Multivariate Cox Proportional Model Research Articles

Impact of sirtuin genes expression on first-line treatment outcomes in patients (pts) with metastatic colorectal cancer (mCRC) enrolled in CALGB/SWOG 80405 (Alliance).

269 Background: Sirtuins (SIRT1-7) are class III histone deacetylases with different roles in CRC as tumor suppressive and oncogenic, mainly influencing proliferation, migration, invasion, DNA damage and chemoresistance. In the present study, we explored the association between tumor gene expression of sirtuins and first-line treatment outcomes in mCRC pts. Methods: We evaluated the impact of the tumor gene expression of sirtuin genes ( SIRT1 -7) on treatment outcomes (overall survival: OS; progression free survival: PFS) in 433 pts enrolled in the randomized, phase III CALGB/SWOG 80405 (NCT00265850) trial. RNA extracted from FFPE tumor samples was sequenced using the HiSeq 2500 (Illumina). Subgroup analyses were based on treatment (bevacizumab [bev] (N = 226) vs. cetuximab [cet] (N = 207)). For each gene, expression was divided into tertiles of high, medium and low. The associations between tumor gene expression and outcomes (PFS and OS) were assessed using log-rank test in univariate analysis. Multivariable Cox proportional hazards regression model was used to compute hazard ratios (HR) and 95% confidence intervals while adjusting for baseline characteristics. Treatment-gene interactions were analyzed using the likelihood ratio test. Results: Of the seven genes analyzed, SIRT3 high was associated with both longer PFS (HR: 0.59 [95% CI: 0.46-0.74], P < 0.001) and OS (HR:0.64 [95% CI: 0.50-0.83], P = 0.002) overall. Treatment-gene interaction testing found significant interactions for SIRT1 and SIRT5 with PFS ( P values: 0.021 and 0.016, respectively) and OS ( P values: 0.038 and 0.014, respectively) with targeted therapies (bev vs. cet). Multivariate analysis showed SIRT1 high associated with longer PFS (HR: 0.62 [95% CI: 0.42-0.89], P = 0.014) and OS (HR: 0.59 [95% CI: 0.40-0.89], P = 0.036) in cet-treated pts; in contrast with shorter observed PFS (HR: 1.38 [95% CI: 0.96-1.99], P = 0.22) and OS (HR: 1.31 [95% CI: 0.90-1.93], P = 0.23) in bev-treated pts. SIRT5 high showed similar results and associated with longer PFS (HR: 0.64 [95% CI: 0.45-0.91], P = 0.039) and OS (HR: 0.57 [95% CI: 0.39-0.83], P = 0.013) in cet-treated pts, with no similar associations in bev-treated pts. Conclusions: Our results highlight a potential role for SIRT3 as prognostic and, SIRT1 and SIRT5 as predictive biomarkers for first-line treatment in mCRC, with differential effects based on targeted agents. Significant interaction favored cet treatment in SIRT1 high and SIRT5 high tumors. However, previous reports suggest an opposite role of SIRT5 that has been linked to chemotherapy and/or cet resistance in CRC via the inactivation of succinate dehydrogenase complex subunit A. Therefore, further studies are warranted to dissect the mechanism behind the interaction of SIRT5 with cetuximab activity and establish the potential of targeting SIRT1/5 in CRC.

The prognostic value of HER2 gene dosage and heterogeneity at a single-cell resolution in gastroesophageal adenocarcinoma.

473 Background: HER2 gene dosage (i.e. level of amplification) and heterogeneity are key prognostic variables for HER2+ gastroesophageal adenocarcinoma (GEA), yet no standardized approach to test these in routine clinical use exists. Here we modify the analytical pipeline for HER2 FISH to quantitatively estimate these prognostic variables and correlate them with clinical outcomes. Methods: Patients with metastatic HER2+ GEA who received trastuzumab-based therapy between 2011-2024 at Dana-Farber Cancer Institute and had available pre-treatment tissue for FISH analysis were included. HER2 FISH was conducted in a CLIA approved clinical pathology laboratory. Standard HER2/CEP17 ratio (an average of 50 cells) and individual cell HER2/CEP17 ratio were calculated. Kaplan-Meier method was used to estimate progression free (PFS) on trastuzumab-based therapy and overall survival (OS). Survival outcomes were adjusted for age, gender, tumor site, grade, prior resection, number of metastatic sites, and HER2 IHC using cox proportional hazard regression models. Results: A total of 77 patients were included. Median age was 60 years, 88% were male, and 92% had HER2 3+ tumors. Individual cells with HER2/CEP17 ratio ≥ 2.0 were defined as amplified (same cutoff as current bulk standard) and those with HER2/CEP17 ratio ≥ 4.95 (population median) were labeled highly HER2 amplified providing objective metrics to assess heterogeneity and gene dosage. Using these metrics we defined three subgroups: 1. Heterogenous (Het, n = 15): <75% cells HER2+; 2. Homogenous, low gene dosage (HL, n = 30): >75% cells HER2+, <50% cells with high HER2 amplification; 3. Homogenous, high gene dosage (HH, n = 32): >75% cells HER2+, >50% cells with high HER2 amplification. Cutoffs for both metrics were determined using data distribution patterns. The subgroups were prognostically relevant and PFS and OS were significantly lower for heterogenous tumors and numerically lower for homogenous tumors with low gene dosage after multivariable adjustment (Table). Conclusions: HER2 gene dosage and heterogeneity significantly impact outcomes in HER2+ GEA. More importantly by deconvoluting clinical HER2 FISH data at single cell level, we demonstrate an objective metric with prognostic value that could be adopted for routine clinical use and for patient stratification. Further insights into differing biology of these molecular subtypes are needed. Outcomes of patients by HER2 heterogeneity and gene dosage. Hazards ratio (HR) and p values are adjusted using multivariable cox proportional hazard regression model. PFS OS Patients, No. Median, mo HR (95%CI) P Value Median, mo HR (95%CI) P Value HH 32 16.2 1 16.4 1 HL 30 12.1 1.70 (0.79-3.66) 0.173 15.7 1.71 (0.93-3.14) 0.085 Het 15 6.7 3.12 (1.35-7.2) 0.008 12.4 2.72 (1.28-5.75) 0.009

