Fine-Gray Model Research Articles

Characterization of atrial arrhythmias following mitral valve repair: Incidence and risk factors.

This study aims to investigate the occurrence, type and correlation of early and late atrial arrhythmias following mitral valve repair in patients with no preoperative history of atrial arrhythmias. Patients undergoing mitral valve (MV) repair for degenerative disease were included. Early and late postoperative electrocardiograms were evaluated for the incidence and type of atrial arrhythmia (atrial fibrillation [AF] or atrial tachycardia [AT]). The 192 patients were included. Early atrial arrhythmias occurred in 100/192 (52.1%) patients; AF in 61 (31.8%) patients, early AT in 15 (7.8%) and both in 24 (12.5%). In total 89% of patients were discharged in sinus rhythm. During a follow-up time of 7.3 years, 14 patients (7.3%) died and 49 (25.5%) patients developed late atrial arrhythmias. At 10 years, the cumulative incidence of any late atrial arrhythmia, with death as competing risk, was 64% (95% confidence interval [CI] = 55%-72%). On Fine-Gray model analysis, only early postoperative AF lasting >24 h was related to the development of late AF (hazard ratio 5.99, 95% CI = 1.78%-20.10%, p = .004). Early postoperative ATs were related to the development of late tachycardias, independent of their duration (<24 h hazard ratio 4.25, 95% CI = 1.89-9.57, p = .001 and >24 h hazard ratio 3.51, 95% CI = 1.65-7.46, p = .001). Early and late atrial arrhythmias were common after MV repair surgery. Only early postoperative AF lasting >24 h was a risk factor for the occurrence of late AF. Conversely, any postoperative AT was correlated to the development of late ATs.

Housing Adaptations and Long-Term Care Facility Admissions among Older Adults with Care Needs in Japan

ObjectivesHousing adaptations may contribute to aging in place for older adults with care needs by reducing the risk of long-term care facility (LTCF) admissions, but this association remains unclear. We examined the association between housing adaptations and LTCF admissions among older adults with care needs. DesignRetrospective cohort study using data from a Japanese municipality. Setting/ParticipantsAdults aged ≥65 years who were newly certified with care needs under the public long-term care insurance system between April 2014 and March 2016. MethodsThe study exposure was the implementation of insurance-covered housing adaptations (maximum covered cost: ¥200,000) during the 2 years after certification. Based on this exposure, participants were assigned to a non-implementation group (no housing adaptations), sub-maximum cost group (housing adaptations below the maximum cost), or maximum cost group (housing adaptations at the maximum cost). A Fine-Gray subdistribution hazards model was used to analyze the associations between the exposure groups and new LTCF admissions after adjusting for various risk factors. Death was regarded as a competing risk, and participants were followed until March 2022. ResultsAmong 4610 participants, 1261 (27.3%) had implemented housing adaptations. Among these, 943 (74.8%) were in the sub-maximum cost group and 318 (25.2%) were in the maximum cost group. During the follow-up period (median: 51 months), the incidence of LTCF admission was 3.9/1000 person-months in the non-implementation group, 3.8/1000 person-months in the sub-maximum cost group, and 2.8/1000 person-months in the maximum cost group. The adjusted subdistribution hazard ratio of LTCF admission (reference: non-implementation) was 0.90 (95% CI: 0.75–1.08) for the sub-maximum cost group and 0.67 (0.49–0.93) for the maximum cost group. Conclusions and ImplicationsHousing adaptations can support aging in place for older adults with care needs. Health care professionals and policymakers should consider the suitability of housing environments to reduce the risk of institutionalization.

What Are the Factors Associated With Revision Surgery on the Residual Limb and Functional Results in Patients With Posttraumatic Lower Limb Amputations?

