Multiple Cox Proportional Hazards Models Research Articles

Prediction of ovarian cancer prognosis using statistical radiomic features of ultrasound images.

Ovarian cancer is the deadliest gynecologic malignancy worldwide. Ultrasound is the most useful non-invasive test for preoperative diagnosis of ovarian cancer. In this study, by leveraging multiple ultrasound images from the same patient to generate personalized, informative statistical radiomic features, we aimed to develop improved ultrasound image-based prognostic models for ovarian cancer. A total of 2,057 ultrasound images from 514 ovarian cancer patients, including 355 patients with epithelial ovarian cancer, from two hospitals in China were collected for this study. The models were constructed using our recently developed Frequency Appearance in Multiple Univariate pre-Screening (FAMUS) feature selection algorithm and Cox proportional hazards model. The models showed high predictive performance for overall survival (OS) and recurrence-free survival (RFS) in both epithelial and nonepithelial ovarian cancer, with concordance indices (C-index) ranging from 0.773 to 0.794. Radiomic scores predicted 2-year OS and RFS risk groups with significant survival differences (log-rank test, P<1.0e-4 for both validation cohorts). OS and RFS hazard ratios between low- and high-risk groups were 15.994 and 30.692 (internal cohort) and 19.339 and 19.760 (external cohort), respectively. The improved performance of these newly developed prognostic models was mainly attributed to the use of multiple preoperative ultrasound images from the same patient to generate statistical radiomic features, rather than simply using the largest tumor ROI among them. The models also revealed that the roundness of tumor lesion shape was positively correlated with prognosis for ovarian cancer. In summary, the newly developed prognostic models based on statistical radiomic features from ultrasound images were highly predictive of the risk of cancer-related death and possible recurrence not only for patients with epithelial ovarian cancer but also for those with nonepithelial ovarian cancer. They thereby provide reliable, non-invasive markers for individualized prognosis evaluation and clinical decision-making for patients with ovarian cancer.

Effect of lipid-lowering therapy on carotid plaque burden in older adults

BackgroundLittle is known about the benefits of lipid-lowering medications in those age ≥ 75 years. We assessed the effect of lipid-lowering medications on progression to severe atherosclerosis in patients age > 75. MethodsData was retrospectively obtained from the Stroke Prevention & Atherosclerosis Research Centre, Canada. Atherosclerosis burden was measured as carotid total plaque area (TPA), a powerful predictor of cardiovascular risk. Survival time free of severe atherosclerosis (SFSA) was defined as the period when TPA remained <1.19 cm2. Kaplan–Meier, multiple Cox proportional hazard and hierarchical mixed-effect models were used to determine the effects of lipid-lowering medications on progression to severe atherosclerosis. ResultsIn total 1404 cases (mean age 81 ± 4 years; women 52%) were included. Those taking lipid-lowering medications were more likely to have a history of diabetes and a higher burden of atherosclerosis at baseline. In Kaplan–Meier analysis, the SFSA was significantly longer in those receiving lipid-lowering therapy. In multivariable-adjusted analyses, those not receiving lipid lowering therapy (irrespective of their vascular disease at baseline) were more likely to have TPA > 1.19 cm2 (hazard ratio (HR) = 1.37, 95% confidence interval (CI): 1.09,0.71). Similar findings were observed in mixed effects models when plaque progression was defined as any change >0.05 cm2 per year (odds ratio (OR):2.17, 95% CI:1.38,3.57). ConclusionLipid-lowering therapy is effective in controlling the burden of atherosclerosis among older adults with and without vascular disease. The measurement of plaque burden can guide selection and follow-up of those who may benefit from treatment.

Optimal timing of GnRH antagonist initiation in IVF-ET: a retrospective cohort study on advanced maternal age women.

Several studies have compared the effects of fixed and flexible gonadotropin releasing hormone antagonist (GnRH-ant) protocols during in vitro fertilization and embryo transfer (IVF-ET). However, which GnRH-ant initiation strategy is better remains controversial. Moreover, no studies have assessed the optimal timing of GnRH-ant initiation in women of advanced maternal age (AMA). In this retrospective cohort study, a total of 472 infertile women aged ≥ 35 years old undergoing their first IVF cycle from August 2015 to September 2021 at a tertiary academic medical center were recruited, of whom 136 followed fixed GnRH-ant protocol and 336 followed flexible GnRH-ant protocol. The primary outcomes measured were the cumulative live birth rate (CLBR) per IVF cycle and the time to live birth (TTLB) from the date of oocyte retrieval. Cox proportional models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of CLBR regarding GnRH-ant timing. No significant difference in CLBR was found between the fixed and flexible GnRH-ant groups (27.9% vs 20.5%, p=0.105). The TTLB was also comparable between groups (10.56 vs 10.30 months, p=0.782). The Kaplan-Meier analysis for CLBR also showed comparable results between groups (P=0.351, HR=0.83; 95%CI: 0.56-1.23). After establishing a multiple Cox proportional hazard model, the fixed GnRH-ant group still had comparable CLBR with the flexible GnRH-ant group (HR=0.85; 95%CI: 0.53-1.38; P=0.518). Subgroup and sensitivity analyses also demonstrated similar results. GnRH-ant protocols can be tailored to the needs of AMA women, and timing of GnRH-ant initiation can be adjusted flexibly.

