Regression Model Selection Research Articles

Adjuvant Vitamin D Injection in Elderly Patients Before Intertrochanteric Fracture Surgery: A Randomised Controlled Trial.

There are multiple recommended protocols for Vitamin D (VitD) supplementation in elderly; however, only a few studies achieved to examine the role of VitD supplements before intertrochanteric fracture surgery on mortality and complications after surgery. This single-center block-randomized double-blinded trial was conducted on 80 patients with intertrochanteric fractures and a sufficient level of 25 (OH) VitD. The intervention group received an intramuscular 300,000IU VitD ampule before surgery. The primary outcome was a 6-month mortality rate, and the secondary outcomes were 1- and 2-year mortality rates and Harris Hip Score (HHS) in 6, 12, and 24months after surgery. Chi-square, t-test, repeated measure ANOVA, and Cox regression survival model was used for statistical analysis. 40 patients were allocated to each group. Demographic, clinical characteristics, and preoperative evaluations were not significantly different between the groups. Mortality rate 6-month after the surgery was 7.5% and 10% for the intervention and placebo groups respectively (P value = .71), 15% and 12.5% at 1-year (P value = .83), and 25% and 27.5% at 2-year (P value = .98). Based on the Cox regression model, only age was significantly associated with mortality (HR = 1.229, P value <.001). Significant HHS changes from baseline through 24 months after surgery were observed within both groups; however, mean differences were not significantly different between groups. A single preoperative 300,000IU VitD did not significantly impact 2-year survival and HHS in patients with intertrochanteric fractures and sufficient serum VitD level.

Comparison of Efficacy and Safety of Second-Line Treatment Options for Advanced Small-Cell Lung Cancer: A Retrospective Analysis.

As monotherapy such as topotecan has reached a plateau of effectiveness, new second-line treatments based on experience have been used in clinical application. This study compared the efficacy and safety of different second-line treatments for advanced small-cell lung cancer (SCLC). A total of 380 patients with advanced SCLC were screened selectively in the retrospective study. Adverse events and patient responses were assessed using Common Terminology Criteria for Adverse Events v5.0 and Response Evaluation Criteria for Solid Tumors v1.1. The progression-free survival (PFS) was estimated using the Kaplan-Meier method or Cox survival regression model and compared using the log-rank test. In the platinum-resistant group, disease control rate (DCR) and median PFS (mPFS) were prolonged in the combination group versus single-agent group (DCR: 49.24% vs 24.39%, P = .004; mPFS: 3.73 vs 1.90 months, P < .001). Grade 3/4 toxicity was similar between the 2 groups (P = .683). The mPFS did not differ among single-agent groups (P = .380). No significant difference was observed in mPFS of different combination therapy groups (P = .170). In terms of platinum-based chemotherapy, the DCR and mPFS were prolonged in irinotecan-platinum group versus taxol-platinum group (DCR: 56.14% vs 9.09%, P = .004; mPFS: 3.87 vs 1.93 months, P = .012). Grade 3/4 toxicity was similar between the 2 groups (P = .614). The mPFS was prolonged in the chemotherapy plus immunotherapy group versus single-agent chemotherapy group (P = .003). In the platinum-sensitive group, the mPFS did not differ between the combination group and single-agent group (P = .200). The mPFS did not differ among different single-agent groups (P = .260) or combination groups (P = .150). There was no difference in mPFS among different platinum-based chemotherapy groups (P = .830). For patients with platinum-resistant SCLC, combination therapy has shown better efficacy and acceptable toxicity profile than monotherapy. Among combination therapies, irinotecan-platinum has shown better efficacy than taxol-platinum. For patients with platinum-sensitive SCLC, the efficacy of different single-agent or combination therapies was similar.

Inferring Diagnostic and Prognostic Gene Expression Signatures Across WHO Glioma Classifications: A Network-Based Approach.

Tumor heterogeneity is a challenge to designing effective and targeted therapies. Glioma-type identification depends on specific molecular and histological features, which are defined by the official World Health Organization (WHO) classification of the central nervous system (CNS). These guidelines are constantly updated to support the diagnosis process, which affects all the successive clinical decisions. In this context, the search for new potential diagnostic and prognostic targets, characteristic of each glioma type, is crucial to support the development of novel therapies. Based on The Cancer Genome Atlas (TCGA) glioma RNA-sequencing data set updated according to the 2016 and 2021 WHO guidelines, we proposed a 2-step variable selection approach for biomarker discovery. Our framework encompasses the graphical lasso algorithm to estimate sparse networks of genes carrying diagnostic information. These networks are then used as input for regularized Cox survival regression model, allowing the identification of a smaller subset of genes with prognostic value. In each step, the results derived from the 2016 and 2021 classes were discussed and compared. For both WHO glioma classifications, our analysis identifies potential biomarkers, characteristic of each glioma type. Yet, better results were obtained for the WHO CNS classification in 2021, thereby supporting recent efforts to include molecular data on glioma classification.

Day 100 Natural Killer Cell/CD14+HLA-DRDIM ratio and survival in lymphoma post-autologous peripheral blood hematopoietic stem cell transplantation.