Association of oxidative balance score with the risk of all-cause and CVD mortality in younger US adults with diabetes

Oxidative balance score (OBS) is a composite measures that assess the balance between pro-oxidant and antioxidant factors in an individual’s diet and lifestyle, with higher scores indicating greater antioxidant exposure. Despite its potential significance, there is a limited body of research exploring the relationship between OBS and all-cause and cardiovascular disease (CVD) mortality specifically in younger patients with diabetes. We aimed to investigate the possible relationship between OBS and all-cause and CVD mortality in younger patients with diabetes. Data for this study were obtained from the 2003–2018 NHANES. This study enrolled 3501 participants. The endpoints were all-cause and CVD mortality, determined by the National Death Index (NDI). OBS, which consists of 16 dietary factors and 4 lifestyle factors, is categorized into pro-oxidants and antioxidants. The OBS was categorized into four quartiles (Q1-Q4). We used multivariable Cox proportional hazards regression models to examine the association between continuous and quartile measures of OBS, lifestyle OBS (lifestyle antioxidants such as physical activity, etc., and lifestyle pro-oxidants such as alcohol, smoking, etc.), and dietary OBS (dietary antioxidants such as fiber, β-carotene, riboflavin, etc., and dietary pro-oxidants, such as total fat, etc.) with all-cause and CVD mortality. Additionally, we explored restricted cubic spline (RCS) analysis and also performed subgroup analyses and interaction tests. The occurrence of 409 all-cause deaths (11.7%) and 108 CVD-related deaths (3.1%) was recorded during the follow-up period. Our results found that OBS, lifestyle OBS, and dietary OBS were negatively associated with patients’ all-cause and CVD mortality. The RCS analysis further validated the association of a linear negative correlation between OBS and all-cause and CVD mortality. The results of our subgroup analyses revealed that the negative association between OBS and CVD mortality may be influenced by alcohol use. In conclusion, results from a nationally representative study of younger American patients with diabetes suggest a negative association between OBS, lifestyle OBS, and dietary OBS and all-cause and CVD mortality. Antioxidant-rich diets and lifestyle improvements are essential for reducing all-cause and CVD mortality in patients.

Risk factors for pancreatic cancer in individuals with intraductal papillary mucinous neoplasms and no high-risk stigmata during up to 5 years of surveillance: a prospective longitudinal cohort study

BackgroundCyst size, its growth rate, and diameter of the main pancreatic duct (MPD) are all associated with pancreatic carcinoma prevalence in intraductal papillary mucinous neoplasms (IPMNs).ObjectiveTo examine the above factors...

Triglyceride-glucose index in predicting the risk of new-onset diabetes in the general population aged 45 years and older: a national prospective cohort study

ObjectiveInsulin resistance (IR) is often present in diabetes, which imposes a heavy burden on the prevention and treatment of diabetes. Triglyceride glucose index (TyG) is simple, reliable and reproducible in detecting IR, and has great advantages in predicting the risk of diabetes. The aim of this study was to analyze the potential association between TyG and the risk of diabetes in Chinese middle-aged and older adults using a prospective cohort study design.MethodsThis study used longitudinal data from five waves of the China Health and Retirement Longitudinal Study (CHARLS) conducted in 2011, 2013, 2015, 2018, and 2020, involving 5886 participants. We used Cox proportional risk regression modeling to investigate the association between TyG index and the risk of new-onset diabetes, and decision tree analysis to identify high-risk groups for diabetes. Finally, ROC curves were applied in order to construct a predictive model for diabetes.ResultsA total of 1054 (17.9%) participants developed diabetes throughout the 9-year follow-up. Our study utilized a multivariate Cox proportional risk regression model and found a significant correlation between TyG index and diabetes risk. The analysis also revealed a nonlinear relationship between TyG index and diabetes risk.Receiver Operating Characteristic(ROC) curve analysis showed that the Area under the curve(AUC) area of TyG index in predicting the risk of new-onset diabetes was 0.652 (P < 0.05).ConclusionsTyG index can be used as a risk factor for predicting new-onset diabetes in the middle-aged and elderly population in China. In addition, there was a nonlinear relationship between TyG index and diabetes. Improving insulin resistance by regulating glucose and lipid metabolism plays an important role in the primary prevention of diabetes.