Healthy lifestyle decreases the risk of the first incidence of non-communicable chronic disease and its progression to multimorbidity and its mediating roles of metabolic components: a prospective cohort study in China

ObjectivesTo identify the influence of healthy lifestyles on the incidence of the first NCD (FNCD), multiple chronic conditions (MCCs), and the progression from FNCD to MCCs. Design: cohort study. Setting: Zhejiang, China Participants10566 subjects (55.5 ± 13.5 years, 43.1% male) free of NCDs at baseline from the Zhejiang Metabolic Syndrome prospective cohort. MeasurementsHealthy lifestyle score (HLS) was developed by 6 common healthy lifestyle factors as smoking, alcohol drinking, physical activity, body mass index (BMI) and waist-to-hip ratio (WHR). Healthy lifestyle data and metabolic biomarkers collected via a face-to-face questionnaire-based interview, clinical health examination and routine biochemical determination. Biochemical variables were determined using biochemical auto-analyzer. Participants were stratified into four group based on the levels of HLS as ≤2, 3, 4 and ≥5. Multiple Cox proportional hazards model was applied to examine the relationship between HLS and the risk of FNCD, MCCs and the progression from FNCD to MCCs. The population-attributable fractions (PAF) were used to assess the attributable role of HLS. Mediating effect was examined by mediation package in R. ResultsAfter a median of 9.92 years of follow-up, 1572 participants (14.9%) developed FNCD, and 149 (1.4%) developed MCCs. In the fully adjusted model, the higher HLS group (≥5) was associated with lower risk of FNCD (HR = 0.68 and 95% CI: 0.56−0.82), MCCs (HR = 0.31 and 95%CI: 0.14−0.69); and the progression from FNCD to MCCs (HR = 0.39 and 95%CI: 0.18−0.85). Metabolic components (TC, TG, HDL-C, LDC-C, FPG, and UA) played the mediating roles with the proportion ranging from 5.02% to 22.2% for FNCD and 5.94% to 20.1% for MCCs. PAFs (95%CI) for poor adherence to the overall healthy lifestyle (HLS ≤ 3) were 17.5% (11.2%, 23.7%) for FNCD, 42.9% (23.4%, 61.0%) for MCCs, and 37.0% (15.5%, 56.3%) for the progression from FNCD to MCCs. ConclusionsHigh HLS decreases the risk of FNCD, MCCs, and the progression from FNCD to MCCs. These effects are partially mediated by metabolic components. Maintaining healthy lifestyles might reduce the disease burden of common chronic diseases.

Predictive factors for survival in borderline resectable and locally advanced pancreatic cancer: are these really two different entities?

BackgroundThe treatment of borderline resectable (BR) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC) has evolved with a wider application of neoadjuvant chemotherapy (NACHT). The aim of this study was to identify predictive factors for survival in BR and LA PDAC.MethodsClinicopathologic data of patients with BR and LA PDAC who underwent surgical exploration between January 2011 and June 2021 were retrospectively collected. Survival from the date of surgery was estimated using the Kaplan-Meier method. Simple and multiple Cox proportional hazards models were fitted to identify factors associated with survival. Surgical resection was analyzed in combination with the involvement of lymph nodes as this last was only known after a formal resection.ResultsNinety patients were surgically explored (BR: 45, LA: 45), of which 51 (57%) were resected (BR: 31, LA: 20). NACHT was administered to 43 patients with FOLFIRINOX being the most frequent regimen applied (33/43, 77%). Major complications (Clavien-Dindo grade III and IV) occurred in 7.8% of patients and 90-day mortality rate was 3.3%. The median overall survival since surgery was 16 months (95% CI 12-20) in the group which underwent surgical resection and 10 months (95% CI 7-13) in the group with an unresectable tumor (p=0.001). Cox proportional hazards models showed significantly lower mortality hazard for surgical resection compared to no surgical resection, even after adjusting for National Comprehensive Cancer Network (NCCN) classification and administration of NACHT [surgical resection with involved lymph nodes vs no surgical resection (cHR 0.49; 95% CI 0.29-0.82; p=0.007)]. There was no significant difference in survival between patients with BR and LA disease (cHR= 1.01; 95% CI 0.63-1.62; p=0.98).ConclusionsSurgical resection is the only predictor of survival in patients with BR and LA PDAC, regardless of their initial classification as BR or LA. Our results suggest that surgery should not be denied to patients with LA PDAC a priori. Prospective studies including patients from the moment of diagnosis are required to identify biologic and molecular markers which may allow a better selection of patients who will benefit from surgery.