Lower limb amputations performed after trauma are associated with a high risk of revision surgery. While the factors influencing revision surgery in the upper limbs have been studied, no studies have analyzed these factors in the lower limbs. Existing explanations for these revision surgeries are unclear, often leaving patients uninformed. Surgeons also lack the tools to explain the factors that influence repeat operations to patients. Therefore, the aim of this study was to provide surgeons with some answers so they can inform their patients undergoing posttraumatic lower limb amputation, whether military or civilian. (1) What was the survivorship of the initial amputation free from any revision surgery? (2) What patient- and injury-related factors were associated with revision amputation? (3) Do these factors influence functional outcomes in these patients? A single-center, retrospective study was conducted between January 2010 and February 2020 on patients who had undergone traumatic lower limb amputation. Between January 2010 and February 2020, 322 patients underwent amputation or were followed up at Percy Military University Hospital. Thirty-one patients had undergone amputation at another center, 178 had undergone amputation for nontraumatic reasons, and 27 patients had only upper limb amputations. Of those remaining, 1 died before 6 months, and 6% (5 of 86) were not fitted with a prosthesis, leaving 99% (85 of 86) for survivorship free from revision analysis and 93% (80 of 86) for functional endpoints analysis in this retrospective study at a median of 6.5 years (IQR 5 to 9) following the index amputation. The median age at the time of amputation was 31 years (IQR 26 to 52), 85% (72 of 85) of patients were men, and 31% (26 of 85) were military personnel. Revision surgery was defined as surgery performed at or after 6 months to ensure that the residual limb was healed and fitted with a prosthesis. Revision procedures performed before 6 months (median 2 [IQR 0 to 7]) were considered as part of the initial residual limb formation surgery. We performed Kaplan-Meier survivorship analysis for the time free from revision amputation from 6 months after amputation. We considered the competitive risk of death using a Fine-Gray model by an ascending stepwise procedure. To answer our third research question, we performed a chart review and assessed patients' use of prostheses and assistive devices and the percentage of patients who returned to work. An ordinal logistic regression was used to analyze the factors influencing functional outcome using an ascending stepwise procedure. A total of 85 patients (94 limbs) were included, of whom 25 (27 limbs) underwent a revision surgery on the residual limb > 6 months after amputation. Kaplan-Meier survival estimates indicated that 5 years after the initial amputation 64% (95% confidence interval 53% to 77%) of the patients remained free from revision surgery on their residual limb. Factors associated with increased odds of revision amputation were smoking (subdistribution HR 2.6 [95% CI 1.2 to 5.8]; p = 0.02) and an age of > 50 years (subdistribution HR 0.3 [95% CI 0.1 to 0.8]; p = 0.01). Ninety-four percent (80 of 85) of patients were fitted with prostheses, and 40% (32 of 80) of patients used material or human assistance for simple activities of daily living. Seventy-one percent of patients (57 of 80) had returned to work. Ordinal logistic regression revealed an association between preinjury sports activity and the absence of need for assistance in daily activities (OR 9 [95% CI 2.9 to 31.8]; p < 0.001). Smoking appeared to be an associated risk factor for residual limb revision surgery in posttraumatic lower limb amputations and is potentially modifiable. Being at least 50 years of age seemed to be associated with a lower incidence of revision surgery, which is probably linked to lower functional demands made on limbs beyond this age. Our study showed a remarkable rate of fitting with a prosthetic device, with an improved functional result if the patient was athletic before the trauma. These results provide more precise information on the care pathway to be considered for each patient. A study with a much larger sample would make it possible to assess the risk factors for the occurrence of each complication involving revision surgery. Level III, therapeutic study.

A biomarker exploration in small-cell lung cancer for brain metastases risk and prophylactic cranial irradiation therapy efficacy

BackgroundSmall-cell lung cancer (SCLC) is an aggressive malignancy with a poor prognosis. Limited-stage (LS)-SCLC comprises only one-third of SCLC cases, resulting in limited molecularly targeted therapies and treatment options. Despite advances in thoracic and cranial irradiation leading to improved outcomes, a notable proportion of patients develop brain metastasis (BM), highlighting the importance of identifying high-risk patients for tailored screening and treatment strategies. Materials and MethodsWe analyzed baseline tumor biopsies from 180 LS-SCLC patients who received frontline definitive chemoradiotherapy (dCRT) using a 474-gene pan-cancer panel. The cumulative incidence of BM was calculated with death scored as a competing risk. Independent prognostic factors for BM risk were identified using the Fine-Gray model. ResultsAlterations in the cell cycle pathway, particularly RB1 mutations, were more common in patients with BM, while FLT4 mutations were more frequent in those without BM (P=0.002 and P=0.021, respectively). Significant risk factors for BM include smoking (subdistribution hazard ratio [SHR]: 1.73; 95 % confidence interval [CI]: 1.11–2.70; P=0.016), RB1 mutations (SHR: 2.19; 95 % CI: 1.27–3.81; P=0.005), and BCL3 amplification (SHR: 2.27; 95 % CI: 1.09–4.71; P=0.028). Conversely, prophylactic cranial irradiation (PCI) (SHR: 0.39; 95 % CI: 0.25–1.60; P<0.001), FLT4 mutations (SHR: 0.26; 95 % CI: 0.07–0.98; P=0.047), and NOTCH pathway alterations (SHR: 0.65; 95 % CI: 0.43–1.00; P=0.049) were associated with a lower incidence of BM in LS-SCLC. Notably, consolidation PCI therapy did not reduce the BM risk in patients with baseline RB1 mutations, with BM occurrence probabilities of 34.7 % at 20 months and 62.6 % at 40 months. ConclusionOur study yields valuable insights into the genetic characteristics of LS-SCLC patients with and without BM, aiding the development of personalized treatment strategies. Identifying risk factors associated with the incidence and timing of BM, within the standard regimen of dCRT followed by PCI, may help optimize clinical decision-making for LS-SCLC.

