Time Bias Research Articles

Survival benefits of radiotherapy in locally advanced unresectable and metastatic pancreatic cancer: a single-institution cohort and SEER database analysis.

Chemotherapy (CT) remains the primary treatment for locally advanced unresectable pancreatic cancer (LAUPC) and metastatic pancreatic cancer (MPC). The role of radiotherapy (RT) in these conditions remains unclear. This study compares the outcomes of CT alone versus CT combined with RT (combined-modality therapy [CMT]) in LAUPC and MPC patients. We conducted a retrospective analysis of LAUPC and MPC patients treated with either CT or CMT from a single institution and Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier curves and Cox hazards models evaluated the association between treatment modalities and overall survival (OS). Propensity score matching (PSM) ensured balanced comparisons. Landmark analysis addressed immortal time bias. Subgroup analyses were based on clinical characteristics. eXtreme Gradient Boosting (XGBoost) and Shapley Additive Explanations (SHAP) assessed outcome prediction and influence of significant predictors. The study included 102 patients receiving CMT and 155 receiving CT at single institution, along with 1733 CMT and 9310 CT patients from the SEER dataset. In the single-institution cohort, CMT showed superior survival compared to CT both before (median OS: 20.5 vs. 11.5 months, hazard ratio [HR]: 0.47, 95% CI: 0.34-0.65, P=0.001) and after PSM (median OS: 22.2 vs. 11.8 months, HR: 0.49, 95% CI: 0.30-0.79, P=0.003). Multivariate analyses confirmed that CMT was independently associated with improved OS both before (HR: 0.54, 95% CI: 0.38-0.77, P=0.001) and after PSM (HR: 0.45, 95% CI: 0.27-0.73, P=0.001). Landmark analysis indicated better OS for patients receiving CMT compared to CT alone. Subgroup analysis revealed an OS benefit for CMT across most subgroups. SHAP value analysis indicated that CMT was the most significant contributor to survival outcomes. SEER database validation confirmed these findings. This study demonstrates that CMT significantly improves OS in LAUPC and MPC patients compared to CT alone. Integrating RT with CT could be beneficial for treating LAUPC and MPC.

Addressing immortal time bias in precision medicine: Practical guidance and methods development.

To compare theoretical strengths and limitations of common immortal time adjustment methods, propose a new approach using multiple imputation (MI), and provide practical guidance for using MI in precision medicine evaluations centered on a real-world case study. Methods comparison, guidance, and real-world case study based on previous literature. We compared landmark analysis, time-distribution matching, time-dependent analysis, and our proposed MI application. Guidance for MI spanned (1) selecting the imputation method; (2) specifying and applying the imputation model; and (3) conducting comparative analysis and pooling estimates. Our case study used a matched cohort design to evaluate overall survival benefits of whole-genome and transcriptome analysis, a precision medicine technology, compared to usual care for advanced cancers, and applied both time-distribution matching and MI. Bootstrap simulation characterized imputation sensitivity to varying data missingness and sample sizes. Case study used population-based administrative data and single-arm precision medicine program data from British Columbia, Canada for the study period 2012 to 2015. While each method described can reduce immortal time bias, MI offers theoretical advantages. Compared to alternative approaches, MI minimizes information loss and better characterizes statistical uncertainty about the true length of the immortal time period, avoiding false precision. Additionally, MI explicitly considers the impacts of patient characteristics on immortal time distributions, with inclusion criteria and follow-up period definitions that do not inadvertently risk biasing evaluations. In the real-world case study, survival analysis results did not substantively differ across MI and time distribution matching, but standard errors based on MI were higher for all point estimates. Mean imputed immortal time was stable across simulations. Precision medicine evaluations must employ immortal time adjustment methods for unbiased, decision-grade real-world evidence generation. MI is a promising solution to the challenge of immortal time bias.