Longitudinal trajectories of atherogenic index of plasma and risks of cardiovascular diseases: results from the Korean genome and epidemiology study

BackgroundAlthough the atherogenic index of plasma (AIP) based on a single measurement is a known risk factor for cardiovascular disease (CVD), little is known about whether changes in AIP over time are related to incident CVD. We aimed to determine whether AIP trajectory, which reflects homogenous AIP trends for a particular period, is associated with CVD risk.MethodsData from 5,843 participants of the Korean Genome and Epidemiology Study (KoGES) were analyzed. The KoGES had been conducted biennially from the baseline survey (2001–2002) to the eighth follow-up survey (2017–2018). The research design specifies the exposure period from baseline to the third follow-up, designates the latent period at the fourth follow-up, and establishes the event accrual period from the fifth to the eighth follow-up. During the exposure period, we identified two trajectories: a decreasing (n = 3,036) and an increasing group (n = 2,807) using latent variable mixture modeling. Information on CVD was collected initially through the self-reporting, followed by in depth person-to-person interview conducted by a well-trained examiner. During the event accrual period, the cumulative incidence rates of CVD between the two AIP trajectory groups were estimated using Kaplan–Meier analysis with the log-rank test. Multiple Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).ResultsThe increasing AIP trajectory group had a significantly higher cumulative incidence rate of CVD than the decreasing AIP trajectory group. Compared to the decreasing AIP trajectory group, the increasing AIP trajectory group had a higher risk of incident CVD (HR: 1.31, 95% CI: 1.02–1.69) after adjusting for confounders.ConclusionsThe risk of incident CVD increased when the AIP level showed an increasing trend and remained high over a long period. This suggests that checking and managing the trajectory of the AIP can be a preventive strategy for incident CVD.

Low bleeding acceptance is associated with increased death risk in patients with atrial fibrillation on oral anticoagulation.

Bleeding is the most feared complication of anticoagulation. We sought to investigate whether the bleeding risk acceptance has a prognostic value during long-term follow-up in the era of direct oral anticoagulants (DOACs) among patients with atrial fibrillation (AF). We studied 167 consecutive AF outpatients [aged 68.8 SD 10.6 years; 141 (84.4%) on DOACs]. The bleeding acceptance was assessed based on the Bleeding Ratio defined as the declared maximum number of major bleedings that a patient would be willing to accept to prevent one major stroke. We recorded cerebrovascular ischemic events, major or clinically relevant non-major bleeds (CRNMB), and mortality. A median Bleeding Ratio was 4 (IQR 2-5). During follow-up of 946 patient-years, cerebrovascular ischemic events and/or death were observed in 28 patients (3.3%/ year) and major bleeding or CRNMB in 33 (4.6%/ year). The Bleeding Ratio was lower in patients who experienced cerebrovascular events or death (p = 0.004), but not bleeding. Patients with the Bleeding Ratio 0-3 were more often non-persistent to the OAC therapy, and more likely to have cerebrovascular event or die than those with higher bleeding acceptance (odds ratio 2.55; 0.95% CI 1.08-6.02) which was driven by the impact on mortality. The multiple Cox proportional hazards model showed that lower Bleeding Ratio, higher CHA2DS2-VASc score, and older age predicted cerebrovascular events or death during follow-up. AF patients who are willing to accept fewer serious bleedings to avoid major stroke during anticoagulation are more likely to experience death and/or cerebrovascular ischemic events, but not bleeding, what might be related to non-persistence.

Abstract 2364: Gut microbiome interacts with clinical characteristics on all-cause mortality of colorectal cancer patients