Factors related to the return to work of head and neck cancer patients diagnosed between 2004–2011 in Belgium: a multivariate Fine-Gray regression model analysis

BackgroundThis study aims to identify the key factors that underlie the return to work (RTW) of head and neck cancer (HNC) patients in Belgium.MethodsWe used data from the EMPCAN database linking data from the Belgian Cancer Registry and the Crossroads Bank for Social Security. We selected HNC patients aged 18–60 at diagnosis who became inactive on the labour market during the follow-up time observed (n = 398). Fine-Gray regression models were used to examine associations between clinical, socio-demographical and work-related factors and RTW over a follow-up of almost 8 years (2004–2011).ResultsThe overall RTW was 21.6%. Stage IV at diagnosis and the use of chemoradiation were associated with a decreased RTW probability but this effect was attenuated by age-adjusted analyses. Multivariate analysis shows that the probability of RTW decreases with age and depends on the household composition. Patients who live alone (SHR 2.2, 95% CI 1.0 – 4.5) and patients who live with another adult and child(ren) (SHR 2.1, 95% CI 1.1 – 4.0) are more likely to RTW than patients who live with another adult without children.ConclusionsThe cumulative incidence of RTW in HNC patients is associated with age and household composition but not with treatment modalities or stage. In future research, this model could be applied to larger cancer patient groups for more accurate estimations. These insights are of importance to better support patients and for informing tailored policy measures which should take into account the sociodemographic profile of HNC patients to tackle societal and health-related inequities and burden of work inactivity.

Association of the panimmune-inflammatory value (PIV) with all-cause and cardiovascular mortality in maintenance hemodialysis patients: a propensity score matching retrospective study.

The panimmune-inflammatory value (PIV) is a novel inflammatory indicator. However, its role in maintenance hemodialysis (MHD) remains unclear. Our goal was to explore the predictive value of PIV for cardiovascular and all-cause mortality in MHD patients. In this retrospective cohort study, 507 patients receiving MHD between November 2017 and December 2022 were enrolled. The PIV value was calculated as follows: neutrophil count × monocyte count × platelet count/lymphocyte count. Patients were divided into two groups on the basis of the median PIV. Propensity score matching (PSM) was used to adjust for imbalances in baseline information between groups. Kaplan‒Meier curves, Cox regression, the Fine‒Gray competing risk model, and restricted cubic spline (RCS) curves were used to analyze the relationship between PIV and mortality. By the end of follow-up, 126 deaths had occurred, 91 of which were due to cardiovascular disease. The Kaplan‒Meier curves demonstrated that MHD patients with higher PIV levels had a poorer prognosis for all-cause death (p = 0.019). PIV levels were linked to all-cause death in multivariate Cox proportional risk regression (HR = 1.76; 95% CI 1.14, 2.72; p = 0.011). The Fine‒Gray model revealed a greater cumulative incidence of cardiovascular death in the higher PIV group (p = 0.035). PIV levels were linked to cardiovascular mortality in the Fine‒Gray competing risk model (HR = 2.06; 95% CI 1.25, 3.42; p = 0.005). The RCS revealed a nonlinear relationship between PIV and mortality risk (p < 0.05). Using 63years of age as the threshold, we observed a multiplicative interaction effect between age and PIV for all-cause mortality (p = 0.006). In MHD patients, PIV is an independent hazard factor for cardiovascular-related mortality and all-cause mortality.

PTH may predict early mortality in incident patients on hemodialysis: results from a large cohort.

Parathyroid hormone (PTH) is merit as a risk factor for mortality in patients with chronic kidney disease in prevalent hemodialysis patients in a U shape. Most studies, however, do not focus on incident patients and those who died within the first 90days of therapy. We evaluated PTH as a risk factor for mortality in a large cohort population in Brazil. This is an observational cohort study that included 4317 adult patients who initiated hemodialysis between July 1st, 2012 and June 30, 2017. The main outcome was all-cause mortality. Fine-gray sub-distribution hazard models were used to evaluate survival in the presence of a competing event (kidney transplant). Median PTH levels of 252 (118, 479) pg/mL. There were 331 deaths during the first 90days of therapy (6.7%), 430 in a 1-year follow-up (10.7%) and 1282 (32%) during the 5-year study period. Deaths according to PTH < 150, 150-600 and > 600pg/mL corresponded to 38.1%, 33.0% and 28.5%, respectively (p < 0.001). In an adjusted model, patients who started dialysis with PTH < 150pg/mL had a higher mortality risk within the first 90days, but not in 1year and 5years after starting dialysis. Analyses in a subset of patients with a repeated PTH in 1year (N = 1954) showed that although persistent PTH low levels (< 150pg/mL) at 1year were significantly associated with all-cause mortality, this result was not sustained after multiple adjustments. PTH < 150pg/mL confers a high mortality risk in the first 90days of dialysis. If this result reflects poor nutritional conditions, it deserves further investigations.