The infusion of autograft Natural Killer Cells (NKC)/CD14+ HLA-DRDIM ratio is a predictor of survival in lymphoma patients undergoing autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). This study evaluated if the Day 100 NKC/CD14+ HLA-DRDIM ratio still functions as a prognostic immune-biomarker. This was a retrospective, single-institution, cohort analysis including 107 patients in this study that had clinical assessment at Day 100 post-APBHSCT from our prior phase III trial. We evaluated the prognostic ability of the Day 100 NKC/CD14+ HLA-DRDIM ratio to predict overall survival (OS) and progression-free survival (PFS) using Cox regression model for outcome analysis and survival by Kaplan-Meier method. The median follow-up from day 100 was 94.7 months (range 4.83-158.1 months) for the entire cohort. Patients with a Day 100 NKC/CD14+ HLA-DRDIM ratio ≥1.67 experienced better OS and PFS versus those with a Day 100 NKC/CD14+ HLA-DRDIM ratio <1.67: median OS was not reached versus 49.7 months, the 5-year OS rates were 91% (95% CI, 81%-96%) versus 40% (95% CI, 27%-55%), p<.0001, respectively; and median PFS was not reached versus 23.5 months, the 5-year PFS rates were 66% (95% CI, 55%-81%) versus 21% (95% CI, 15%-40%), p<.0001, respectively. Day 100 NKC/CD14+ HLA-DRDIM ratio was an independent predictor for OS and PFS in the multivariate analysis. Day 100 NKC/CD14+ HLA-DRDIM ratio is a prognostic immune-biomarker in lymphoma patients post- APBHSCT.

Incidence and risk of dementia in people with Anxiety over 50 years old – an electronic health records study

AbstractBackgroundDepression is a well‐established risk factor for dementia, but we know far less about the links between Anxiety and future dementia risk in older people. The aim was therefore to investigate the incidence of dementia in people with and without Anxiety above the age of 50 years over a 10‐year period.MethodThe Health Improvement Network (THIN) was used, a large UK primary care dataset, that includes approximately 15.6 million patients, which is representative of the UK population. All people between 1st January 2008 and 31 December 2018 who had new onset Anxiety over the age of 50 years were identified. At the time of the first record of Anxiety, each person was individually matched to 4 unexposed persons based on their sex and age and Exposure Density Sampling was used, creating a dynamic cohort. Weibull survival regression models were fitted and hazard ratios (HR) were estimated for modelling time‐to‐dementia in those with and without Anxiety; and when determining the risk of developing dementia in those with Anxiety. Hazard ratio estimates were adjusted for sociodemographic and lifestyle factors, and relevant physical and mental health conditions.ResultIn this cohort study, there were 37,824 men and 68,761 women diagnosed with a first episode of Anxiety. Of those who had Anxiety, 2,792 people developed dementia during the follow up period, compared to 19,000 people in the non‐Anxiety group. The incidence of dementia in those with and without Anxiety was 7.21 (95% CI 6.94‐7.48) and 3.22 (95% CI 3.18‐3.28) respectively per 1,000 person‐years. The risk of dementia was increased 2.47‐fold [HR 2.47 (CI 2.37‐ 2.57)] in the Anxiety group when compared to the non‐Anxiety group after adjustment for age, sex, social deprivation, alcohol, smoking, BMI, diabetes mellitus, cardiovascular diseases, learning disabilities, HIV, multiple sclerosis, brain injury and hearing impairment.ConclusionThe incidence of dementia was greater in those with Anxiety and the risk of developing dementia was more than doubled in people with Anxiety compared to those without. This provides further evidence that Anxiety is a potential risk factor for dementia.

Low-density lipoprotein receptor promotes crosstalk between cell stemness and tumor immune microenvironment in breast cancer: a large data-based multi-omics study

BackgroundTumor cells with stemness in breast cancer might facilitate the immune microenvironment’s suppression process and led to anti-tumor immune effects. The primary objective of this study was to identify potential targets to disrupt the communication between cancer cell stemness and the immune microenvironment.MethodsIn this study, we initially isolated tumor cells with varying degrees of stemness using a spheroid formation assay. Subsequently, we employed RNA-seq and proteomic analyses to identify genes associated with stemness through gene trend analysis. These stemness-related genes were then subjected to pan-cancer analysis to elucidate their functional roles in a broader spectrum of cancer types. RNA-seq data of 3132 patients with breast cancer with clinical data were obtained from public databases. Using the identified stemness genes, we constructed two distinct stemness subtypes, denoted as C1 and C2. We subsequently conducted a comprehensive analysis of the differences between these subtypes using pathway enrichment methodology and immune infiltration algorithms. Furthermore, we identified key immune-related stemness genes by employing lasso regression analysis and a Cox survival regression model. We conducted in vitro experiments to ascertain the regulatory impact of the key gene on cell stemness. Additionally, we utilized immune infiltration analysis and pan-cancer analysis to delineate the functions attributed to this key gene. Lastly, single-cell RNA sequencing (scRNA-seq) was employed to conduct a more comprehensive examination of the key gene’s role within the microenvironment.ResultsIn our study, we initially identified a set of 65 stemness-related genes in breast cancer cells displaying varying stemness capabilities. Subsequently, through survival analysis, we pinpointed 41 of these stemness genes that held prognostic significance. We observed that the C2 subtype exhibited a higher stemness capacity compared to the C1 subtype and displayed a more aggressive malignancy profile. Further analysis using Lasso-Cox algorithm identified LDLR as a pivotal immune-related stemness gene. It became evident that LDLR played a crucial role in shaping the immune microenvironment. In vitro experiments demonstrated that LDLR regulated the cell stemness of breast cancer. Immune infiltration analysis and pan-cancer analysis determined that LDLR inhibited the proliferation of immune cells and might promote tumor cell progression. Lastly, in our scRNA-seq analysis, we discovered that LDLR exhibited associations with stemness marker genes within breast cancer tissues. Moreover, LDLR demonstrated higher expression levels in tumor cells compared to immune cells, further emphasizing its relevance in the context of breast cancer.ConclusionLDLR is an important immune stemness gene that regulates cell stemness and enhances the crosstalk between breast cancer cancer cell stemness and tumor immune microenvironment.