The Association Between Metabolic Syndrome and the Risk of Endometrial Cancer in Pre- and Post-Menopausal Women: A UK Biobank Study

Background: Metabolic syndrome (MetS) is a syndrome that comprises central obesity, increased serum triglyceride (TG) levels, decreased serum HDL cholesterol (HDL) levels, raised blood pressure (BP), and impaired glucose regulation, including prediabetic and diabetic glycaemic levels. Recently, the association with endometrial cancer (EC) has been described but it is unclear if the risk associated with MetS is higher than the individual effect of obesity alone. This study investigates the association between MetS components and differing MetS definitions on EC risk and compares the risk of MetS with the risk posed by obesity alone. It also analyses how MetS affects the risk of EC development in the pre- and post-menopausal subgroups. Methods: A prospective cohort study was undertaken using data from the UK biobank. Multivariable Cox proportional risk models with the time to diagnosis (years) were used to estimate the hazard ratio (HR) and 95% confidence interval (CI) of MetS and its components on the risk of EC. A subgroup analysis was also undertaken for pre- and post-menopausal participants. Kaplan–Meier (KM) was undertaken to assess the difference in the risk of EC development in differing BMI classes, and in pre- and post-menopausal subgroups. Results: A total of 177,005 females from the UK biobank were included in this study. Of those participants who developed EC (n = 1454), waist circumference &gt; 80 cm, BMI &gt; 30 kg/m2, hypertension &gt; 130/80 mmHg, hyperlipidaemia and diabetes (HbA1C &gt; 48 mmol/L were significant predictors of EC development, with waist circumference being the strongest predictor (HR = 2.21; 95% CI: 1.98–2.47, p &lt; 0.001). Comparing the pre- and post-menopausal subgroup, hypertriglyceridaemia and diabetes were the strongest predictors of EC in the pre-menopausal subgroup (HR = 1.53; 95% CI: 1.18–1.99 and HR = 1.51; 95% CI: 1.08–2.12, p &lt; 0.05, respectively). Raised waist circumference was not a significant independent predictor in the pre-menopausal subgroup. A KM curve analysis showed a clear distinction between those with and without MetS in the pre-menopausal group, suggesting a benefit of testing for MetS components in pre-menopausal women with obesity. Conclusions: Components of MetS, both independently and in combination, significantly increase the risk of EC. Screening those with obesity for MetS in their pre-menopausal years may help to identify those at the highest risk.

Baseline Fasting Glucose Level, Age, Sex, and Body Mass Index and the Development of Diabetes in US Adults

Understanding the interplay between diabetes risk factors and diabetes development is important to develop individual, practice, and population-level prevention strategies. To evaluate the progression from normal and impaired fasting glucose levels to diabetes among adults. This retrospective community-based cohort study used data from the Rochester Epidemiology Project, in Olmsted County, Minnesota, on 44 992 individuals with at least 2 fasting plasma glucose (FPG) measurements from January 1, 2005, to December 31, 2017. People who met criteria for diabetes on or before their first FPG measurement were excluded. Data were electronically retrieved in December 2019 with analyses finalized in November 2024. The exposure was baseline FPG level, with covariates including the following measures that are consistently recorded in the electronic health record: body mass index (BMI), age, and sex. The cumulative probability of freedom from diabetes was estimated and presented graphically using a Kaplan-Meier curve. Multivariable Cox proportional hazards regression modeling was used to estimate the partial hazard ratios (HRs) for variables of interest. Diabetes was defined as an FPG level greater than 125 mg/dL. A total of 44 992 individuals (mean [SD] age at baseline, 43.7 [11.8] years; 26 025 women [57.8%]) were included. The baseline mean (SD) BMI was 28.9 (6.6). Over a median follow-up of 6.8 years (IQR, 3.6-9.7 years), 3879 individuals (8.6%) developed diabetes. The Kaplan-Meier 10-year cumulative risk of incident diabetes was 12.8% (95% CI, 12.4%-13.2%). All initial FPG levels outside a range of 80 to 94 mg/dL were associated with increased risk for diabetes (ie, FPG <70 mg/dL: HR, 3.49 [95% CI, 2.19-5.57]; FPG 120-125 mg/dL: HR, 12.47 [10.84-14.34]). Other independent risk factors were male sex (HR, 1.31 [95% CI, 1.22-1.40]), older age (≥60 years: HR, 1.97 [95% CI, 1.71-2.28]), and any abnormal category of BMI, including underweight (BMI <18.5: HR, 2.42 [95% CI, 1.77-3.29]; BMI ≥40: HR, 4.03 [95% CI, 3.56-4.56]). There was a significant additive association of variables, particularly FPG level and BMI. For instance, a woman aged 55 to 59 years with a BMI of 18.5 to 24.9 and an FPG level of 95 to 99 mg/dL had an estimated 10-year diabetes risk of 7.0%. However, an almost doubling of risk to 13.0% was observed if the BMI was 30.0 to 34.9, and risk more than doubled again to 28.0% if FPG level also increased to 105 to 109 mg/dL. A nomogram was generated to facilitate individual classification into one of four 10-year risk categories. This retrospective cohort study of 44 992 individuals suggests that FPG level, age, BMI, and male sex were all associated with development of diabetes, with significant interaction between these variables. These data contribute to understanding the clinical course of diabetes and highlight the substantial individual variation in diabetes risk according to commonly measured clinical variables. The findings facilitate lifestyle and pharmacologic interventions to treat those at highest risk of diabetes to reduce future morbidity and mortality. Further work is needed to validate this risk categorization tool for different populations.

