 was significantly higher than those without ETV6::RUNX1 (118 cases) ((83±9)% vs. (26±5)%, χ2=14.04, P<0.05). The 5-year OS for those accepted hematopoietic stem cell transplantation (HSCT) after relapse (42 cases) was higher than those without HSCT (94 cases) ((56±8)% vs. (27±5)%, χ2=15.18, P<0.05). Multivariate analysis identified very early/early relapse (HR=3.91, 95%CI 1.96-7.79; HR=4.15, 95%CI 1.99-8.67), bone marrow relapse including isolated bone marrow relapse and combined relapse (HR=6.50, 95%CI 2.58-16.34; HR=5.19, 95%CI 1.78-15.16), with ETV6::RUNX1 (HR=0.23, 95%CI 0.07-0.74) and HSCT after relapse (HR=0.24, 95%CI 0.14-0.43) as independent prognostic factors for OS (all P<0.05). Conclusions: Relapsed pediatric ALL mainly occurs very early and often affects bone marrow, which confer poor outcome. ETV6::RUNX1 is the most common genetic aberration with a favorable outcome. HSCT could rescue the outcome of relapsed children, though the survival rate is still poor.

Interactions of genes with alcohol consumption affect insulin sensitivity and beta cell function.

Alcohol consumption has complex effects on diabetes and metabolic disease, but there is widespread heterogeneity within populations and the specific reasons are unclear. Genetic factors may play a role and warrant exploration. The aim of this study was to elucidate genetic variants modulating the impact of alcohol consumption on insulin sensitivity and pancreatic beta cell function within populations presenting normal glucose tolerance (NGT). We recruited 4194 volunteers in Nanjing, 854 in Jurong and an additional 5833 in Nanjing for Discovery cohorts 1 and 2 and a Validation cohort, respectively. We performed an OGTT on all participants, establishing a stringent NGT group, and then assessed insulin sensitivity and beta cell function. Alcohol consumption was categorised as abstinent, light-to-moderate (<210 g per week) or heavy (≥210 g per week). After excluding ineligible individuals, an exploratory genome-wide association study identified potential variants interacting with alcohol consumption in 1862 NGT individuals. These findings were validated in an additional cohort of 2169 NGT individuals. Cox proportional hazard regression was further employed to evaluate the effect of the interaction between the potential variants and alcohol consumption on the risk of type 2 diabetes within the UK Biobank cohort. A significant correlation was observed between drinking levels and insulin sensitivity, accompanied by a consequent inverse relationship with insulin resistance and beta cell insulin secretion after adjusting for confounding factors in NGT individuals. However, no significant associations were noted in the disposition indexes. The interaction of variant rs56221195 with alcohol intake exhibited a pronounced effect on the liver insulin resistance index (LIRI) in the discovery set, corroborated in the validation set (combined p=1.32 × 10-11). Alcohol consumption did not significantly affect LIRI in rs56221195 wild-type (TT) carriers, but a strong negative association emerged in heterozygous (TA) and homozygous (AA) individuals. The rs56221195 variant also significantly interacts with alcohol consumption, influencing the total insulin secretion index INSR120 (the ratio of the AUC of insulin to glucose from 0 to 120 min) (p=2.06 × 10-9) but not disposition index. In the UK Biobank, we found a significant interaction between rs56221195 and alcohol consumption, which was linked to the risk of type 2 diabetes (HR 0.897, p=0.008). Our findings reveal the effects of the interaction of alcohol and rs56221195 on hepatic insulin sensitivity in NGT individuals. It is imperative to weigh potential benefits and detriments thoughtfully when considering alcohol consumption across diverse genetic backgrounds.

MECOM Locus classical transcript isoforms affect tumor immune microenvironment and different targets in ovarian cancer

The MECOM locus is a gene frequently amplified in high-grade serous ovarian carcinoma (HGSOC). Nevertheless, the body of research examining the associations among MECOM transcripts, patient prognosis, and their role in modulating the tumor immune microenvironment (TIME) remains sparse, particularly in large cohorts. This study assessed the expression of MECOM transcripts in 352 HGSOC patients and 88 normal ovarian tissues from the combined GTEx/TCGA database. Using resources such as the UCSC Genome Browser, Ensembl, and NextProt, two transcripts corresponding to classical protein isoforms from MECOM were identified. Cox proportional hazards regression analysis, Kaplan-Meier survival curves, and a comprehensive TIME evaluation algorithm were employed to elucidate the connections between the expression levels of these transcripts and both patient prognosis and TIME status. Chromatin Immunoprecipitation sequencing (ChIP-seq) data for the two protein isoforms, as well as RNA sequencing data post-targeted silencing, were analyzed to identify potential regulatory targets of the different transcription factors. Elevated expression of the MECOM isoform transcripts was correlated with poorer survival in HGSOC patients, potentially through the modulation of cancer-associated fibroblasts (CAFs) and immunosuppressive cell populations. In contrast, higher levels of EVI1 isoform transcripts were linked to enhanced survival, possibly due to the regulation of CD8+ T cells, macrophages, and a reduction in the expression of JUN protein, or its DNA-binding activity on downstream genes. Diverse protein isoforms derived from MECOM were found to differentially affect the survival and tumor development in ovarian cancer patients through specific mechanisms. Investigating the molecular mechanisms underlying disease pathogenesis and identifying potential drug target proteins at the level of splice variant isoforms were deemed crucial.