Relationship between obesity indicators and hypertension–diabetes comorbidity in an elderly population: a retrospective cohort study

BackgroundThe prevalence of obesity, hypertension and diabetes is increasing. Hypertension and diabetes are common complications. Additionally, obesity and hypertension–diabetes comorbidity (HDC) are both closely related to insulin resistance. The aim of this study was to determine the association of obesity indicators with HDC in elderly individuals.MethodsThis retrospective cohort study included 74,955 subjects aged ≥ 60 years living in Xinzheng, Henan Province, from January 2011 to December 2019. The data were collected from the annual health examination dataset. Cox proportional hazard regression models and competing-risk survival regression models were used to examine the relationships between the three indicators and HDC risk.ResultsAfter 346,504 person-years of follow-up, HDC developed in 9,647 subjects. After further adjustments for confounders and death competing risks, compared with a body mass index (BMI) of 18.5–23.9 kg/m2, the fully adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of BMI < 18.5, 24–27.9 and ≥ 28 kg/m2 for HDC morbidity were 0.651(0.538,0.788),1.00,1.396(1.336,1.459) and 1.769(1.666,1.878), respectively. Moreover, participants with abdominal obesity measured via waist circumference (WC) or waist-to-height ratio (WtHR) had a higher risk of HDC (HR:1.513; 95% CI: 1.45,1.578 and HR:1.412;95% CI: 1.353,1.473), respectively, than participants with low WC or with low WtHR. In the joint analyses, the highest risk was observed in participants who were overweight and who had central obesity (HR: 1.721; 95% CI: 1.635, 1.811) compared with the nonoverweight and noncentral obesity groups.ConclusionsIncreased BMI, WC and WtHR were associated with an increased risk of HDC. There was an additive interaction between general body adiposity (as measured via BMI) and central obesity (as measured via WC and WtHR) for HDC. Therefore, reasonable control of BMI, WC and WtHR may be an effective measure to prevent HDC among elderly individuals.

Prognostic Factors and Treatment Strategy in Patients with Hodgkin Lymphoma and HIV Infection Treated with ABVD and CART: A Retrospective Study from Spanish Group Geltamo

Background Hodgkin lymphoma (HL) is one of the most frequent non-AIDS defining neoplasm in people living with HIV (PLWH). Since the widespread use of combined antiretroviral therapy (cART), the incidence of most types of non-Hodgkin lymphoma affecting PLWH have decreased, but the incidence of HL has increased. The International Prognostic Score (IPS) is the most widely used score for HL. However, its implementation in PLWH is still controversial. Current HL treatment guidelines consider early and advanced stage. In function of the presence of unfavorable risk factors in early stages, an interim PET-CT can be used to guide therapeutic strategy. Unfavorable risk factors have been described by international groups (EORT, GHSG, NCI-C, and NCCN), which are: ≥3-4 involved lymph node areas, elevated RDW, age ≥50 years, ≥1 extranodal involvement and presence of B symptoms. There is a lack of evidence of the impact of this strategy in patients with HIV. Methods Retrospective multicentric study of patients with HIV infection diagnosed with HL in 9 hospitals from the GELTAMO group in Spain, from 1995 to 2022. All patients were treated with ABVD and cART +/- radiotherapy. The main clinical and biological variables were collected. Peripheral absolute neutrophil, lymphocyte and monocyte counts were studied, including L/M ratio and CD4 + lymphocyte count. Moreover, serum lactate dehydrogenase (LDH), albumin and RDW were evaluated. Univariable and multivariable analysis were performed using the binary logistic regression model for complete response (CR) rate and Cox proportional-hazards regression model for overall survival (OS) and progression-free survival (PFS). Survival curves were plotted by the Kaplan-Meier method and compared by the log-rank test. Results Ninety patients were retrospectively analyzed with a median follow up of 5.89 [0,4;24,78] years. The characteristics of the patients are summarized in Table 1. Extranodal involvement, hemoglobin &amp;lt;105 g/L, leucocytosis, high RDW, hypoalbuminemia and high LDH were associated with worse probabilities of complete response (CR) achievement. In the univariate analysis, bone marrow involvement and monocytes count ≥0.6 x10^9/L were associated with shorter overall survival (OS) and progression free survival (PFR) probabilities. A lymphocyte/monocyte (L/M) ratio &amp;lt;1.09 was associated with shorter PFR probabilities. By multivariable analysis, only monocyte count ≥0.6 x10^9/L emerged as an unfavorable prognostic factor for OS and PFS ( Figure 1). Data about treatment strategy and CR achievement is described in Table 1. Most patients (74%) presented advanced stage and the presence of unfavorable prognostic factors (described by international groups) was detected in most of the patients with localized stages ( Table 1). Conclusions High monocyte count is a strong prognostic factor which can be used in PLWH with HL. Most patients with HL and HIV infection present an advanced stage at diagnosis or a localized stage with unfavorable prognosis factors. In patients with localized stage, interim PET-CT guided strategy seems to be feasible.