Abstract Background: Gut microbiota has been introduced to involve in the migration and invasion stage of metastasis of colorectal cancer (CRC) cells and interact with both the pharmacokinetics and pharmacodynamics of chemotherapeutic agents and immune checkpoint inhibitors. In this study, we examined microbiome features in association with all-cause mortality of CRC patients and examined their interactions with clinical factors. Methods: We performed 16S rRNA sequencing for 331 preoperative fecal samples of CRC patients at Seoul National University Hospital, Korea. Multiple Cox proportional hazard model was applied to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of all-cause mortality due to microbiome features (within-sample diversity indices, species patterns, genus abundance, and taxonomic co-occurrence networks) and clinical factors (tumor grade and stage, surgical methods, neoadjuvant and adjuvant therapies, and invasion). We added the multiplicative term into the model to test the interaction between gut microbiota and clinical characteristics. Results: During a median follow-up of 3.7 years, deaths from any causes were reported in 46 patients. From 172 species, the principal component analysis identified 4 patterns, which explained a total 66.1% variation in species abundance. Of 77 genera, 9 co-occurrence networks were identified by the SParse InversE Covariance Estimation for Ecological Association Inference. For genus level, the risk of death was positively associated with Butyricicoccus (HR=1.54, 95% CI=1.17-2.04), but inversely associated with Lactococcus (HR=0.60, 95% CI=0.37-0.95), Acidaminococcus (HR=0.57, 95% CI=0.34-0.96), Megasphaera (HR=0.79, 95% CI=0.64-0.99), Mitsuokella (HR=0.75, 95% CI=0.57-0.99). All-cause mortality was associated with well or moderately differentiated adenocarcinoma (HR=3.84, 95% CI=1.83-8.07), neoadjuvant therapy (HR=4.10, 95% CI=1.40-12.0), tumor stage IV (HR=8.64, 95% CI=3.42-21.8), and presence of venous invasion (HR=2.32, 95% CI=1.08-4.97). Among clinical pathological factors associated with all-cause mortality, Bacteroides abundance significantly interacted with both tumor stage (pinteraction=0.013) and venous invasion (pinteraction=0.001). Conclusion: Our study identified several microbiome features in links with either increasing or decreasing mortality from any causes. Interactions between the gut microbiome and clinical factors might inform insights on how the gut microbiota modulates the effect of clinical factors on CRC prognosis after the curative operation. Further research using postoperative information is needed to confirm our findings. Citation Format: Tung Hoang, Min Jung Kim, Ji Won Park, Seung-Yong Jeong, Aesun Shin. Gut microbiome interacts with clinical characteristics on all-cause mortality of colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2364.

Stage migration as a surrogate of survival in hepatocellular carcinoma treated with transarterial chemoembolization.

Locoregional therapies, including transarterial chemoembolization (TACE), are recommended for the treatment of HCC; however, clinical trials evaluating their effectiveness have been complicated by a lack of validated surrogate outcomes. We aimed to evaluate if stage migration could serve as a potential surrogate of overall survival in patients undergoing TACE. We conducted a retrospective cohort study of adult patients with HCC who underwent TACE as initial therapy from 3 centers in the US from 2008 to 2019. The primary outcome was overall survival from the date of the first TACE treatment, and the primary exposure of interest was Barcelona Clinic Liver Cancer stage migration to a more advanced stage within 6 months of TACE. Survival analysis was completed using Kaplan-Meier and multiple Cox proportional hazard models adjusted by the site. Of 651 eligible patients (51.9% Barcelona Clinic Liver Cancer stage A and 39.6% stage B), 129 (19.6%) patients experienced stage migration within 6 months of TACE. Those with stage migration had larger tumors (5.6 vs. 4.2cm, p < 0.01) and higher AFP levels (median 92 vs. 15ng/mL, p < 0.01). In multivariate analysis, stage migration was significantly associated with worse survival (HR: 2.82, 95% CI: 2.66-2.98), with a median survival of 8.7 and 15.9 months in those with and without stage migration. Other predictors of worse survival included the White race, higher AFP levels, a higher number of tumors, and a larger maximum HCC diameter. Stage migration is associated with increased mortality after TACE in patients with HCC and could serve as a surrogate end point in clinical trials evaluating locoregional therapies such as TACE.

Observational study on dry period length and its associations with milk production, culling risk, and fertility in Italian dairy farms

From an initial data set involving 84,189 lactations, this research evaluated the relationship between dry period length (DPL) and milk production, culling risk, and fertility. The data set included a total of 48,297 multiparous cow lactation records, with a calving event occurring in 2019 and 2020, belonging to 62 Italian herds with at least 150 cows. The DPL was classified into 5 categories (<40, 40-49, 50-60, 61-70, and >70 d) and these categories were used to establish the association between DPL and the outcome variables. All data obtained were assessed with simple and multiple linear regressions and Cox proportional hazard models. Cumulative milk production at 60 d in milk (DIM) was the highest in DPL categories of 61 to 70 d (2,480.29 kg/cow) and 50 to 60 d (2,474.39 kg/cow), and the lowest in <40 d (2,281.29 kg/cow). Similarly, DPL categories 61 to 70 d (10,830.94. kg/cow) and 50 to 60 d (10,817.48 kg/cow) had the highest 305-d milk production, whereas the <40 d (10,200.96 kg/cow) had the lowest one. The groups with a DPL of 40 to 49 d and >70 d had slightly, but significant, lower milk production both as cumulative 60 DIM and predicted 305-d milk production. Culling risk had a curvilinear behavior, with DPL <40 d and DPL >70 d showing significantly higher odds for culling during the first 60 DIM compared with DPL of 50 to 60 d [relative risk (RR): 1.53; RR: 1.46]. Within the same comparison, DPL of 61 to 70 d also had a slightly higher risk for culling (RR: 1.13). The DPL was associated also with fertility, with DPL of 40 to 49 d and 50 to 60 d having the greatest odds for pregnancy within the first 200 DIM. The DPL of <40, 61 to 70, and >70 d were negatively associated with fertility and showed pregnancy risks of 0.87, 0.95, and 0.94, respectively. This paper reinforces the importance of DPL as we demonstrated its association with milk production, culling, and fertility. Despite being attractive for high production dairy cows, very short dry periods are at the same time also associated with higher culling risk, lower milk production and fertility. Long DPL is detrimental, especially regarding culling and fertility. In summary, reducing variability in DPL and avoiding extremes by improving reproductive performance, maximizing late lactation milk production and making wise decisions on dry-off timing, may lead to better performances and lower early culling under Italian dairy conditions.