DOP086 Burden of depression and anxiety among patients with pediatric-onset Inflammatory Bowel Diseases: A nationwide study from the epi-IIRN

Abstract Background Data regarding burden of depression and anxiety in pediatric-onset inflammatory bowel diseases (PIBD) are limited. We aimed to study the prevalence of depression and anxiety in a nationwide cohort of PIBD Methods Data were retrieved from the epi-IIRN, a nationwide cohort of the 4 Israeli Health Maintenance Organizations covering 98% of the population from 2005. We matched PIBD children to non-IBD controls for calculating time to depression/anxiety. Patients with depression/anxiety prior to IBD diagnosis were excluded. Poor disease course (PDC) was defined as IBD-related surgery, steroid-dependency, or need for more than one biologic class. A time-dependent Cox-proportional-hazard-ratio model was fit to examine predictors of the development of depression/anxiety over time. Inverse probability weights (IPW) were calculated to estimate the probability that an individual will develop depression at each time point within an individual follow up period Results In total, 4,960 PIBD cases were included [mean age 13.4±3.8 years; 3,304 (67%) with Crohn's disease (CD) and 1,656 (33%) ulcerative colitis (UC)], translating into 32,700 person-years of follow-up. These were individually matched to 4,806 non-IBD children. In a univariable Cox proportional regression model, PIBD was associated with overall anxiety/depression compared to controls (HR=1.9 95%CI 1.7-2.2). The probability of depression/anxiety was higher in PIBD patients vs controls at 3 (6% vs 2.5%) and 10 years (17.5% vs 10.2%; p&amp;lt;0.001, Figure 1). There were no differences in the probability of depression/anxiety between patients with UC and CD (HR=0.96 95%CI 0.81-1.1, p=0.62). In multivariable Cox proportional regression model in patients with CD; perianal disease [HR=1.5 (95%CI 1.3-2)], need for &amp;gt;1 biologic class, [HR=1.6 (95%CI 1.03-2.63)], and hospitalizations [HR=1.4 (95%CI 1.1-1.9)] were associated with developing anxiety/depression. Risk for anxiety/depression was lower among patients after CD related surgery compared with those who did not undergo surgery [HR 0.5 (95%CI 0.28-0.99)]. For patients with UC, steroid dependency was associated with anxiety/depression [HR 1.5, (95%CI 1.05-2.1)]. Figure 1 (Depression free survival probability) Conclusion Our study highlights the substantial burden of depression/anxiety in PIBD and identifies risk factors for these conditions. These findings emphasize the need for mental health monitoring and early intervention in this vulnerable population

P0475 Differential characteristics and predictors of time to colectomy in ulcerative colitis: stratified by medical refractory disease vs. colitis-associated neoplasia

Abstract Background Colectomy rates for ulcerative colitis (UC) have likely decreased in recent decades due to advancements in therapy, but surgery remains crucial for managing medically refractory disease or UC-associated neoplasia. This study aimed to evaluate the differential characteristics and predictors of early colectomy in UC patients undergoing colectomy for medical refractoriness versus UC-associated neoplasia. Methods We retrospectively reviewed the medical records of 569 UC patients who underwent colectomy at Mount Sinai Hospital, Toronto, between January 2010 to June 2023. Patients with pathologically confirmed UC and surgery due to medical refractoriness (MR) or UC-associated neoplasia were included. We analyzed the clinical characteristics and their impact on time to colectomy from diagnosis using Kaplan-Meier survival analysis and multivariate Cox proportional hazards regression models. Results Among the 394 patients who met the criteria, 57.1% were male, 94.7% had extensive colitis. The median ages at UC diagnosis and colectomy were 25 years (IQR 19–36) and 36 years (IQR 26-49), respectively. Of these, 288 patients (73.1%) underwent colectomy for MR, and 106 patients (26.9%) for UC-associated neoplasia. The median age at colectomy differed between the MR and neoplasia groups (33 years [IQR 24-44] vs 47 years [IQR 35-55], P &amp;lt; 0.001), as did the median UC duration (4 year [IQR 2-8] vs 16 years [IQR 9-21], P &amp;lt; 0.001). The proportion of patients with primary sclerosing cholangitis was higher in the neoplasia group (2.4% vs 20.5%, P &amp;lt; 0.001). The use of systemic steroids (67.7% vs 15.1%, P &amp;lt; 0.001) and biologics or small molecules (68.8% vs 43.4%, P &amp;lt; 0.001) prior to surgery was higher in the MR group. In the MR group, male sex (HR 1.30, 95% CI 1.02-1.66, P = 0.036), never smoking (HR 1.42, 95% CI 1.02-1.98, P = 0.039), and diagnosis age &amp;gt; 40 year (HR 1.58, 95% CI, 1.15-2.16, P = 0.005) were associated with a shorter time to colectomy. In contrast, in the neoplasia group, age at diagnosis &amp;gt; 40 years (HR 0.39, 95% CI 0.25–0.63, P &amp;lt; 0.001) was linked to a longer time to colectomy. Conclusion Significant differences in clinical characteristics were identified between UC patients undergoing colectomy for MR compared with UC-associated neoplasia. Late-onset UC, diagnosed after the age of 40, may be linked to a shorter time to colectomy for medically refractory disease while it seems to have a lower likelihood of early colectomy for neoplasia.