Evaluation of the Impact of Tocilizumab Use in Recipients of CAR T Cells for Non-Hodgkin Lymphoma

Introduction: CAR T has revolutionized the treatment of patients with relapsed or refractory (R/R) Non-Hodgkin lymphoma (NHL). Treatment of the major toxicity of cytokine release syndrome (CRS) is tocilizumab (toci) and corticosteroids based on the ASTCT grade. Real-world experiences in the United States and Europe have reported a higher rate of tocilizumab use than in pivotal trials; however, the impact of single or multiple administrations on clinical outcomes is not clear. Methods: Patients diagnosed with diffuse (DLBCL), high grade (HGBCL) and primary mediastinal B cell lymphoma (PMBL) treated at our institution with commercial CAR T were retrospectively identified. The association between the number of doses received with best overall response by day 100, PFS, and OS was investigated through a Cox regression model using a 14-day landmark analysis. Late neutropenia was defined as an ANC &amp;lt;1000/mmc for two consecutive counts beyond day 30 post CAR-T infusion and a 30-day landmark analysis was performed in this case. Results: 230 patients with R/R DLBCL (80%), HGBCL (17%) and PMBL (3%) were included in the analysis. Axicabtagene ciloleucel (Axi-cel), tisagenlecleucel (Tisa-cel), and lisocabtagene maraleucel (Liso-cel) were administered in 62%, 29% and 9% of cases, respectively. Median age at time of CAR-T infusion was 65 years (range 20-86), with a male predominance (63%). The median number of prior treatment lines was 3 (range 1-12), and 21% underwent a prior autologous hematopoietic cell transplant. Disease burden prior to CAR-T infusion can be inferred by the following: bridging therapy was deemed necessary in 77% of patients, pre-lymphodepletion LDH was elevated in 40%, and bulky disease with largest mass diameter was &amp;gt; 10 cm in 10%. CRS and ICANS were grade 2 in 107 patients (46%) and 46 patients (20%), respectively. Median time to first administration of toci was 4 days (range 1-16) with patients receiving 0 (51%), 1 (27%), 2 (14%), or 3-4 (8%) doses. Best response by day 100 for the whole cohort was CR in 138 (60%) and PR in 36 (16%) patients. In univariable analysis, factors associated with a lower likelihood of response were the administration of Tisa-cel (p=0.014), bulky disease (p&amp;lt;0.001), administration of bridging therapy (p=0.009), and being refractory to the last treatment line (p=0.006). Number of doses of tocilizumab did not impact the likelihood of response (p=0.72). In a Cox regression model for survival, number of doses of tocilizumab was not associated with worse PFS (p=0.38, Figure 1) or OS (p=0.64), while other known negative predictors of response had impact on survival, such as bulky and refractory disease. By univariable analysis, tocilizumab administration was significantly associated with prolonged neutropenia (p&amp;lt;0.001). The likelihood to observe an ANC&amp;lt;1000/mmc beyond day 30 increased accordingly to the number of doses received (Figure 2). Other factors associated with late neutropenia were bulky disease (P=0.013), need of bridging therapy (p=0.004), and corticosteroids administration (p&amp;lt;0.001). Conclusion: The number of tocilizumab infusions did not impact CAR T efficacy in terms of overall response and long-term survival, a finding that is concordant with other real-world experiences. The cumulative incidence of late neutropenia events was impacted by the number of doses received. We speculate that a severe CRS driven systemic inflammatory response, requiring several tocilizumab and corticosteroids administrations, may hinder the bone marrow function and recovery.

Impact of the COVID-19 pandemic on routine HIV care and antiretroviral treatment outcomes in Kenya: A nationally representative analysis.