Apixaban, edoxaban and rivaroxaban but not dabigatran are associated with higher mortality compared to vitamin-K antagonists: A retrospective German claims data analysis.

Vitamin-K antagonists (VKAs) have widely been replaced by non-VKA oral anticoagulants (NOACs). This includes Austria, Germany and Switzerland, where as VKA, instead of warfarin, the much longer-acting phenprocoumon is used, which was not compared to NOACs in clinical trials. Using administrative data from a large German health insurance, we included all anticoagulation-naïve patients with a first prescription of a NOAC or VKA between 2012 and 2020. We analysed overall survival, major adverse cardiac and cerebrovascular events, major thromboembolic events and major bleeding. Overall, 570,137 patients were included (apixaban: 26.9%, dabigatran: 4.6%, edoxaban: 8.8%, rivaroxaban: 39.1% and VKA: 20.7% of these 99.4% phenprocoumon). In the primary analysis using a 1:1 propensity score matching-cohort (PSM-cohort), a significantly higher overall mortality was found for apixaban, edoxaban and rivaroxaban (all p<0.001) but not for dabigatran (p=0.13) compared to VKA. In this PSM-cohort, 5-year mortality was 22.7% for apixaban versus 12.7% for VKA, 19.5% for edoxaban versus 11.4% for VKA, 16.0% for rivaroxaban versus 12.3% for VKA (all p<0.001) and 13.0% for dabigatran versus 12.8% for VKA (p=0.06). The observed effect was confirmed in sensitivity analyses using un-weighted and three different weighted Fine-Gray regression models on the basis of the entire cohort. In this large real-world analysis, apixaban, edoxaban and rivaroxaban, but not dabigatran, were associated with worse survival compared to VKA. These findings, consistent with a few other studies including phenprocoumon, cast profound doubts on the unreflected, general use of NOACs. Randomized trials should assess whether phenprocoumon might actually be superior to NOACs.

Competing risk analysis to estimate amputation incidence and risk in lower-extremity peripheral artery disease.

Background: Patients with peripheral artery disease face high amputation and mortality risk. When assessing vascular outcomes, consideration of mortality as a competing risk is not routine. We hypothesize standard time-to-event methods will overestimate major amputation risk in chronic limb-threatening ischemia (CLTI) and non-CLTI. Methods: Patients undergoing peripheral vascular intervention from 2017 to 2018 were abstracted from the Vascular Quality Initiative registry and stratified by mean age (⩾ 75 vs < 75 years). Mortality and amputation data were obtained from Medicare claims. The 2-year cumulative incidence function (CIF) and risk of major amputation from standard time-to-event analysis (1 - Kaplan-Meier and Cox regression) were compared with competing risk analysis (Aalen-Johansen and Fine-Gray model) in CLTI and non-CLTI. Results: A total of 7273 patients with CLTI and 5095 with non-CLTI were included. At 2-year follow up, 13.1% of patients underwent major amputation and 33.4% died without major amputation in the CLTI cohort; 1.3% and 10.7%, respectively, in the non-CLTI cohort. In CLTI, standard time-to-event analysis overestimated the 2-year CIF of major amputation by 20.5% and 13.7%, respectively, in patients ⩾ 75 and < 75 years old compared with competing risk analysis. The standard Cox regression overestimated adjusted 2-year major amputation risk in patients ⩾ 75 versus < 75 years old by 7.0%. In non-CLTI, the CIF was overestimated by 7.1% in patients ⩾ 75 years, and the adjusted risk was overestimated by 5.1% compared with competing risk analysis. Conclusions: Standard time-to-event analysis overestimates the incidence and risk of major amputation, especially in CLTI. Competing risk analyses are alternative approaches to estimate accurately amputation risk in vascular outcomes research.