Hepcidin, Incident Heart Failure and Cardiac Dysfunction in Older Adults: the ARIC Study.

Hepcidin regulates plasma and tissue iron levels. We studied the association of hepcidin levels with the risk of incident heart failure (HF) and cardiac dysfunction in older adults. We included adults from the ongoing, longitudinal Atherosclerosis Risk in Communities (ARIC) study who were free from prevalent anemia and HF at Visit 5 (2011-2013) and had available hepcidin and covariate data. Associations of plasma hepcidin levels with overall adjudicated incident HF, HF with reduced and HF with preserved ejection fraction (HFrEF and HFpEF) were assessed using multivariable Cox proportional hazards regression models. Cross-sectional associations of hepcidin with echocardiographic measures of cardiac structure and function were estimated using multivariable linear regression models. The mean age was 75±5 years old and 56% were women. In fully adjusted models, lower hepcidin levels were associated with a higher risk of overall incident HF (HR [95% CI] per 50% lower hepcidin: 1.15 [1.05-1.26]; P=0.003) and HFpEF (HR [95% CI]: 1.25 [1.10-1.42]; P=0.001). Plasma hepcidin level was not significantly associated with the risk of incident HFrEF (HR [95% CI]: 1.08 [0.94-1.24]; P=0.30). Lower hepcidin levels were associated with higher E wave (P=0.046), higher E/e' ratio (P=0.002), higher left atrial volume index (P=0.005) and higher pulmonary artery systolic pressure (P=0.02). In community-dwelling older adults without anemia, lower plasma hepcidin levels associate with a higher risk of incident HF (particularly HFpEF) and diastolic dysfunction. The findings imply the importance of monitoring iron metabolism dysregulation, even in absence of anemia, in late life.

Associations between the Global Diet Quality Score and risk of type 2 diabetes: Tehran lipid and glucose study.

Previous studies reported that focusing on healthy lifestyle, especially high diet quality is necessary for preventing type 2 diabetes (T2D). This study investigated the association between the innovative index, the Global Diet Quality Score (GDQS), and the risk of Type 2 Diabetes incidence. In this secondary analysis, we included elective adult participants (n = 5948) from the third and fourth survey of the Tehran Lipid and Glucose Study. Participants checked out until the sixth phase with an average follow-up of 6.65 years. Expert nutritionists collected dietary data using a valid and reliable semi-quantitative food frequency questionnaire. The GDQS were calculated, including healthy and unhealthy food group scores. Biochemical and anthropometric characteristics were assessed during the first and follow-up surveys. Multivariable Cox proportional hazards regression models were used to estimate the progression of T2D in association with the GDQS. This study was implemented on 2,688 men and 3,260 women, respectively with the mean (SD) age of 41.5(14.1) and 39.3(13.02) years. A total of 524 subjects were found to have had T2D incidence. The healthy component of GDQS was conversely associated with T2D incidence [HR: 1, 0.91 (0.84-0.98), 0.91 (0.84-0.98), 0.84 (0.77-0.92) P trend = <0.001] in an adjusted model. The unhealthy component of GDQS was conversely associated with T2D incidence in an adjusted model [HR: 1, 0.86 (0.80-0.92), 0.93 (0.86-1.01), 0.89 (0.81-0.98) P trend = 0.009]. The results of this study suggested that higher adherence to the healthy component of GDQS and lower intake of the unhealthy component decreased the risk of T2D incidence.

Suppression of MCP-1, IFN-γ and IL-6 production of HNSCC ex vivo by pembrolizumab added to docetaxel and cisplatin (TP) exceeding those of TP alone is linked to improved survival