Phosphodiesterase 5 Inhibitor Treatment Is Associated With Improved Survival in Pulmonary Hypertension Associated With COPD in the Pulmonary Vascular Research Institute GoDeep Meta-Registry

BackgroundPatients with COPD frequently develop pulmonary hypertension (PH-COPD). Severe PH-COPD, identified by a pulmonary vascular resistance (PVR) >5 Wood Units (WU), is closely linked to impaired transplant-free survival. The impact of PH-targeting pharmacotherapy in this context remains unclear. Research QuestionIs PH-targeted therapy associated with improved transplant-free survival in PH-COPD? Study Design and MethodsThis study included PVRI GoDeep meta-registry patients with PH-COPD and available right heart catheterization at diagnosis. We investigated PH-targeted therapy prevalence and its association with transplant-free survival using diverse statistical methods, including Cox regression and subgroup analyses based on PH severity, comorbidities, and pulmonary function tests. Immortal time bias was addressed through a landmark approach. ResultsAs of December 2023, the GoDeep meta-registry included 26981 patients (28% PH-Group 1, 13% PH-Group 2, 12% PH-Group 3, 10% PH-Group 4, 2% PH-Group 5, 26% undefined and 9% control). Out of these, 836 patients were diagnosed as PH-COPD and included in this analysis, with median age 66 [59,73]years, FEV1 51 [34,69]%predicted, mPAP 35 [28,44]mmHg, PVR 5 [4,8]WU, cardiac index 2.5 [2.0,2.9]L/min.m2, and mostly WHO functional class III were included. 5-year transplant-free survival was 42%, significantly worse than group 1 PH. A multivariable Cox proportional hazards model identified PVR, but not FEV1 as a major predictor of outcome. 418 patients (50%) received phosphodiesterase-5 inhibitor (PDE5i) therapy, which was associated with significantly reduced mortality: hazard ratio 0.65 [0.57,0.75] for the entire PH-COPD cohort and 0.83 [0.74,0.94] when performing landmark analysis. This PDE5i effect was robustly reproduced when performing subgroup analyses for patients with moderate/severe PH, various comorbidities, and supplemental oxygen requirement, and when assessing the impact of unobserved confounders. InterpretationPH-COPD patients exhibit poor transplant-free survival, with PVR being a predictor of mortality. In this meta-registry, PDE5i therapy was associated with a significant reduction in mortality across all tested models.

785. MANAGEMENT OF ESOPHAGEAL CANCER WITH CONCURRENT CERVICAL NODE METASTASIS: A NATIONWIDE POPULATION-BASED COHORT STUDY

Abstract Background In the Netherlands, the standard treatment of locally advanced, resectable esophageal cancer without metastasis is neoadjuvant chemoradiotherapy followed by esophagectomy. There is a small subset of patients that present with concurrent cervical lymph node metastasis (LNM). Historically this was seen as distant metastasis and surgical intervention has usually not been an option for these patients. The contemporary TNM classification now categorizes these lymph node stations as locoregional disease. Our current study aims to describe current treatment paradigms in the Netherlands for patients presenting with esophageal cancer and concurrent cervical LNM. Methods This population-based cohort study utilized data from the Netherlands Cancer Registry (NCR), encompassing patients with locally advanced thoracic esophageal or gastroesophageal junction cancer and concurrent cervical lymph node metastasis. Treatment modalities were categorized into five options: neoadjuvant therapy followed by surgery (Neo + S), definitive chemoradiotherapy (dCRT), chemotherapy with or without radiotherapy < 30 Gray (CT), radiotherapy (RT), and best supportive care (BSC). Overall survival (OS) was assessed using the Kaplan-Meier method and compared via the log-rank test. Hazard rates were computed using Cox proportional hazards regression, with adjustment for confounding achieved through inverse probability of treatment weighting (IPTW). Results Between 2015 and 2021, a cohort of 412 patients was identified from the NCR database. Median survival durations were observed as follows: 24.2 months for Neo + S, 18.0 months for dCRT, 14.5 months for CT, 7.0 months for RT, and 3.2 months for BSC (Figure). A comparison between the Neo + S group and dCRT demonstrated a significant improvement in survival (p=0.02). Further subdivision of the surgical group into neoadjuvant CRT or chemotherapy did not reveal a significant difference in survival (p=0.6). Utilizing IPTW to adjust for confounding factors, Neo + S maintained its survival advantage. Conclusion The retrospective cohort findings suggest that neoadjuvant therapy followed by surgery may represent the optimal approach for managing esophageal cancer patients with cervical LNMs Yet, it's vital to recognize the influence of confounding by indication, which statistical adjustments may not entirely rectify. Furthermore, immortal time bias notably skews results favorably toward surgery. Nevertheless, the results emphasize the importance of considering surgery as a viable option for these patients. These limitations underscore the critical need for a prospective study, prompting the launch of the NODE-II trial.