Circulating tumor DNA predicts venous thromboembolism in patients with cancers

BackgroundDespite rapid advances in liquid biopsy for circulating tumor DNA (ctDNA), its prognostic value for venous thromboembolism (VTE) in patients with cancer is underexplored, particularly in underserved and minoritized populations. Objectives▪. MethodsWe analyzed data from 1038 cancer patients who underwent ctDNA measurement for oncologic care at a large safety-net hospital system in the United States. We investigated the association between ctDNA and VTE after adjusting for cancer type, stage, treatment, and time from initial diagnosis using Fine–Gray models. We further assessed the discrimination of the genetic, clinical-only, and combined models using the area under the time-dependent receiver operating characteristic curve (AUC). ResultsThe presence of pathogenic ctDNA was independently associated with VTE after adjusting for clinical variables. Independent of tumor type, the number of pathogenic ctDNA mutations was predictive of future VTE risk (adjusted subdistribution hazard ratios of 2.75, 1.94, and 1.38 for ≥3, 2, and 1 pathogenic mutation, respectively, compared with none; P < .0001). The association was primarily driven by mutations in KRAS, PTEN, CDKN2A, NF1, and EGFR genes. Compared with the clinical-only model (AUC, 0.71; 95% CI, 0.64-0.76), the combined clinical and ctDNA model had a numerically higher time-dependent AUC (AUC, 0.74; 95% CI, 0.67-0.80). ConclusionctDNA testing may serve as an adjunctive tool to clinical risk assessment models in cancer patients to improve personalized VTE risk assessment and management.

A nomogram to predict cancer-specific mortality in adult patients with malignant meningioma: a competing risk analysis

BackgroundComprehensive investigations of the prognosis factors and treatment strategies with adjustment of competing causes of death for patients with malignant meningioma (MM) is still lacking.Patient and methodThe surveillance, Epidemiology, and End Results (SEER) database were used to include adult patients with this rare disease between 2004 and 2018. The probability of MM-caused mortality (MMCM) and non-MM-caused mortality (non-MMCM) were presented by cumulative incidence function curves. Then, the association between variates with non-MMCM was evaluated by the cox proportional hazard model, and the prognostic factors of MMCM were identified by Fine-Gray competing risk regression model. Furthermore, a nomogram was developed to predict the 1-year, 2-year, and 5-year MMCM and the performance was tested by a time-dependent area under the receiver operating characteristic (ROC) curve and calibration.Result577 patients were included, with a median age of 62 (18–100) years old and a median overall survival time of 36 (0–176) months. The percentage of non-MMCM was 15.4% (n = 89) in the entire population and 21.7% (n = 54) in elderly patients. The multivariable Cox proportional hazard regression model revealed that older age and other tumor(s) before or after MM had an independently significant association with higher non-MMCM. After adjustment of competing causes of death, the multivariable Fine-gray regression model identified age group ≥ 65 year, tumor size > 5.3 cm, recurrent MM, and histologic type 9530/3 (Meningioma, malignant) had an independently significant association with higher MMCM. Compared with gross total (GTR) of tumor, subtotal resection of tumor (HR 1.66, 95%CI 1.08–2.56, P = 0.02), partial resection of lobe (HR 2.26, 95%CI 1.32–3.87, P = 0.003), and gross total resection of lobe (HR 1.69, 95%CI 1.12–2.51, P = 0.01) had an independently significant association with higher MMCM.ConclusionThe competing risk nomogram including age group, tumor size, initial status, histologic type, and extent of resection is discriminative and clinically useful. This study emphasized the importance of the GTR of tumor in the treatment of MM patients, which had a significantly lower incidence of MMCM compared with biopsy, STR of tumor, partial resection of lobe, and GTR of lobe.

Risk analysis of blood pressure changes on cardiovascular disease in Chinese population.

The study aimed to assess the impact of changes in blood pressure on cardiovascular events in the Chinese population. It enrolled 33 179 Chinese participants aged ≥35 years (57.1% women) without CVD at baseline. BP status was defined according to the 2017 ACC/AHA hypertension guidelines. The type of BP change was defined as change in BP status from baseline to the end of follow-up, included stable BP<130/80, <130/80 to ≥130/80, ≥130/80 to<130/80mm Hg, persistent BP ≥130/80mm Hg. The hazard ratio (HR) of incident CVD by change in BP category was estimated using Cox proportional hazards and Fine-Gray models. During median follow-up of 3.17 years, 2023 CVD events occurred. Compared with BP<120/80, 120-129/<80mm Hg at baseline (HR=1.66, 95% CI: 1.09-2.53), 130-139/80-89mm Hg (HR=1.35, 95% CI: 0.94-1.95), and ≥140/90mm Hg (HR=2.46, 95% CI: 1.78-3.40) were risk factors for CVD. Compared with the group with stable BP<130/80mm Hg, the risk of CVD was 1.88 (95% CI: 1.40-2.53) in the group with persistent BP ≥130/80mm Hg and 1.40 (95% CI: 1.01-1.94) in the group of BP decreased to<130/80mm Hg. These results showed that BP 120-129/<80, 130-139/80-89, and ≥140/90mm Hg were associated with a high risk of CVD. Over time, persistent BP ≥130/80mm Hg increased the risk of CVD, but a return to<130/80mm Hg from hypertension decreased the risk of CVD.