BackgroundAdding pembrolizumab, an anti-PD-1 antibody approved for treatment of head and neck squamous cell carcinoma (HNSCC) to neoadjuvant (induction-) chemotherapy utilizing docetaxel and cisplatin (TP) followed by radiotherapy may improve outcome in larynx organ-preservation (LOP) that is investigated in the European Larynx-Organ preservation Study (ELOS). As biomarkers for response to TP and pembrolizumab +TP are missing but may include cytokines, this work aims on determining cytokines potentially linked to outcome as prognostic markers sufficient to predict and/or monitor response to successful LOP.MethodsCollagenase IV digests were generated from 47 histopathological confirmed HNSCC tumor samples and seeded in 96-well plates containing pembrolizumab, docetaxel, cisplatin either solely or in binary or ternary combination. According to the FLAVINO protocol, supernatants were collected after 3 days, adherent cells fixed using ethanol, air-dried and pan-cytokeratin positive epithelial cells counted using fluorescence microscopy. The cytokines IL-6, IL-8, IFN-γ, IP-10, MCP-1, TNF-α, and VEGF in the supernatant were quantified by sandwich ELISA.ResultsThe mode of interaction between pembrolizumab and TP was assessed and correlated to outcome (overall, disease-specific and progression-free survival of patients). Suppression of MCP-1, IFN-γ and IL-6 production by pembrolizumab + TP exceeding the suppressive effect of TP was detected in the majority of samples and linked to improved survival. Multivariate Cox proportional hazard regression modeling revealed MCP-1, IFN-γ and IL-6 as independent outcome predictors.ConclusionsComparing response to TP vs. pembrolizumab vs. TP + pembrolizumab may allow for identification of patients with superior outcome independent from treatment applied.

Longitudinal increase in physical activity and adverse cardiovascular outcomes following the diagnosis of acute coronary syndrome

ObjectivesPhysical activity (PA) provides protective effects against cardiovascular diseases, including ischaemic heart disease. However, recommending moderate to vigorous PA (MVPA) to patients with recent acute coronary syndrome (ACS) raises concerns...

Association Between Chewing Capacity and Mortality Risk: The Role of Diet and Ageing.

Masticatory dysfunction due to tooth loss is a potentially modifiable risk for mortality, but the pathway behind that remains to be investigated. This prospective study aimed to examine the role of diet and ageing in the associations between chewing capacity and long-term mortality. Data were obtained from participants (aged ≥ 20) in the National Health Nutritional and Health Survey (NHANES 1999-2010, n = 22,900). The mortality follow-up ended on 31 December 2019. Chewing capacity was determined by the number of functional tooth units (FTUs). Diet information in NHANES was collected using a 24-h-recall questionnaire, and diet quality was measured by three index-based dietary patterns, namely the nutrition index (NI), energy-adjusted dietary inflammatory index (E-DII) and healthy eating index-2015 (HEI-2015). The biological ageing process was reflected using phenotypic age acceleration (PhenoAgeAccel) and frailty index. Mediation analyses were conducted to assess the role of diet quality in the association between FTUs and ageing, as well as the role of ageing in the association between impaired chewing capacity (ICC) and mortality. Participants with more FTUs were found to have a slower biological ageing process. Diet quality scores were estimated to mediate 9.0%-23.0% of the association between chewing capacity and biological ageing. Multivariable Cox proportional hazards regression models found a positive association between ICC and all-cause mortality (hazard ratio = 1.282 [95% confidence interval: 1.189-1.382]). Also, ICC was significantly associated with a 28.9% higher risk of mortality due to cardiovascular disease (CVD) and a 32.7% higher risk of mortality due to cancer. Mediation analyses indicated that PhenoAgeAccel mediated the effect of ICC on all-cause, CVD and cancer mortality with proportions of 18.1%, 17.3% and 12.5%, respectively. Similar mediating proportions were observed in the frailty index (range: 11.6%-23.5%). ICC was associated with poorer diet quality and accelerated ageing, resulting in higher mortality risk. Therefore, it is plausible that dietary interventions and oral rehabilitation would promote healthy longevity, although further investigations are needed.

Sugar-sweetened or artificially sweetened beverage consumption, physical activity and risk of type 2 diabetes in US adults.

A positive association between sugar-sweetened beverages (SSBs) and diabetes risk has been shown, with inconsistent evidence between artificially sweetened beverages (ASBs) and diabetes. Moreover, it is uncertain if physical activity can mitigate the negative effects of these beverages on diabetes development. Therefore, we aimed to evaluate the independent and joint associations between SSB or ASB consumption and physical activity on the risk of type 2 diabetes. We followed 64,029 women in the Nurses' Health Study (1980-2016), 88,340 women in the Nurses' Health Study II (1991-2017) and 39,436 men in the Health Professionals Follow-up Study (1986-2016). SSB and ASB consumption was calculated from food-frequency questionnaires administered every 4 years, while physical activity data were collected biennially. A validated supplementary questionnaire on diabetes symptoms, diagnostic tests and treatment confirmed type 2 diabetes cases. Multivariable Cox proportional hazards regression models were used to calculate HRs and 95% CIs for developing type 2 diabetes. During 5,105,351 person-years of follow-up, we recorded 19,940 new cases of type 2 diabetes. Compared with those who never or rarely consumed SSBs or ASBs, those who consumed ≥2 servings/day had a 41% (HR 1.41 [95% CI 1.33, 1.50]) and 11% (HR 1.11 [95% CI 1.07, 1.16]) higher risk of type 2 diabetes, respectively. For participants meeting physical activity guidelines (≥7.5 metabolic equivalent of task [MET] h/week) and consuming ≥2 servings/week of SSBs or ASBs, the risk was 22% (HR 1.22 [95% CI 1.15, 1.29]) and 7% (HR 1.07 [95% CI 1.02, 1.12]) higher, respectively, compared with those who met physical activity guidelines and never or rarely (<1 serving/month) consumed these beverages. For participants meeting the physical activity guidelines and consuming 1-4 servings/month of SSBs, there was a 9% (HR 1.09 [95% CI 1.02, 1.15]) higher risk of type 2 diabetes. Compared with the reference group (those who met physical activity guidelines and consumed <1 SSB serving/month), adults who did not meet physical activity guidelines (<7.5 MET h/week) and who never or rarely (<1 serving/month) consumed SSBs, had 1-4 SSB servings/month, or had ≥2 SSB servings/week, the HRs (95% CIs) were 1.22 (1.13, 1.31), 1.28 (1.20, 1.37), and 1.51 (1.43, 1.61), respectively. Similarly, for ASB consumption, adults who did not meet physical activity guidelines and who never or rarely (<1 serving/month) consumed ASBs, had 1-4 servings/month, or had ≥2 servings/week, the HRs (95% CIs) were 1.21 (1.14, 1.28), 1.21 (1.13, 1.30), and 1.30 (1.23, 1.37) compared with the reference group (who met physical activity guidelines and consumed <1 ASB serving/month). Even when individuals were physically active, a higher consumption of SSBs or ASBs was associated with a higher risk of type 2 diabetes. Meeting physical activity guidelines reduced the impact of SSB and ASB consumption on diabetes risk, underscoring the need to promote physical activity as part of lifestyle modifications to lower diabetes incidence.