An Emulated Target Trial Case Study of Real-World Overall Survival With Second-Line Maintenance Niraparib Versus Active Surveillance in Patients With Recurrent Ovarian Cancer.

This retrospective real-world study compared overall survival (OS) between patients with BRCA wild-type (BRCAwt) recurrent epithelial ovarian cancer (OC) who received niraparib second-line maintenance (2LM) versus active surveillance (AS) using target trial emulation, cloning, inverse probability of censoring weighting (IPCW) methodology to minimize immortal time bias. Eligible patients from a United States-based, deidentified, electronic health record-derived database were diagnosed with epithelial OC (January 1, 2011-May 31, 2021), were BRCAwt, and completed second-line (2L) therapy (January 1, 2017-March 2, 2022). Patient data were cloned at index (2L last treatment date), assigned to niraparib 2LM and AS cohorts, and censored when treatment deviated from clone assignment. Follow-up was measured from index to earliest of study end (May 31, 2022), last activity, or death. Median OS (mOS) and hazard ratios were estimated from stabilized IPCW Kaplan-Meier curves and Cox regression models. Overall, 199 patients received niraparib 2LM, and 707 had their care managed with AS. Key characteristics were balanced across cohorts after cloning and stabilized IPCW. Median follow-up was 15.6- and 9.3-months pre-cloning. IPCW mOS was 24.1 months (95% CI: 20.9-29.5) and 18.4 months (95% CI: 15.1-22.8) in niraparib 2LM and AS cohorts, respectively (hazard ratio, 0.77; 95% CI: 0.66-0.89). This real-world study provides supportive evidence of an OS benefit for patients with BRCAwt recurrent OC who received 2LM niraparib monotherapy compared with those whose care was managed with AS. The analytic strategies implemented were useful in minimizing immortal time bias and measured confounding.

Do corticosteroids affect immunotherapy efficacy in malignancy? - A systematic review.

Early studies indicated that corticosteroids may limit the survival benefit from immunotherapy. We conducted this systematic review to evaluate the effect corticosteroids have on immunotherapy in patients with malignancy, when adjusted for potentially confounding effects of corticosteroids given for palliative indications. Three electronic databases (PubMed, Embase and Medline) were searched on 1 February 2023. Studies that measured response or survival to immunotherapy in people receiving corticosteroids for non-cancer indications compared to either no corticosteroids or corticosteroids for cancer-related indications were included. Studies exclusively evaluating the effect of corticosteroids administered for immune-related adverse events (irAE) were excluded to avoid immortal time bias. Pooled odds and hazard ratios with 95% confidence intervals (CI) were calculated using a random effects model. Study heterogeneity was assessed using the I2 statistic, and publication bias was evaluated by funnel plot and Egger's regression model. Eight thousand four hundred and twenty-six titles were identified on our search. Eight studies met our inclusion criteria for meta-analysis. Administration of corticosteroids does not have a statistically significant effect on survival and response to immunotherapy when administered for non-cancer-related indications, with a pooled odds ratio for overall response rate 1.01 (95% CI 0.64-1.60); pooled hazard ratio (HR) for progression free survival 0.87 (95% CI 0.68-1.12); and pooled HR for overall survival 0.79 (95% CI 0.59-1.05). This systematic review indicates that administration of corticosteroids does not affect response to immunotherapy nor survival outcomes, when removing confounding palliative corticosteroid indications. These results are limited by the retrospective nature of the studies included, small sample sizes, lack of information about corticosteroid dosing and the inclusion of irAE in two of the studies which could bias the results.