P209 Delayed IBD diagnosis increases risk of requiring biologics in first 4-years - an Inception cohort study

Abstract Background Delays in diagnosis can be due to patient and health-system related factors. The impact of such delays in Inflammatory Bowel Diseases (IBD), particularly on biological therapies, continues to be of interest. The aim of the study was to investigate if delays could predict need for biologics and report on related adverse outcomes (AOs). Methods New patients referred for suspected IBD to a single tertiary care centre between Jan 2013 to Dec 2017 were identified using EMR. For this study, delay-types and cut-off times for each type were set based on best average hospital waiting times. The reasons for delays until start of treatment were recorded; data on the start of biologics, duration, and reasons for switch (if required) were recorded. Data was analysed using multiple Pearson correlations and Cox proportional Hazard model to determine whether any delay-types could predict need for biologics and compare the risk between patients with or without delay. Results 105 patients were identified using stringent criteria (M=58; median age=32y) with a median follow-up of 55 months. 65, 27 and 13 patients had a final diagnosis of Ulcerative colitis, Crohn’s disease, and Unclassified colitis respectively, and were analysed collectively. A model that combined delay in seeking medical attention, and time taken from specialty review to index endoscopy exhibited the best predictive power with average AUROC of 0.67. When individual delay-types were analysed, it was noted that most delay-types increased the risk of biologic use: a) delay in seeking medical attention [OR-1.08(1.03 1.17)] b) delay from GP referral to specialty review [OR-1.10(1.0 1.23)] c) delay from specialty review to index endoscopy [OR-1.09(1.01 1.21)] On further analysis, there was a statistically significant increase noted in the risk of requiring biologics at any time during the follow-up period. Fig 1A illustrates survival without biologics when there is a delay of &amp;gt;2 weeks in seeking medical attention (p=0.042). Figure 1B illustrates survival without biologics when there is delay of &amp;gt;6 weeks from GP referral to index endoscopy (p=0.021). Figure 1A- Patient-related delay of &amp;gt;2weeks and risk of needing biologics (p=0.042) Figure 1B- Health-system related delay of &amp;gt;6weeks and risk of needing biologics (p=0.021) Conclusion The risk of requiring biologic therapy is higher in those patients who have faced any type of delay in their diagnosis of IBD. A patient-related delay of &amp;gt;2weeks and cumulative health-system related delay of &amp;gt;6weeks increase the risk of requiring biologic therapy at any time during their follow-up. Both primary and secondary care must work to reduce any delays as this has long-term implications for patients and economic implications for health care providers.

P190 Delayed IBD diagnosis leads to worse outcomes over years, with multiple implications on service delivery

Abstract Background Delays in diagnosis can be patient and health-system related. Such delays have been reported to increase overall complications in Inflammatory Bowel Diseases (IBD). The aim of our study was to report on the impact of delays on IBD-related adverse outcomes (AOs), as hospitals currently face challenges with long waiting lists in the post-COVID-19 era. Methods New patients referred for suspected IBD to a single tertiary care centre between Jan 2013 to Dec 2017 were identified using EMR. A cut-off time was set for each delay-type based on best average hospital waiting times. Reasons for delays until start of treatment and data on pre-defined AOs (steroid &amp; other rescue therapies, hospitalisations, surgery) were recorded for each patient until end of June 2021. Data was analysed using multiple Pearson correlations and Cox proportional Hazard model to determine if there was a difference in survival without AOs between patients with and without delay. Results 105 patients were identified using strict criteria (M=58; median age=32y) with a median follow-up of 55 months. The most frequent presenting complaints were abdominal pain (44, 41.9%), loose stools (40, 38.1%), bloody diarrhoea (37, 35.2%) and bleeding per-rectum (33, 31.4%). 65, 27 and 13 patients had a final diagnosis of Ulcerative colitis, Crohn’s disease and Unclassified colitis respectively, and were analysed jointly. The longest delay-types noted: patients seeking medical attention (median=4 months; range 1 to 84 months); arranging gastroenterology clinic review after GP referral (median=5 weeks; 1 to 30 weeks); and waiting for index endoscopy (median=3 weeks; 1 to 36 weeks). Patient stratification based on delay-type, using specific cut-off times for each showed a statistically significant difference in survival without AOs for all (when comparing delay vs no delay). - delay in seeking medical attention (cut-off=1m; p=0.004) (Fig 1A) - delay in GP referral to specialty review (cut-off=1w; p=0.048) - delay in index endoscopy (cut-off=4w; p=0.01) (Fig 1B) - delay in starting treatment (cut-off=4w; p=0.03) Fig 1A-Time to seek medical attention (survival without AOs; p=0.004) Fig 1B-Time from clinic review to index endoscopy (survival without AOs; p=0.01) Conclusion Several bottlenecks of delays increase AOs in IBD over the follow-up period. A delay as short as a week, between GP referral to specialty review, is significant in determining AOs, relevant for specialist IBD centres particularly in the post-Covid period. Endoscopy units should prioritise suspected IBD patients to reduce AOs, which is likely to have implications on service delivery and planning. Long delays observed in patients seeking medical attention highlights the need for better patient education in the community.