Association Between Running Characteristics and Lower Extremity Musculoskeletal Injuries in United States Military Academy Cadets.

Running-related overuse injuries are common among recreational runners; however, there is currently little prospective research investigating the role of running characteristics on overuse injury development. To investigate the relationship between running characteristics and lower extremity musculoskeletal injury (MSKI). Cohort study; Level of evidence, 2. The study included 827 incoming cadets of the class of 2020 at the United States Military Academy. Before cadet basic training, running spatiotemporal parameters (stride length, ground contact time, and cadence) were recorded for each participant, and foot-strike pattern was analyzed. Demographic data were recorded and analyzed as potential covariates. Lower extremity MSKIs sustained over the 9 weeks of cadet basic training were documented. Kaplan-Meier survival curves were estimated, with time to incident lower extremity MSKI as the primary outcome, by level of the independent predictor variables. Risk factors or potential covariates were carried forward into multivariate Cox proportional hazards regression models. Approximately 18.1% of participants incurred a lower extremity MSKI resulting in ≥3 days of activity limitation during cadet basic training. Univariate analysis indicated that participants with the shortest stride length (<133.0 cm) were 39% more likely to incur any lower extremity MSKI and 45% more likely to incur an overuse MSKI than those with the longest stride length (>158.5 cm), and that participants with the longest ground contact time (>0.42 seconds) were twice as likely to incur any MSKI than those with the shortest contact time (<0.28 seconds). After adjusting for sex, weekly distance running 3 months before cadet basic training, and history of injury, multivariate regression analysis indicated that participants with the longest contact times were significantly more likely to incur overuse lower extremity MSKI than those with the shortest contact times (hazard ratio, 2.15; 95% CI, 1.06-4.37). There was no significant difference in risk of MSKI associated with foot-strike pattern or cadence. Study participants running with the longest ground contact times were 2.15 times more likely to incur an overuse lower extremity MSKI during cadet basic training than those with the shortest contact times. Also, study participants with the shortest stride length were 45% more likely to incur an overuse MSKI than those with the longest stride length.

Incense Use and the Risk of Chronic Limb-Threatening Ischemia Among Middle-Aged and Older Adults in the Singapore Chinese Health Study.

Epidemiologic studies have shown that daily exposure to incense smoke is associated with greater risk of cardiovascular mortality, which suggests that chronic exposure to incense could be linked to atherosclerosis. We studied the association between home incense use and the risk of chronic limb-threatening ischemia (CLTI), the most severe outcome of peripheral arterial disease. We used data from the Singapore Chinese Health Study, which recruited 63,257 Chinese participants 45-74 years old from 1993-1998. Data were collected via in-person interviews conducted at the participants' homes by trained interviewers. Linkage to the nationwide hospital discharge database was used to determine incident cases, defined as participants who underwent revascularization or lower extremity amputation for CLTI. Association between use of incense and risk of CLTI was examined using multivariable Cox proportional hazards regression models, adjusted for demographics and cardiovascular risk factors. In this cohort, 76.9% were current users of incense at recruitment, and 92.6% of those used incense daily at home. During a mean 18.8 years of follow-up, 1,097 participants developed CLTI. Compared to never or former users, current users had a 22% higher risk of CLTI [hazard ratio ; 95% confidence interval (CI): 1.04, 1.43]. The risk was greater with chronicity of use, and the HR was highest and statistically significant in participants who had used incense daily for years [ (95% CI: 1.06, 1.46)]. The results did not differ by sex, history of diabetes, or smoking status. Daily exposure to incense in the home environment for more than 40 years was associated with a greater risk of developing CLTI. https://doi.org/10.1289/EHP14674.