Too good to be true: Are GLP-1 receptor agonists the new metformin?

Recently, a health-care database study showed that persons with type 2 diabetes taking GLP-1 receptor agonists (GLP-1 RA) had a significantly lower risk of 10 out of 13 obesity-related cancers than patients taking insulin (Wang L, et al. JAMA Netw Open. 2024 7: e2421305). For some cancers, hazard ratios <0.5 were reported. This is reminiscent of studies published >10 years ago showing that people with type 2 diabetes taking metformin had a lower risk of many types of cancer than those not taking metformin. In some studies, also risk reductions of >50 % were reported.The strong effects observed in the metformin studies were explained by time-related biases, in particular, immortal time bias. In the current GLP-1 RA study, it was striking that the curves for the cumulative incidence of several cancers in GLP-1 RA and insulin users diverged immediately after therapy onset. This indicates that there is most likely a time-related bias: insulin is given at much later stages of type 2 diabetes than GLP-1 RA.The current study suggests that one should be sceptical about database results when spectacular risk reductions are reported. Time-related bias should always be considered as an alternative explanation.

Transient characteristics of carrier transport in an isotopically enriched 28Si/SiGe undoped heterostructure

An isotopically enriched 28Si/SiGe undoped heterostructure is a promising platform for Si-based qubits due to the long coherence time by reducing 29Si isotopes with non-zero nuclear spins. Carriers in the buried Si quantum well (QW) of the Si/SiGe heterostructures could tunnel to the oxide/Si interface, increasing charge noise and leading to charge instability. In this work, we investigate the tunneling effects on carrier distribution and transport properties in an isotopically enriched 28Si/SiGe undoped heterostructure and its transient characteristics by controlling the hold time of gate biasing under different drain biases. By holding the gate bias for a longer time, the drain is reduced since more carriers in the buried QW tunnel to the oxide interface. Furthermore, under a larger drain bias, more carriers can move across the Si/SiGe heterojunction to the oxide interface and are trapped, resulting in a stronger current reduction, which is explained by a lucky electron model.

US Real-World Effectiveness Study of Nirmatrelvir/Ritonavir in Preventing Hospitalization of High-Risk COVID-19 Patients

PurposeWe describe nirmatrelvir/ritonavir (NMV/r) effectiveness in preventing hospitalization among COVID-19 patients at high risk of severe disease. MethodsAn ongoing US population-based observational cohort study with retrospective and prospective collection of national electronic healthcare data collected from the US Optum® deidentified COVID-19 Electronic Health Record dataset during December 22, 2021−July 20, 2022. Participants were ≥12 years old; had a positive SARS-CoV-2 test, COVID-19 diagnosis, or NMV/r prescription; and were at high risk of severe COVID-19 based on demographic/clinical characteristics. Potential confounders between groups were balanced using propensity score matching. Immortal time bias was addressed. Hospitalization rates within 30 days from COVID-19 diagnosis were evaluated. Sensitivity analyses included 15-day hospitalization, chart review to investigate incidental hospitalization effects, and exclusion of patients identified as having COVID-19 based on NMV/r prescription alone. Outcomes were also evaluated by race, age, and COVID-19 vaccine status. FindingsOverall, 12,440 and 234,123 patients were included in the NMV/r and non-NMV/r groups, respectively. After propensity score matching, baseline characteristics were well balanced across groups (NMV/r, n = 12,439; non-NMV/r, n = 36,490). Incidence of hospitalization (95% CI) within 30 days was 0.90% (0.74%−1.08%) for the NMV/r group and 5.91% (5.67%−6.16%) for the non-NMV/r group, with relative risk (95% CI) of 0.15 (0.13−0.18; 85% risk reduction). NMV/r was comparably effective in Black patients (relative risk, 0.19 [0.10−0.34]; 81% risk reduction). Sensitivity analyses supported the main outcomes. ImplicationsReal-world NMV/r effectiveness against hospitalization during Omicron predominance among COVID-19 patients at high risk of severe disease supports demonstrated clinical trial efficacy. Black patients underutilized NMV/r despite high effectiveness.