Systematic total arch replacement with thoraflex hybrid graft in acute type A aortic dissection: A single centre experience.

IntroductionIn the last two decades, a more aggressive approach has been encouraged to treat patients with acute type A aortic dissection (ATAAD), extending the repair to the aortic arch and proximal descending thoracic aorta with the frozen elephant trunk (FET) implantation. Here, we report our single-centre experience with the FET technique for the systematic treatment of emergency type A aortic dissection.Materials and methodsBetween December 2017 and January 2022, 69 consecutive patients were admitted with ATAAD; of those, 66 patients (62.9 ± 10.2 years of age, 81.8% men) underwent emergency hybrid aortic arch and FET repair with the multibranched Thoraflex hybrid graft and were enrolled in the study. Primary endpoints were 30 days- and in-hospital mortality. Secondary endpoints were postoperative morbidity and follow-up survival. To better clarify the impact of age on surgical outcomes, we have divided the study population into two groups: group A for patients <70 years of age (47 patients), and group B for patients ≥70 years (19 patients). Time-to-event analysis has been conducted using the Log-rank test and is displayed with Kaplan-Meier curves. A multiple Cox proportional Hazard model was developed to identify predictors of long-term survival with a stepwise backward/forward selection process.Results30-days- and in-hospital mortality were 10.6 and 13.6%, respectively. Stroke occurred in three (4.5%) patients. Two (3.0%) patients experienced spinal cord ischemia. We did not find any statistically significant difference between the two groups in terms of main post-operative outcomes. The multivariable Cox proportional hazard model showed left ventricular ejection fraction (HR: 0.83, 95% CI: 0.79–0.92, p < 0.01), peripheral vascular disease (HR: 15.8, 95% CI: 3.9–62.9, p < 0.01), coronary malperfusion (HR: 0.10, 95% CI: 0.01–0.77, p =0.03), lower limbs malperfusion (HR: 5.1, 95% CI: 1.10–23.4, p = 0.04), and cardiopulmonary bypass time (HR: 1.02, 95% CI: 1–1.04, p = 0.01) as independent predictors of long term mortality.ConclusionsFrozen elephant trunk repair to treat emergency type A aortic dissection appears to be associated with good early and mid-term clinical outcomes even in the elderly.

The association between dietary sodium intake and osteoporosis

The association of inadequate dietary sodium intake with bone mineral density (BMD) and the risk of osteoporosis is controversial. To find the association between low sodium diet and the risk of incipient osteoporosis, we performed a population-based cross-sectional analysis using Tanaka method for estimation 24-h urinary sodium excretion (e24hUNaETanaka) as a candidate indicator of sodium intake. We identified 3869 participants without osteoporosis and classified them into quartiles according to their value of e24hUNaETanaka. BMD was measured to find participants at risk of osteoporosis. Lower e24hUNaETanaka was related to decreasing BMD of the distal radius. Multiple Cox-proportional hazard models demonstrated that e24hUNaETanaka had an inverse association with the risk of osteoporosis (adjusted HR = 0.859, 95% CI = 0.751–0.982) and survival analysis revealed that the lowest quartile group had poor osteoporosis-free survival (PLog-rank < 0.0001). Furthermore, our restricted cubic spline analysis revealed that the relationship between e24hUNaETanaka and HR of osteoporosis was negative curvilinear in males and postmenopausal females and positive linear in premenopausal females. Our findings suggest that lower sodium intake was a significant predictor of incipient osteoporosis and there was wide variation in this relationship according to sex and female hormone status.

Prognostic implications of cellular senescence in resected non-small cell lung cancer.