The COVID-19 pandemic adversely disrupted global health service delivery. We aimed to assess impact of the pandemic on same-day HIV diagnosis/ART initiation, six-months non-retention and initial virologic non-suppression (VnS) among individuals starting antiretroviral therapy (ART) in Kenya. Individual-level longitudinal service delivery data were analysed. Random sampling of individuals aged >15 years starting ART between April 2018 -March 2021 was done. Date of ART initiation was stratified into pre-COVID-19 (April 2018 -March 2019 and April 2019 -March 2020) and COVID-19 (April 2020 -March 2021) periods. Mixed effects generalised linear, survival and logistic regression models were used to determine the effect of COVID-19 pandemic on same-day HIV diagnosis/ART initiation, six-months non-retention and VnS, respectively. Of 7,046 individuals sampled, 35.5%, 36.0% and 28.4% started ART during April 2018 -March 2019, April 2019 -March 2020 and April 2020 -March 2021, respectively. Compared to the pre-COVID-19 period, the COVID-19 period had higher same-day HIV diagnosis/ART initiation (adjusted risk ratio [95% CI]: 1.09 [1.04-1.13], p<0.001) and lower six-months non-retention (adjusted hazard ratio [95% CI]: 0.66 [0.58-0.74], p<0.001). Of those sampled, 3,296 (46.8%) had a viral load test done at a median 6.2 (IQR, 5.3-7.3) months after ART initiation. Compared to the pre-COVID-19 period, there was no significant difference in VnS during the COVID-19 period (adjusted odds ratio [95% CI]: 0.79 [95%% CI: 0.52-1.20], p = 0.264). In the short term, the COVID-19 pandemic did not have an adverse impact on HIV care and treatment outcomes in Kenya. Timely, strategic and sustained COVID-19 response may have played a critical role in mitigating adverse effects of the pandemic and point towards maturity, versatility and resilience of the HIV program in Kenya. Continued monitoring to assess long-term impact of the COVID-19 pandemic on HIV care and treatment program in Kenya is warranted.

Amivantamab compared with real-world therapies in patients with advanced non-small cell lung cancer EGFR Exon 20 insertion mutations after platinum-based chemotherapy

Background In the single-arm CHRYSALIS trial, advanced non-small cell lung cancer patients harboring epidermal growth factor receptor (EGFR) exon 20 insertion (Exon 20ins) showed durable responses to amivantamab, an EGFR-MET bispecific antibody targeting tumors with EGFR Exon 20ins. This study compared the effectiveness of amivantamab to real-world systemic anti-cancer therapies in Japan. Patients and methods External control patients were selected by applying CHRYSALIS eligibility to Japanese patients from LC-SCRUM-Asia. External control patients were included for every qualifying line of therapy after platinum-based chemotherapy. Propensity score weighting was applied to external control patients to adjust for differences in baseline characteristics. Outcomes were compared between external control patients, and all and Asian-only CHRYSALIS patients using weighted Cox proportional hazards regression models for progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS), and generalized estimating equations with repeated measurements for overall response rate (ORR). Results One hundred fifteen CHRYSALIS and 94 external control patients were identified. Compared to external control patients, amivantamab-treated patients had significantly longer OS (median OS 19.88 vs 14.09 months, HR [95% CI] 0.59 [0.40–0.88]), PFS (median PFS 6.74 vs 4.73 months, HR 0.59 [0.45–0.78]), TTNT (median TTNT 12.16 vs 5.09 months, HR 0.39 [0.29–0.53]), and significantly higher ORR (41.7% vs 14.1%). Analyses of amivantamab-treated Asian patients (n = 61) showed similar clinical benefits. Conclusion In the absence of clinical evidence from randomized clinical trials, this study reflects the benefit of amivantamab after platinum-based chemotherapy for advanced non-small cell lung cancer patients harboring EGFR Exon 20ins, compared to current real-world therapies.

Abstract 13402: Outcomes of Cardiac Resynchronization Therapy in Ischemic versus Non-Ischemic Cardiomyopathy: A Patient-Level Meta-Analysis of 7 Randomized Clinical Trials

Background: Data on whether CRT results in better clinical and echocardiographic outcomes in patients with NICM versus patients with ICM are conflicting. Objective: To determine if there are differences in clinical and echocardiographic outcomes of CRT in patients with ICM versus NICM. Methods: We analyzed patient-level data from 7 CRT trials (MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, COMPANION, RAFT, MADIT-CRT, REVERSE) using Bayesian Hierarchical Weibull survival regression modeling, adjusted for baseline characteristics and presence of an ICD, to determine the effect of etiology of cardiac dysfunction on time to all-cause mortality alone and in combination with heart failure hospitalization (HFH). Kaplan-Meier (KM) survival curves were developed with unadjusted frequentist analyses. Linear regression was used to assess the effect of etiology of cardiomyopathy on echocardiographic measurements. Results: Of the 6252 patients included, 1535 (25%) were women, the median age was 66 (IQR 58-73), 3704 (59%) had ICM, and 3778 (60%) received CRT. Of those who received CRT, 2207 (58%) patients had ICM. Overall, CRT increased the time to HFH or death (hazard ratio (HR) 0.67, 95% credible interval (CrI) 0.56-0.82, p&lt;0.001) with no difference by etiology (HR ratio 1.06, CrI 0.87-1.29, p=0.57). CRT increased the time to death (HR 0.71, CrI 0.55-0.93, p=0.019) with no difference by etiology (HR ratio 1.06, CrI 0.80-1.43, p=0.70), although overall event rate was higher in ICM. CRT in ICM increased the median survival and time free of HFH (70 versus 50 months, p=0.0015) and had borderline effect in NICM (p=0.05) (Figure). Echocardiographic data that were available for 2430 (39%) patients showed that CRT improvements in LVEF, LVEDD, and LVESD were larger for patients with NICM. Conclusion: CRT increased the time to HFH or death independent of etiology of cardiac dysfunction. However, CRT led to greater increases in LVEF and reductions in ventricular dimensions for patients with NICM.