Association between four insulin resistance surrogates and the risk of esophageal cancer: a prospective cohort study using the UK Biobank

PurposeThis study explored the association between triglyceride-glucose (TyG), TyG index with body mass index (TyG-BMI), triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C), metabolic score for insulin resistance (IR) (METS-IR) and the risk of esophageal cancer.MethodsA total of 388,900 participants from the United Kingdom Biobank from 2006 to 2010 were included. Fine-Gray models, restricted cubic spline (RCS), and receiver operating characteristic (ROC) curves were used to assess the association between the four IR surrogates and the risk of esophageal cancer, specifically, esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC).ResultsTen years after recruitment, 0.16% (95%CI 0.11–0.26%) had esophageal cancer and 4.17% (95%CI 3.86–4.46%) are deceased. For each standard deviation increase in the TyG index, TyG-BMI, TG/HDL-C, and METS-IR, the risk of EAC increased by Hazard ratios (HR)1.16, 1.37, 1.08, and 1.36, respectively (all P < 0.05), while the risk of ESCC decreased by HRs 0.80, 0.67, 0.77, and 0.65, respectively. RCS analysis indicated that most relationships were nonlinear (P < 0.05). ROC curves showed that METS-IR had a more robust diagnostic efficacy than TyG, TyG-BMI, and TG/HDL-C.ConclusionTyG index, TyG-BMI, TG/HDL-C, and METS-IR were closely associated with the risk of EAC and ESCC. Additionally, METS-IR surpassed the other three IR indices in predicting and diagnosing the risks of EAC and ESCC. The METS-IR is expected to become a more effective metric for identifying populations at early risk of esophageal cancer and for improving risk stratification.

Oxidative stress mediates the association between triglyceride-glucose index and risk of cardiovascular and all-cause mortality in metabolic syndrome: evidence from a prospective cohort study.

The aim of this study was to investigate the relationship between triglyceride-glucose (TyG) index and cardiovascular disease (CVD) and all-cause mortality in adults with metabolic syndrome (MeS) and explore the mediating role of oxidative stress. This study included 6131 adults with MeS from the National Health and Nutrition Examination Survey (NHANES). The relationships between TyG index and mortality were elucidated using multivariate Cox proportional hazards models, restricted cubic splines (RCS) Fine-Gray competing risk model. In addition, mediation analysis was used to test the indirect effect of oxidative stress indicators. Over a median 106-month follow-up, a total of 357 CVD and 1292 all-cause deaths were recorded. After multivariate adjustment, there was a J-type relationship between TyG index and CVD and all-cause mortality, with optimal inflection point of 9.13 and 8.92. After the threshold point, TyG index was positively associated with CVD (HR: 4.21, 95%CI: 1.82, 9.78) and all-cause mortality(HR: 2.93, 95%CI: 2.05, 4.18). Even using non-cardiovascular mortality as a competitive risk, the Fine-Gray model also illustrated that the cumulative CVD mortality incidence was higher in MeS with TyG index >9.13 (Fine-Gray P< 0.01). Mediation analysis revealed that biomarkers of oxidative stress, including gamma-glutamyl transferase and uric acid, collectively mediated 10.53% of the association between the TyG index and CVD mortality, and 8.44% of the association with all-cause mortality (P < 0.05). In the cohort study, TyG index was found to have a J-shaped association with CVD mortality and all-cause mortality in MeS population and oxidative stress may play a key mediating role in this relationship.

Fracture risk assessment in the presence of competing risk of death.