BackgroundCure and long-term survival for non-small cell lung cancer (NSCLC) remains hard to achieve. Cellular senescence, an emerging hallmark of cancer, is considered as an endogenous tumor suppressor mechanism. However, senescent cancer cells can paradoxically affect the surrounding tumor microenvironment (TME), ultimately leading to cancer relapse and metastasis. As such, the role of cellular senescence in cancer is highly controversial.MethodsIn 155 formalin-fixed paraffin-embedded (FFPE) samples from surgically resected NSCLC patients with pathological tumor-node-metastasis (pTNM) stages I–IV (8th edition), cellular senescence was assessed using a combination of four immunohistochemical senescence markers, i.e., lipofuscin, p16INK4a, p21WAF1/Cip1 and Ki67, and correlated to clinicopathological parameters and outcomes, including overall survival (OS) and disease-free survival (DFS).ResultsA tumoral senescence signature (SS) was present in 48 out of 155 NSCLC patients, but did not correlate to any clinicopathological parameter, except for p53 mutation status. In a histologically homogenous patient cohort of 100 patients who fulfilled the following criteria: (I) one type of histology, i.e., adenocarcinoma, (II) without known epidermal growth factor receptor (EGFR) mutation, (III) curative (R0) resection and (IV) no neoadjuvant systemic therapy or radiotherapy, the median OS and DFS for patients with a tumoral SS (n=30, 30.0%) compared to patients without a tumoral SS (n=70, 70.0%) was 53 versus 141 months (P=0.005) and 45 versus 55 months (P=0.25), respectively. In multiple Cox proportional hazards (Cox PH) model analysis correcting for age, pTNM stage I–III and adjuvant therapy, a tumoral SS remained a significant prognostic factor for OS (HR =2.03; P=0.014).ConclusionsThe presence of a tumoral SS particularly based on high p16INK4a expression significantly affects OS in NSCLC adenocarcinoma. In this light, adjuvant senolytic therapy could be an interesting strategy for NSCLC patients harboring a tumoral SS, ultimately to improve survival of these patients.

Cross-sectional and longitudinal associations between lipid accumulation product and hyperuricemia

Background and aimsLipid accumulation product (LAP) is a novel, sex-specific, index-describing lipid over accumulation. Previous studies used baseline LAP for predicting hyperuricaemia; however, the relationship between them is unclear. We aimed to investigate the relationship between LAP and the risk of hyperuricaemia in the Central Chinese population. Methods and resultsThis large-scale observational study comprised a cross-sectional population sample and a prospective cohort of 44,294 healthy subjects. This study examined the association between LAP and the risk of hyperuricaemia in the total sample and subgroups using multiple logistic regression analysis and multivariate cox proportional hazards model analysis. As a result, there was a dose-response relationship between LAP and the risk of hyperuricaemia. The prevalence of hyperuricaemia was 13.4% in the cross-sectional study. During 9 years of follow-up, hyperuricaemia occurred in 928 (19.8%) participants. The corresponding hazard ratios after multiple adjustments of hyperuricaemia in the second, third and fourth quartile were 1.34 (95% confidence interval [CI], 1.04–1.72), 2.01 (95% CI, 1.54–2.63), and 2.44 (95% CI, 1.80–3.30)-fold higher vs. the first quartile, respectively. Subgroup analyses showed that the association between LAP and the risk of hyperuricaemia was more pronounced in females, individuals≤49 years old and subjects with eGFR ≥60 ml/min/1.73 m2. ConclusionLAP was positively related to the risk of hyperuricaemia in the Central Chinese population, particularly in women, individuals≤49 years old and adults with relatively normal renal function. These findings suggested the potential of LAP as an independent risk indicator in preventing hyperuricaemia.

Clinical outcomes in patients receiving edoxaban or phenprocoumon for prevention of stroke in atrial fibrillation: a German real-world cohort study

BackgroundAppropriate and timely anticoagulant therapy with vitamin K antagonists (VKAs) or non-vitamin K oral antagonists (NOACs) is essential for stroke prevention in non-valvular atrial fibrillation (NVAF). Comparative data regarding effectiveness and safety for edoxaban vs phenprocoumon, the predominant VKA in Germany, are scarce.ObjectivesThe study evaluates effectiveness and safety of edoxaban vs phenprocoumon in NVAF patients in a German real-world setting.MethodsGerman statutory health insurance claims data of the Institute for Applied Health Research Berlin (InGef) Research Database from 2014 until 2019 were analyzed. In NVAF patients, new users of edoxaban and phenprocoumon were compared to assess effectiveness (stroke/systemic embolism (SE)) and safety (bleeding) during therapy. Hazard ratios (HR) were estimated through multiple outcome-specific cox proportional hazard models adjusting for baseline characteristics. Outcomes of geriatric patients were analyzed in subgroup analyses.ResultsBetween 2015 and 2018, 7,975 and 13,319 NVAF patients newly initiated treatment with edoxaban or phenprocoumon. After adjusting for baseline confounders, the risk of stroke/SE (HR: 0.85, 95% CI: 0.70–1.02) was numerically but not significantly lower, while the risk of major bleeding (HR: 0.69, 95% CI: 0.58–0.81) was significantly lower for edoxaban. In the geriatric subgroups, homogenous results compared to the main analysis were obtained.ConclusionThe results of this real-world analysis indicated better effectiveness and safety outcomes in patients with NVAF initiating edoxaban treatment compared to phenprocoumon. The findings confirm that the beneficial effects observed in the pivotal ENGAGE AF-TMI 48 trial can also be achieved in real-world use of edoxaban.