Patterns of substance use among adolescents in and out of foster care: An analysis of linked health and child welfare administrative data

BackgroundYoung adults with a history of foster care have higher risk for substance use disorders. Social systems can deliver substance use prevention to youth; however, the timing of intervention delivery and how needs differ for youth in foster care are unclear. ObjectiveTo compare initiation and rates of substance use among adolescents in foster care to demographically similar adolescents never in foster care as identified by the healthcare system, and identify factors associated with increased substance use. Participants and settingYouth in foster care (n = 2787, ages 10–20, inclusive) and demographically matched youth never in foster care (n = 2787) were identified using linked child welfare and electronic health records from a single pediatric children's hospital and county over a five-year period (2012–2017). MethodsAll healthcare encounters were reviewed and coded for substance use by type (alcohol, tobacco, cannabis, other). Age of first reported or documented substance use was also captured. Demographic and child welfare information was extracted from administrative records. Survival and logistic regression models were estimated. ResultsIn adjusted models, youth in foster care initiated substance use at earlier ages (HR = 2.50, p < .01) and had higher odds of engaging in use (AOR = 1.54; p < .01) than youth never in care. By age 12, substance use initiation was more likely while youth were in foster care than when they were not in foster care (HR = 1.42, p < .01). Placement stability and family care settings reduced odds of lifetime substance use. ConclusionsFoster care placement is associated with substance use. Screening may be important for prevention.

Changes in physical activity and all-cause mortality in the oldest old population: Findings from the Chinese Longitudinal Healthy Longevity Survey (CLHLS)

BackgroundInsufficient or decreasing physical activity is common in older adults. Most studies on physical activity changes and mortality were conducted in adults younger than 80 years old in developed countries. We aimed to investigate the relationship between changes in physical activity and longevity in the oldest old (80 years or older) population using the Chinese Longitudinal Healthy Longevity Survey. MethodsParticipants aged 80 or older at baseline were categorized into four groups: 1) remaining physically inactive (n = 14,287), 2) remaining physically active (n = 5411), 3) shifting from being inactive to active (n = 1364), and 4) shifting from being active to inactive (n = 1401). We fitted accelerated failure time Weibull survival regression models, adjusting for baseline sociodemographics, lifestyle factors and disease status. We further examined whether the associations differed by subgroups. ResultsA total of 15,707 participants died during follow-up (median duration of follow-up = 3.0 years). Compared with participants who remained physically inactive, those who remained active (fully adjusted event time ratio (ETR): 1.14, 95%CI: 1.11–1.17) or shifted from being inactive to active (fully adjusted ETR: 1.14, 95%CI: 1.08–1.20) had statistically significant longer survival time. No significant association was observed between remaining physically inactive and shifting from being active to inactive. Subgroup analyses showed consistent associations in nearly all strata. ConclusionMaintaining frequent physical activity or shifting from being physically inactive to active was consistently associated with longer survival time in the oldest old population. Our findings provide evidence for encouraging older adults to regularly engage in physical activity to gain longevity benefits.

Colposcopy referral rates post-introduction of primary screening with human papillomavirus testing: evidence from a large British Columbia cohort study

Shifting from cytology to human papillomavirus (HPV)-based cervical cancer screening will initially increase colposcopy referrals. The anticipated impact on health systems has been raised as a concern for implementation. It is unclear if the higher rate of colposcopy referrals is sustained after initial HPV-based screens or reverts to new lower baselines due to earlier detection and treatment of precancer. This study aimed to investigate long-term rates of colposcopy referrals after participation in HPV-based screening. Participants of HPV for Cervical Cancer Screening trial (HPV FOCAL) received one (HPV1, N=6204) or two (HPV2, N=9540) HPV-based screens. After exit, they returned to British Columbia's (BC) cytology screening program. A comparison cohort from the BC screening population (BCS, N=1,140,745) was identified, mirroring trial inclusion criteria. All participants were followed for 10-14 years through the provincial screening registry. Colposcopy referral rates per 1000 screens were calculated for each group. Trial colposcopy referrals for HPV1 and HPV2 were calculated under two referral scenarios: (1) all HPVpositivereferred to colposcopy; (2) cytology triage with ASCUSor greaterreferred to colposcopy. Colposcopy referrals from post-trial screens in HPV1 an HPV2 and all screens in BCS were based on actual recommendations from the screening program. A multivariable flexible survival regression model compared hazard ratios (HR) throughout follow-up. Scenario 2 referral rates were higher during initial HPV screen(s) vs cytology screen (HPV1: 28 per 1000 screens (95% CI: 24, 33), HPV2: 32 per 1000 screens (95% CI: 29, 36), BCS: 8 per 1000 screens (95% CI: 8.9)). However, post-trial rates in HPV1 and HPV2 were significantly lower than in BCS. Cumulative rates in HPV1 and HPV2 approached the cumulative rate in BCS 11-12 years after HPV-based screening (HPV1: 11 per 1000 screens (95% CI: 10, 12), HPV2: 16 per 1000 screens (95% CI: 15-17), BCS: 11 per 1000 screens (95% CI: 10, 11)). Adjusted models demonstrated reductions in referral rates in HPV1 (HR=0.6, 95% CI: 0.5, 0.7) and HPV2 (HR=0.7, 95% CI: 0.6, 0.8) relative to BCS by 54 and 72 months post-final HPV screen respectively. Reduced colposcopy referral rates were observed after initial rounds of HPV-based screening. After initial HPV screening, referral rates to colposcopy after cytology triage were below the current rates seen in a centralized cytology program after approximately four years. Any expected increase in referrals at initiation of HPV-based screening could be countered by staged program implementation. This work was supported by the National Institutes of Health (R01 CA221918), Michael Smith Health Research BC (RT-2021-1595), and the Canadian Institutes of Health Research (MCT82072).