Glymphatic system dysfunction and risk of clinical milestones in patients with Parkinson disease.

Glymphatic dysfunction may play a significant role in the development of neurodegenerative diseases. We aimed to evaluate the association between glymphatic dysfunction and the risk of malignant event/clinical milestones in Parkinson disease (PD). This study included 236 patients from August 2014 to December 2020. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index was calculated as an approximate measure of glymphatic function. The primary outcomes were four clinical milestones including recurrent falls, wheelchair dependence, dementia, and placement in residential or nursing home care. The associations of DTI-ALPS with the risk of clinical milestones were examined using multivariate Cox proportional hazards regression models. Then, logistic regression was repeated using clinical variables and DTI-ALPS index individually and in combination of the two to explore the ability to distinguish patients who reached clinical milestones within a 5-year period. A total of 175 PD patients with baseline DTI-ALPS index and follow-up clinical assessments were included. A lower DTI-ALPS was independently associated with increased risk of recurrent falls, wheelchair dependence, and dementia. Additionally, in 103 patients monitored over 5 years, a logistic regression model combining clinical variables and DTI-ALPS index showed better performance for predicting wheelchair dependence within 5 years than a model using clinical variables or DTI-ALPS index alone. Glymphatic dysfunction, as measured by the DTI-ALPS index, was associated with increased risk of clinical milestones in patients with PD. This finding implies that therapy targeting the glymphatic system may serve as a viable strategy for slowing down the progression of PD.

Nationwide study on development and validation of a risk prediction model for CIN3+ and cervical cancer in Estonia

Transitioning to an individualized risk-based approach can significantly enhance cervical cancer screening programs. We aimed to derive and internally validate a prediction model for assessing the risk of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) and cancer in women eligible for screening. This retrospective study utilized data from the Estonian electronic health records, including 517,884 women from the health insurance database and linked health registries. We employed Cox proportional hazard regression, incorporating reproductive and medical history variables (14 covariates), and utilized the least absolute shrinkage and selection operator (LASSO) for variable selection. A 10-fold cross-validation for internal validation of the model was used. The main outcomes were the performance of discrimination and calibration. Over the 8-year follow-up, we identified 1326 women with cervical cancer and 5929 with CIN3+, with absolute risks of 0.3% and 1.1%, respectively. The prediction model for CIN3 + and cervical cancer had good discriminative power and was well calibrated Harrell’s C of 0.74 (0.73–0.74) (calibration slope 1.00 (0.97–1.02) and 0.67 (0.66–0.69) (calibration slope 0.92 (0.84–1.00) respectively. A developed model based on nationwide electronic health data showed potential utility for risk stratification to supplement screening efforts. This work was supported through grants number PRG2218 from the Estonian Research Council, and EMP416 from the EEA (European Economic Area) and Norway Grants.

The value of assessing deep disease healing by probe-based confocal laser endomicroscopy and histology for long-term prognosis of ulcerative colitis.

The benefits of deep disease healing need evaluation by long-term clinical research in different populations. Confocal laser endomicroscopy (CLE) is a superior method for evaluating deep disease healing. This prospective study enrolled ulcerative colitis (UC) patients in clinical remission who underwent colonoscopy, CLE, and histological assessment. Patients were monitored for relapse by patient-reported outcomes and colonoscopy evaluation of mucosal healing. The ability of different methods of mucosal healing to predict long-term disease recurrence was assessed using Kaplan-Meier estimation and Cox proportional hazard regression. Forty-two patients in clinical remission were assessed by colonoscopy. Those with Mayo endoscopic subscores (MES)≤1 were enrolled. The 48-month recurrence rates in present healing group, assessed by CLE (colonic barrier assessment and ENHANCE index) and by histological examination (Geboes scale), were 20.0%, 26.7%, and 11.1%, respectively, and were significantly lower than absent healing group (P<0.05). Univariate Cox proportional risk regression analysis in absent of healing disease, determined by the ENHANCE index and Geboes scale, indicated an increased risk of recurrent events, with hazard ratios (HR) of 3.87 (95% CI: 1.18, 12.62) and 8.20 (95% CI: 1.06, 63.30), respectively. Multivariate Cox proportional hazard regression analysis adjusted for the extent of inflammation (E3 or not) showed a significant difference only for the ENHANCE index, with an HR of 3.53 (95% CI: 1.03, 12.10), P=0.045. Deep disease healing has a lower recurrence rate. The colonic barrier healing assessment, ENHANCE index, and histological Geboes scale have superior long-term prognostic value for UC patients.