To identify the optimal statistical approach for predicting the risk of fragility fractures in the presence of competing event of death. We used real-world data from the Dubbo Osteoporosis Epidemiology Study that has monitored 3035 elderly participants for bone health and mortality. Fragility fractures were ascertained radiologically. Mortality was confirmed by the State Registry. We considered four statistical models for predicting fracture risk: (i) conventional Cox's proportional hazard model, (ii) cause-specific model, (iii) Fine-Gray sub-distribution model, and (iv) multistate model. These models were fitted and validated in the development (60% of the original sample) and validation (40%) subsets, respectively. The model performance was assessed by discrimination and calibration analyses. During a median follow-up of 11.3 years (IQR: 7.2, 16.2), 628 individuals (34.5%) in the development cohort fractured, and 630 (34.6%) died without a fracture. Neither the discrimination nor the 5-year prediction performance was significantly different among the models, though the conventional model tended to overestimate fracture risk (calibration-in-the-large index = - 0.24; 95% CI: - 0.43, - 0.06). For 10-year risk prediction, the multistate model (calibration-in-the-large index = - 0.05; 95% CI: - 0.20, 0.10) outperformed the cause-specific (- 0.23; - 0.30, - 0.08), Fine-Gray (- 0.31; - 0.46, - 0.16), and conventional model (- 0.54; - 0.70, - 0.39) which significantly overestimated fracture risk. Adjustment for competing risk of death has minimum impact on the short-term prediction of fracture. However, the multistate model yields the most accurate prediction of long-term fracture risk and should be considered for predictive research in the elderly, who are also at high mortality risk. Fracture risk assessment might be compromised by the competing event of death. This study, using real-world data found a multistate model was superior to the current competing risk methods in fracture risk assessment. A multistate model is considered an optimal statistical method for predictive research in the elderly.

Abuse-deterrent formulations and opioid-related harms in North Carolina, 2010-2018.

Abuse-deterrent formulations of opioid analgesics (ADFs) were introduced to reduce opioid-related harms among pain patients, but post-marketing study results have been mixed. However, these studies may be subject to bias from selection criteria, comparator choice, and potential confounding by "indication," highlighting the need for thorough study design considerations. In a sample of privately insured patients prescribed ADF or non-ADF extended-release/long-acting (ER/LA) opioids in North Carolina, we implemented a version of the prevalent new-user design to evaluate the relationship between ADFs and opioid use disorder (OUD, n=235) and opioid overdose (n=18) through six months of follow-up using inverse probability-weighted cumulative incidence functions and Fine-Gray models. The weighted hazard [HRw] of opioid overdose among patients initiating ADFs was 0.87 (95% CI: 0.23, 3.24) times as high as among patients who initiated, restarted, or continued non-ADF ER/LA opioids. We observed a short-term benefit of ADFs for incident OUD (HRw=0.58; 95% CI: 0.35, 0.93) compared to non-ADF ER/LA opioids in the first six weeks of follow-up, but this benefit disappeared later in follow-up (HRw=1.30; 0.86, 1.95). In summary, our findings add to the expanding body of evidence that there is no clear long-term reduction in harm from ADF opioids among patients in outpatient use.

Blood Hemoglobin Concentrations and the Incidence of Lower Extremity Peripheral Arterial Disease in Patients Undergoing Hemodialysis: 10-Year Outcomes of the Q-Cohort Study.

Lower extremity peripheral arterial disease is a potentially lethal cardiovascular complication in patients undergoing hemodialysis. Anemia is a risk factor for cardiovascular disease among the hemodialysis population. However, whether blood hemoglobin concentration is associated with the risk of peripheral arterial disease progression in this population remains undetermined. This is an extension of a 4-year multicenter, prospective, observational cohort study to 10 years. A total of 3504 Japanese patients undergoing maintenance hemodialysis were recruited between 2006 and 2007. The primary exposure was blood hemoglobin concentration at baseline. The main outcome was the first-ever incidence of major adverse limb events (MALE), composed of endovascular treatment, bypass surgery, and amputation. Multivariable-adjusted Cox proportional hazards model, Fine-Gray subdistribution hazards model, restricted cubic spline analysis, and restricted mean survival time analysis were used to determine the association of blood hemoglobin concentration with the incidence of MALE. During a median follow-up of 8.0 years, 257 patients experienced MALE. A Cox proportional hazards model showed that the risk of MALE in patients with blood hemoglobin concentrations <10.0 g/dL was significantly higher than in patients with concentrations of 11.0 to 11.9 g/dL, even after adjusting for confounding factors. In contrast, elevated hemoglobin concentration (≥12.0 g/dL) was not significantly associated with increased risk of MALE. Similar associations were observed when the Fine-Gray subdistribution regression model was used by setting all-cause mortality as the competing risk. A low blood hemoglobin concentration is an independent risk factor for peripheral arterial disease progression in patients undergoing maintenance hemodialysis.

Assessment of prognostic factors in patients with primary ocular adnexal lymphoma when considering competing risk elements.