Reconsidering the Cutoff Value for Sensitive and Refractory Relapses in Extensive-Stage SCLC in the Era of Immunotherapy

IntroductionTraditionally, relapsed SCLC has been classified as “sensitive” or “refractory” on the basis of cutoff values (60 or 90 d) for the duration between the last chemotherapy and disease progression. Nevertheless, these cutoff values are not derived from rigorous analytical methods, and their applicability to contemporary treatments remains uncertain. MethodsWe conducted a retrospective multicenter study on patients with extensive-stage SCLC who underwent second-line therapy after platinum-doublet chemotherapy with or without immune checkpoint inhibitor (ICI) resistance before (pre-ICI cohort) and after (post-ICI cohort) approval of combination immunotherapy. We selected the optimal platinum-free interval cutoff value with the lowest two-sided p value in the multivariable Cox regression model for second-line overall survival. The internal validity of the chosen cutoff value was assessed using twofold cross-validation. ResultsThere were 235 and 98 patients in the pre-ICI and post-ICI cohorts, respectively. In the pre-ICI cohort, the optimal cutoff was 59 days (p = 0.0001); the hazard ratio calculated using twofold cross-validation was 1.31 (95% confidence interval: 0.95–1.82]). In the post-ICI cohort, although the 60- and 90-day cutoff values could predict prognosis (60 d; p = 0.002, 90 d; p = 0.005), the optimal cutoff value was 75 days (p = 0.0002), which resulted in a median second-line overall survival of 15.9 and 5.0 months for patients with sensitive and refractory relapse, respectively (hazard ratio = 2.77, 95% confidence interval: 1.56–4.93). ConclusionsWe clarified the previously ambiguous cutoff values for classifying relapsed SCLC and revealed that the 75-day cutoff most accurately predicts subsequent prognosis than the traditional cutoffs in the post-ICI era.

Comorbidities and clinical response to cardiac resynchronization therapy: Patient-level meta-analysis from eight clinical trials.

Patients with heart failure usually have several other medical conditions that might alter the effects of interventions. We investigated whether the burden of comorbidity modified the clinical response to cardiac resynchronization therapy (CRT). Original patient-level data from eight randomized trials exploring the effects of CRT versus no CRT were pooled (BLOCK-HF, MIRACLE, MIRACLE-ICD, MIRACLE-ICD II, RAFT, COMPANION, MADIT-CRT and REVERSE). A prior history of the following comorbidities was considered: episodic or persistent atrial fibrillation (n = 920), coronary artery disease (n = 3732), diabetes (n = 2171), and hypertension (n = 3353). Patients were classified into three groups based on the number of comorbidities: 0, 1-2, or ≥3. The outcomes of interest were time to all-cause mortality and time to the composite outcome of heart failure hospitalization (HFH) or all-cause mortality. Outcomes were evaluated within each comorbidity group using a Bayesian hierarchical Weibull survival regression model. Of 6324 patients, 970 (15%) had no comorbidities, 4052 (64%) had 1-2 and 1302 (21%) had ≥3 comorbidities. The adjusted hazard ratio (aHR) for CRT versus no CRT for all-cause mortality in the overall cohort was 0.79 (95% credible interval [CI] 0.68-0.93) (p = 0.010); for no comorbidities the aHR was 0.54 (95% CI 0.34-0.86), for 1-2 comorbidities was 0.81 (95% CI 0.67-0.97) and for ≥3 comorbidities was 0.83 (95% CI 0.64-1.07) (no significant interaction between CRT and comorbidity burden: p = 0.13). For the endpoint of HFH or all-cause mortality, the aHR for the overall cohort was 0.74 (95% CI 0.65-0.84) (p = 0.001), for no comorbidities was 0.69 (95% CI 0.50-0.94), for 1-2 comorbidities was 0.77 (95% CI 0.66-0.90) and for ≥3 comorbidities was 0.68 (95% CI 0.55-0.82) (no significant interaction between CRT and comorbidity burden: p = 0.081). In a meta-analysis of patient-level data from eight major trials, the totality of evidence suggests that CRT reduces HFH and/or all-cause mortality even when several comorbid diseases are present. NCT00271154, NCT00251251, NCT00267098, NCT00180271.

Low disease activity state associated with fewer incident vertebral fractures in Mestizo women with systemic lupus erythematosus.