Association of SGLT2 inhibitors with lower incidence of death in type 2 diabetes mellitus and causes of death analysis

Sodium-glucose cotransporter 2 inhibitor (SGLT2i) potentially decrease all-cause and cardiovascular death, however, associations with non-cardiovascular death remain unclear. Therefore, we investigated SGLT2i associations with death and the cause of death. We used the Taiwanese National Health Institutes Research database linked to the National Register of Deaths (NRD). Incident type 2 diabetes mellitus (T2DM) patients and propensity score matched T2DM SGLT2i and Dipeptidyl peptidase 4 inhibitor (DPP4i) users were investigated. The index year was the SGLT2i or DPP4i prescription date from May 2016. Patients were followed-up until death or December 2018. Deaths verified by the NRD and grouped accordingly. Multiple Cox proportional hazards models were used. In total, 261,211 patients were included in the population; 47% of the patients were female and the average age was 62 years. The overall incidence of all-cause death was 8.67/1000 patient-years for SGLT2i and 12.41 for DPP4i users during follow-up. After adjusting for potential risk factors in the propensity score matched population, SGLT2i users were associated with lower risks of all-cause death, cardiovascular death, cancer death, and non-cancer, non-vascular death compared with DPP4i-users. For specific death causes, significantly lower death risks from heart disease, cerebrovascular disease, and accidents were associated with SGLT2i-use. SGLT2i benefits for T2DM patients were not different across subgroups. Compared with DPP4i-use, SGLT2i-use for T2DM was associated with lower disease and death risk.

Decreased Risk of Stroke in People Using Red Yeast Rice Prescriptions (LipoCol Forte®): a Total Population-Based Retrospective Cohort Study.

The influence of red yeast rice (RYR) on the risk of incident stroke remains underexplored. We aimed to compare the risk of stroke between people with and without use of RYR prescriptions. We used research data from the National Health Insurance Program in Taiwan and identified 34,723 adults (aged ≥20 years) who first received the RYR prescription from 2010 to 2014. To select the appropriate control group, we used frequency matching by age and sex (case-control ratio = 1 : 1) and identified a non-RYR cohort that included 34,723 adults who first received lovastatin. Events of an incident stroke that occurred during the follow-up period of 2010–2017 were identified from medical claims. The adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of stroke risk associated with RYR prescription were calculated in the multiple Cox proportional hazard model. Compared with the non-RYR cohort, patients who received RYR prescriptions had a decreased risk of stroke (HR 0.65, 95% CI 0.59–0.71), including hemorrhagic stroke (HR 0.60, 95% CI 0.44–0.83), ischemic stroke (HR 0.49, 95% CI 0.43–0.57), and other types of strokes (HR 0.53, 95% CI 0.42–0.67). The association between RYR prescription and stroke risk was significant in both sexes and in people aged more than 40 years, as well as in those individuals with various medical conditions. The frequency of RYR prescription (HR 0.57, 95% CI 0.50–0.64) was associated with a decreased risk of stroke with a dose-response relationship (p for trend<0.0001). This study showed a potentially positive effect of RYR on the risk of stroke. However, compliance with medication use should be cautioned. The findings of this study require future studies to validate the beneficial effects of RYR prescription on stroke risk.

Clinical characteristics of COVID-19 hospitalized patients associated with mortality: A cohort study in Spain

BackgroundThe heterogeneity of patients with COVID-19 may explain the wide variation of mortality rate due to the population characteristics, presence of comorbidities and clinical manifestations. MethodsIn this study, we analyzed 5342 patients' recordings and selected a cohort of 177 hospitalized patients with a poor prognosis at an early stage. We assessed during 6 months their symptomatology, coexisting health conditions, clinical measures and health assistance related to mortality. Multiple Cox proportional hazards models were built to identify the associated factors with mortality risk. ResultsWe observed that cough and kidney failure triplicate the mortality risk and both bilirubin levels and oncologic condition are shown as the most associated with the demise, increasing in four and ten times the risk, respectively. Other clinical characteristics such as fever, diabetes mellitus, breathing frequency, neutrophil-lymphocyte ratio, oxygen saturation, and troponin levels, were also related to mortality risk of in-hospital death. ConclusionsThe present study shows that some symptomatology, comorbidities and clinical measures could be the target of prevention tools to improve survival rates.