Accurate prognostic factors for primary ocular adnexal lymphoma (POAL) are scarce. Survival models and prognostic factors derived without considering competing risk factors suffer from major statistical errors. This study aimed to accurately assess prognostic factors in POAL patients using competing risk models, and compare this to the traditional COX proportional hazards model. This retrospective study utilised data from the Surveillance, Epidemiology, and End Results (SEER) program 2010-2015 and included patients with B-cell POAL. The cumulative incidence function and Gray's test for cause-specific survival were calculated as univariate analysis. The competing risk models were a Fine-Gray subdistribution hazard model and a cause-specific model, and a traditional COX model was employed as a multivariate analysis. This study enrolled 846 eligible patients with POAL: 60 patients (7.09%) died from POAL and 123 patients (14.54%) died from other causes. Multivariate competing risk models indicated that age, laterality, histology subtype, the 7th edition of American Joint Committee on Cancer stage T, and radiotherapy were independent predictors for cause-specific survival of patients with POAL. There was high consistency between the two competing risk models. The COX model made several misestimations on the statistical significance and hazard ratios of prognostic factors. This study established competing risk models as a method to assess POAL prognostic factors, which was more accurate than traditional methods that do not consider competing risk elements.

Cardiac Substructure Radiation Dose and Associations With Tachyarrhythmia and Bradyarrhythmia After Lung Cancer Radiotherapy

BackgroundArrhythmias are common following radiotherapy for non–small cell lung cancer. ObjectivesThe aim of this study was to analyze the association of distinct arrhythmia classes with cardiac substructure radiotherapy dose. MethodsA retrospective analysis was conducted of 748 patients with locally advanced non–small cell lung cancer treated with radiotherapy. Cardiac substructure dose parameters were calculated. Receiver-operating characteristic curve analyses for predictors of Common Terminology Criteria for Adverse Events grade ≥3 atrial fibrillation (AF), atrial flutter, non-AF and non–atrial flutter supraventricular tachyarrhythmia (SVT), bradyarrhythmia, and ventricular tachyarrhythmia (VT) or asystole were calculated. Fine-Gray regression models were performed (with noncardiac death as a competing risk). ResultsOf 748 patients, 128 (17.1%) experienced at least 1 grade ≥3 arrhythmia, with a median time to first arrhythmia of 2.0 years (Q1-Q3: 0.9-4.2 years). The 2-year cumulative incidences of each arrhythmia group were 8.0% for AF, 2.7% for atrial flutter, 1.8% for other SVT, 1.4% for bradyarrhythmia, and 1.1% for VT or asystole. Adjusting for baseline cardiovascular risk, pulmonary vein (PV) volume receiving 5 Gy was associated with AF (subdistribution HR [sHR]: 1.04/mL; 95% CI: 1.01-1.08; P = 0.016), left circumflex coronary artery volume receiving 35 Gy with atrial flutter (sHR: 1.10/mL; 95% CI: 1.01-1.19; P = 0.028), PV volume receiving 55 Gy with SVT (sHR: 1.03 per 1%; 95% CI: 1.02-1.05; P < 0.001), right coronary artery volume receiving 25 Gy with bradyarrhythmia (sHR: 1.14/mL; 95% CI: 1.00-1.30; P = 0.042), and left main coronary artery volume receiving 5 Gy with VT or asystole (sHR: 2.45/mL; 95% CI: 1.21-4.97; P = 0.013). ConclusionsThis study revealed pathophysiologically distinct arrhythmia classes associated with radiotherapy dose to discrete cardiac substructures, including PV dose with AF and SVT, left circumflex coronary artery dose with atrial flutter, right coronary artery dose with bradyarrhythmia, and left main coronary artery dose with VT or asystole, guiding potential risk mitigation approaches.

The Effect of Temporal Persistence of Loneliness on Dementia: A Longitudinal Analysis From the Hunter Community Study.

Loneliness is common and becoming a public health concern. Although there is the clear evidence of the variable effect of temporal differences in loneliness (transient/situational and persistent/chronic) on health, their effect on dementia risk is unclear. This study aims to assess the effect of transient/situational and persistent/chronic loneliness on dementia risk. Participants aged 55years and older from the Hunter Community Study were recruited. Loneliness was measured using a single item measure. Dementia was defined as per International Classification of Disease-10 (ICD 10) codes. The Fine-Gray subdistribution hazard model was performed to calculate dementia risk. Of 1968 total participants with mean age of 66years, (3%) 57 developed dementia and (7%) 135 died over the mean follow up of 10years. Both persistent/chronic and transient/situational loneliness significantly increased the risk of all cause dementia in adjusted models (HR 2.74, 95% CI 1.11-6.88, p 0.03 and HR 2.35, 95% CI 1.21-4.55, p 0.01 respectively) with mean time to event of 9.7years. Feeling lonely below the age of 70years elevated the risk of dementia in later life (HR 4.01, 95% CI 1.40-11.50, p 0.01). Loneliness (both persistent/chronic and transient/situational) was associated with increased risk of all cause dementia, especially if loneliness was experienced before the age of 70years. These results suggest that promoting coping strategies for loneliness especially in persons 70years and younger may play a role in preventing dementia.