Systematic reviews and meta-analyses in the cerebrovascular space: essential domains for readers.

Systematic Review and Meta-Analysis (SRMAs) in neurosurgery have significantly increased. With approximately 1million patients affected by cerebrovascular disease annually, interpreting SRMAs necessitates a systematic approach. The objective of this review is to identify and describe four essential domains for SRMA interpretation. This review outlines the necessities of reviewing existing literature and methodological frameworks essential for interpreting cerebrovascular neurosurgery SRMAs. Each domain is to accurately assess study design variations, heterogeneity assessment methods, outcome comparability strategies, and the impact of technological advancements and time bias on study outcomes. Study design evaluation distinguishes between randomized controlled trials (RCTs) and non-randomized studies. RCTs provide high internal validity, but as seen in the ARUBA trial, can contain internal flaws that necessitate a deeper understanding before application to clinical practices. Non-randomized studies offer valuable real-world insights. A heterogeneity assessment involves readers and writers accurately using forest plots, Cochrane's Q test, Higgins I² statistics, subgroup analysis, and meta-regressions to understand a study's clinical findings. The expertise thresholds, as in the NASCET trial, significantly impact a study's external validity. Strategies such as the GRADE approach can assist in managing diverse outcome measures. Technological advancements, particularly in endovascular procedures and SRS, influence the accuracy of comparing studies across periods, and thus swiftly outdate older studies, lowering the applicability of SRMAs. Effective interpretation of cerebrovascular neurosurgery SRMAs requires attention to study design, heterogeneity, outcome comparability, and technological advancements. These domains collectively enable evidence-based clinical decision-making and optimized patient care in a dynamic field.

Long-range LBL underwater acoustic navigation considering Earth curvature and Doppler effect

The accuracy of underwater acoustic navigation is significantly influenced by geometry configuration and systematic errors coming from geophysical environment. Long baseline (LBL) systems exhibit superior positioning precision than other acoustic navigation systems, primarily attributable to the better Geometric Dilution of Precision (GDOP). However, the geometry configuration tends to degrade when the underwater vehicle is far away from the seafloor beacons. Factors such as acoustic ray bending error, Doppler effect and Earth curvature may seriously affect the navigation accuracy. To address these issues, we present a robust Kalman filter with systematic error compensation for long-range LBL systems. Firstly, a reversed acoustic ray tracking method is proposed for a unique phenomenon in acoustic wave propagation. Following that, we construct an acoustic positioning model with a time bias parameter, to weaken the impact of Doppler effect on acoustic ranging. This additional parameter was estimated with the state of the user vehicle in real time. At last, an observation equation of pressure gauge considering Earth curvature is presented for depth constraint. Long-range LBL experiments conducted in the South China Sea is employed to validate the performance of the proposed methods, taking the positioning results of inverted ultra-short baseline (iUSBL) system as reference. The results show that the proposed method outperform traditional method with a decrease of about 60 % in the three-dimensional root mean square (3DRMS) of navigation errors. With mentioned three improvements, the 3DRMS of the long-range LBL system with the longest distance of 20 km from the beacon center is less than 14 m. These findings can provide theoretical basis for other long-range LBL systems.

A Protocol for Electron Probe Microanalysis (EPMA) of Monazite for Chemical Th-U-Pb Age Dating

A protocol for the monazite (LREE,Y,Th,U,Si,Ca)PO4 in situ Th-U-Pb dating by electron probe microanalyser (EPMA) involves a suitable reference monazite. Ages of several potential reference monazites were determined by TIMS-U-Pb isotope analysis. The EPMA protocol is based on calibration with REE-orthophosphates and a homogeneous Th-rich reference monazite at beam conditions of 20 kV, 50 nA, and 5 µm for best possible matrix matches and avoidance of dead time bias. EPMA measurement of samples and repeated analysis of the reference monazite are performed at beam conditions of 20 kV, 100 nA, and 5 µm. Analysis of Pb and U on a PETL crystal requires YLg-on-PbMa and ThMz-on-UMb interference corrections. Offline re-calibration of the Th calibration on the Th-rich reference monazite, to match its nominal age, is an essential part of the protocol. EPMA-Th-U-Pb data are checked in ThO2*-PbO coordinates for matching isochrones along regressions forced through zero. Error calculations of monazite age populations are performed by weighted average routines. Depending on the number of analyses and spread in ThO2*-PbO coordinates, minimum errors &lt;10 Ma are possible and realistic for Paleozoic monazite ages. A test of the protocol was performed on two garnet metapelite samples from the Paleozoic metamorphic Zone of Erbendorf-Vohenstrauß (NE-Bavaria, western Bohemian Massif).