Association between Daily Sesame Consumption and the Risk of Sarcopenia in Elderly Adults: The Tianjin Chronic Low-Grade Systemic Inflammation and Health Cohort Study.

Sarcopenia is an age-related, progressive, and systemic skeletal muscle disorder that can lead to numerous adverse outcomes. Animal studies have shown that sesame can enhance skeletal muscle blood flow and improve physical performance. However, no studies have yet explored the association between sesame consumption and the incidence of sarcopenia in the general population. This study aimed to clarify the association between daily sesame consumption and the risk of sarcopenia in a cohort of Chinese elderly aged 60 y and over. This cohort study was conducted in Tianjin, China, involving 3017 elderly participants (1270 men). Sesame consumption frequency was assessed using a validated self-administered food frequency questionnaire. Sarcopenia was defined according to the consensus of the Asian Working Group for Sarcopenia. Multivariable Cox proportional hazards regression models were used to evaluate the association between daily sesame consumption and the risk of sarcopenia. After adjusting for potential confounders (age, BMI, smoking status, alcohol consumption, physical activity, marital status, educational level, personal history of diseases, depressive state, total energy intake, and dietary patterns), the multivariable hazard ratios and 95% confidence interval for sarcopenia among the elderly with different levels of daily sesame consumption were as follows: almost never consuming sesame (reference value), ≤1 time/wk: 1.06 (0.81, 1.39), and ≥2-3 times/wk: 0.62 (0.46, 0.84), respectively (P values <0.01). This study indicates that daily sesame consumption in the elderly aged 60 y and over is associated with a reduced risk of sarcopenia. Further research is needed to explore the causal mechanisms underlying this association.

Association of blood cadmium and physical activity with mortality: A prospective cohort study.

Physical activity (PA) may be considered an alternative method to ameliorate the elevated mortality risks associated with cadmium exposure. In this prospective cohort study, a total of 20,253 participants (weighted mean age, 47.79 years), including 10,247 men (weighted prevalence: 50.1 %), aged 18 years or older, were selected from the National Health and Nutrition Examination Survey from 2007 to 2018. Multivariable Cox proportional hazards regression models were utilized to evaluate the associations between blood cadmium levels, PA, and the risks of mortality. Restricted cubic spline analyses were employed to investigate the nonlinear relationships between blood cadmium and PA levels and mortality risks. During a median follow-up of 7.6 years, a total of 2002 (9.89 %) all-cause deaths occurred, of which 581 (2.87 %) participants were due to cardiovascular disease (CVD) and 498 (2.46 %) died of cancer. J-shaped associations were observed for blood cadmium with risks of mortality (all Poverall < 0.001; all Pnonlinearity < 0.001). Blood cadmium and PA had multiplicative interactions on mortality risk (all Pinteraction < 0.05). Compared with the subgroup with the lowest quartile of blood cadmium and recommended PA, the combination of the highest quartile of blood cadmium and without recommended PA was associated with the highest risks of all-cause and cancer mortality, followed by those meeting recommended PA but in the highest quartile of blood cadmium (hazard ratios, 2.43; 95 % confidence interval, 1.95-3.02). Achieving recommended PA significantly attenuated the detrimental effects of blood cadmium on all-cause, CVD, and cancer mortality risks.

COVID-19 vaccine effectiveness against severe omicron-related outcomes in children aged 5 to 11 years in Ontario: A Canadian immunization research network (CIRN) study

BackgroundUnderstanding how the efficacy of COVID-19 vaccines translates from clinical trials to real-world settings is critical to inform evolving vaccination policies. The objective of this study was to assess COVID-19 vaccine effectiveness (VE) against severe COVID-19-related outcomes in children aged 5–11 years, including COVID-19-related hospital admissions and multisystem inflammatory syndrome in children (MIS-C). MethodsWe conducted a retrospective, population-based cohort study using linked health administrative data in the first year following the emergence of the Omicron variant (January 2 to December 31, 2022) in Ontario, Canada. Baseline differences between subgroups of interest were compared using standardized differences. We used multivariable Cox proportional hazard regression models to estimate VE by time since last vaccine dose by treating vaccination as a time-varying exposure, compared to unvaccinated children. ResultsWe included a total of 1,058,740 children, of which 583,867 (55.1 %) had received at least one vaccine dose by the end of the study period. In total, there were 185 COVID-19-related hospital admissions and 39 cases of MIS-C. The rate of COVID-19-related admission was substantially higher in children with an underlying comorbid condition compared to children who were previously healthy (adjusted hazard ratio [aHR] = 4.77, 95 %CI, 3.56–6.38). VE against COVID-19-related admission ranged from 93 % (95 %CI, 52–99 %) 7–29 days after a second dose to 63 % (95 %CI; 41–77 %) ≥120 days after a second dose. There was no statistically significant difference in the rate of MIS-C in children who received at least one dose of the vaccine compared to unvaccinated children (aHR = 0.71; 95 %CI, 0.38–1.34). ConclusionsWe found that, for children aged 5–11 years, VE against COVID-19-related hospitalization was high in the first four months after a second dose. Children with comorbid conditions were found to be at much higher risk of COVID-19-related severe outcomes and thus may benefit most from COVID-19 vaccination.