Low disease activity state (LDAS) has been linked to a significant reduction in flares and damage accrual in patients with systemic lupus erythematosus (SLE); however, the effect of LDAS on the risk of vertebral fractures (VFs) in subjects with SLE is unknown, considering that low bone mineral density (BMD) and VF are frequent in SLE. to evaluate whether achieving LDAS ≥50% of the observation time prevents new VF and BMD changes in Mestizo women. We carried out a longitudinal, observational, and retrospective study. Mestizo women with SLE were included for a median of an 8-year follow-up. LDAS was described as Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score ≤4, prednisone ≤7.5mg/day, and stable immunosuppressive therapies. BMD measurements and lateral thoracic and lumbar radiographs for a semiquantitative analysis for VF were assessed at baseline and during the follow-up. Uni- and multivariable interval-censored survival regression models were carried out. We included 110 patients: 35 (31.8%) had new VF. A total of 56 patients (50.1%) achieved LDAS ≥50% of the time during the follow-up and achieved a significantly lesser risk of incident VF (HR = 0.16; 95% CI, 0.06-0.49). After adjusting by age, BMI, menopause, prevalent VF, baseline BMD, cumulative glucocorticoid use, and anti-osteoporotic therapy, LDAS-50 was significantly related to a decrease in the risk of a new VF (HR = 0.39; 95% CI, 0.16-0.98). There was no association between LDAS and BMD measurement changes. When only patients on LDAS but not in remission (n = 43) were evaluated for the risk of incident VF, both uni- and multivariate analyses were significant (HR = 0.12; 95 CI, 0.04-47; p = 0.001, and HR = 0.26; 95% CI, 0.7-0.88; p = 0.03). LDAS ≥50% of the time was significantly associated with a diminished risk of new VF in Mestizo women with SLE, even in patients not in remission. However, LDAS did not help modify BMD changes over time.

Change in Splenic Volume as a Surrogate Marker for Immunotherapy Response in Patients with Advanced Urothelial and Renal Cell Carcinoma-Evaluation of a Novel Approach of Fully Automated Artificial Intelligence Based Splenic Segmentation.

In the treatment of advanced urothelial (aUC) and renal cell carcinoma (aRCC), biomarkers such as PD-1 and PD-L1 are not robust prognostic markers for immunotherapy (IO) response. Previously, a significant association between IO and a change in splenic volume (SV) was described for several tumour entities. To the best of our knowledge, this study presents the first correlation of SV to IO in aUC and aRCC. All patients with aUC (05/2017-10/2021) and aRCC (01/2012-05/2022) treated with IO at our academic centre were included. SV was measured at baseline, 3 and 9 months after initiation of IO using an in-house developed convolutional neural network-based spleen segmentation method. Uni- and multivariate Cox regression models for overall survival (OS) and progression-free survival (PFS) were used. In total, 35 patients with aUC and 30 patients with aRCC were included in the analysis. Lower SV at the three-month follow-up was significantly associated with improved OS in the aRCC group. We describe a new, innovative artificial intelligence-based approach of a radiological surrogate marker for IO response in aUC and aRCC which presents a promising new predictive imaging marker. The data presented implicate improved OS with lower follow-up SV in patients with aRCC.

Surgical Intervention for Primary B-cell Lymphoma of the Spine: A Systematic Review and Meta-analysis of Clinical Presentation, Treatment, Postoperative Outcomes, and Histologic Markers.

Systematic review and meta-analysis. To perform a systematic review of the clinical symptoms, radiographic findings, and outcomes after spinal decompression in B-cell lymphoma. B-cell lymphoma is a potential cause of spinal cord compression that presents ambiguously with nonspecific symptoms and variable imaging findings. Surgical decompression is a mainstay for both diagnosis and management, especially in patients with acute neurological deficits; however, the efficacy of surgical intervention compared with nonoperative management is still unclear. The databases of Medline, PubMed, and the Cochrane Database of Systemic Reviews were queried for all articles reporting spinal B-cell lymphoma. Data on presenting symptoms, treatments, survival outcomes, and histologic markers were extracted. Using the R software "survival" package, we generated bivariate and multivariate Cox survival regression models and Kaplan-Meier curves. In total, 65 studies were included with 72 patients diagnosed with spinal B-cell lymphoma. The mean age was 56.22 (interquartile range: 45.00-70.25) with 68% of patients being males and 4.2% of patients being immunocompromised. Back pain was the most common symptom (74%), whereas B symptoms and cauda equina symptoms were present in 6% and 29%, respectively. The average duration of symptoms before presentation was 3.81 months (interquartile range: 0.45-3.25). The most common location was the thoracic spine (53%), with most lesions being hyperintense (28%) on T2 magnetic resonance imaging. Surgical resection was performed in 83% of patients. Symptoms improved in 91% of patients after surgery and in 80% of patients treated nonoperatively. For all 72 patients, the overall survival at 1 and 5 years was 85% (95% CI: 0.749-0.953; n = 72) and 66% (95% CI: 0.512-0.847; n = 72), respectively. Although surgery is usually offered in patients with acute spinal cord compression from B-cell lymphoma, chemotherapy and radiation alone offer a hopeful alternative to achieve symptomatic relief, particularly in patients who are unable to undergo surgery.