Midwifery Students' Experiences of Bias in the Clinical Setting: Prevalence, Types, and Impact.

Exposure to bias in clinical learning environments may undermine students' confidence, cause emotional harm, impede learning, and potentially delay graduation. However, little is known about the prevalence of bias experienced by midwifery students in the United States. This cross-sectional, descriptive study aimed to quantify clinical midwifery students' experiences of bias based on 7 self-identified characteristics (gender identity, race or ethnicity, body size, age, sexual orientation, religion, and occupational background). Additionally, this research explored the impact of bias on student well-being, learning, and professional commitment. The survey consisted of 39 items addressing (1) prevalence and types of bias, (2) emotional impact and influence on clinical learning, (3) ways students coped, (4) whether anyone spoke up at the time bias occurred, (5) whether students reported bias to faculty, and (6) impact of bias on commitment to midwifery. The survey was distributed to midwifery students and recent graduates in 2022 via American College of Nurse-Midwives email discussion lists and social media. Participants were eligible if they were in a clinical rotation in an Accreditation Commission for Midwifery Education-accredited midwifery program between 2019 and 2022. Surveys were returned by 383 participants, with 301 meeting inclusion criteria. Most participants (66.5%) reported personally experiencing or witnessing bias against at least 1 of 7 personal characteristics. The most commonly reported biases were related to gender, occupational background, age, and race or ethnicity. Only half of the participants reported these occurrences to someone with academic authority, and nearly a third considered withdrawing from their educational programs. In this study bias was common and significantly impacted students. These results underscore the need for creative and bold interventions at personal, educational, and institutional levels to prevent and mitigate bias. Safeguarding clinical learning environments will enable students to thrive, graduate with confidence and competence, and thereby contribute to the diversification and strengthening of the midwifery profession.

Positive and negative controls in rheumatology research.

Observational research from large population databases may be affected by unmeasured confounding and time-related biases, such as immortal time bias. Modern causal inference practice applies propensity score-based methods, new-user designs, and other strategies to mitigate bias. The degree to which these methodologic approaches adequately address bias for any particular study may be difficult to measure. Recently, the incorporation of positive and negative controls has been identified as a means to assess for the impacts of residual confounding and/or time-related biases. The objective of this commentary is to describe the role of positive and negative controls in observational research. We offer recommendations for incorporating controls into critical appraisal and observational research projects.

Decreased Long-Term Survival of Patients With Newly Diagnosed Cancer Discharged Home After Unplanned ICU Admission: A Prospective Observational Study.

To compare the 18-month survival between patients with newly diagnosed cancer discharged home after early unplanned ICU admission and those without early unplanned ICU admission; we also evaluated the frequency and risk factors for early unplanned ICU admission. Observational study with prospectively collected data from September 2019 to June 2021 and 18 months follow-up. Single dedicated cancer center in São Paulo, Brazil. We screened consecutive adults with suspected cancer and included those with histologically proven cancer from among 20 highly prevalent cancers. None. The exposure was early unplanned ICU admission, defined as admission for medical reasons or urgent surgery during the first 6 months after cancer diagnosis. The main outcome was 18-month survival after cancer diagnosis, and the main analysis was Cox's proportional hazards model adjusted for confounders and immortal time bias. Propensity score matching was used in the sensitivity analysis. We screened 4738 consecutive adults with suspected cancer and included 3348 patients. Three hundred twelve (9.3%) had early unplanned ICU admission, which was associated with decreased 18-month survival both in the unadjusted (hazard ratio, 4.03; 95% CI, 2.89-5.62) and adjusted (hazard ratio, 1.84; 95% CI, 1.29-2.64) models. The sensitivity analysis confirmed the results because the groups were balanced after matching, and the 18-month survival of patients with early ICU admission was lower compared with patients without early ICU admission (87.0% vs. 93.9%; p = 0.01 log-rank test). Risk factors for early unplanned ICU admission were advanced age, comorbidities, worse performance status, socioeconomic deprivation, metastatic tumors, and hematologic malignancies. Patients with newly diagnosed cancer discharged home after early unplanned ICU admission have decreased 18-month survival compared with patients without early unplanned ICU admission.

Injurious Fall Risk Differences Among Older Adults With First-Line Depression Treatments

One-third of older adults in the US have depression, often treated with psychotherapy and antidepressants. Previous studies suggesting an increased risk of falls and related injuries (FRI) associated with antidepressant use may be affected by confounding by indication or immortal time bias. To evaluate the association between FRI risk and first-line treatments in older adults with depression. This cohort study used a target trial emulation framework with a cloning-censoring-weighting approach with Medicare claims data from 2016 to 2019. Participants included fee-for-service beneficiaries aged 65 years or older with newly diagnosed depression. Data were analyzed from October 1, 2023, to March 31, 2024. First-line depression treatments including psychotherapy, sertraline, escitalopram, citalopram, mirtazapine, duloxetine, trazodone, fluoxetine, bupropion, paroxetine, and venlafaxine. One-year FRI rate, restricted mean survival time (RMST), and adjusted hazard ratio (aHR) with 95% CI. Among 101 953 eligible beneficiaries (mean [SD] age, 76 [8] years), 63 344 (62.1%) were female, 7404 (7.3%) were Black individuals, and 81 856 (80.3%) were White individuals. Compared with the untreated group, psychotherapy use was not associated with FRI risk (aHR, 0.94 [95% CI, 0.82-1.17]), while other first-line antidepressants were associated with a decreased FRI risk (aHR ranged from 0.74 [95% CI, 0.59-0.89] for bupropion to 0.83 [95% CI, 0.67-0.98] for escitalopram). The FRI incidence ranged from 63 (95% CI, 53-75) per 1000 person-year for those treated with bupropion to 87 (95% CI, 83-90) per 1000 person-year for those who were untreated. The RMST ranged from 349 (95% CI, 346-350) days for those who were untreated to 353 (95% CI, 350-356) days for those treated with bupropion. In this cohort study of older Medicare beneficiaries with depression, first-line antidepressants were associated with a decreased FRI risk compared with untreated individuals. These findings provide valuable insights into their safety profiles, aiding clinicians in their consideration for treating depression in older adults.

Dementia Incidence in Survivors of Multiple Myeloma: A National Case-Control Study Conducted in Korea (The CAREMM-2106 Study)

BackgroundDementia, a growing global health issue, affects older adults and specific groups like long-term cancer survivors. The link between cancer survival and dementia is debated. Multiple myeloma (MM), a common blood cancer in older adults, is often linked with cognitive issues. This study investigated dementia incidence in long-term MM survivors using Korean national data. MethodsA retrospective case-control study used data from the Korea National Health Insurance Service (KNHIS), covering about 50 million Koreans. Patients diagnosed with MM between 2009 and 2020 formed the case cohort, while the control cohort included matched individuals without MM using propensity-score matching. Analyzing baseline characteristics, comorbidities, and socioeconomic status, the primary outcome was dementia incidence identified via ICD-10 codes. Statistical methods included Kaplan-Meier plots, cause-specific and Fine–Gray subdistribution hazard models, and a 3-year landmark analysis for immortal time bias. ResultsThe study included 33,864 patients, with 16,932 in each cohort. The overall cumulative dementia incidence was lower in the MM cohort compared to controls. However, in the first 3 years, MM patients had a higher dementia risk (HR: 1.711, 95% CI, 1.562-1.874) than controls. After 3 years, the risk significantly decreased (HR: 0.625, 95% CI, 0.560-0.696). Age-specific analysis showed a consistent pattern, particularly among MM patients aged 70-79, where dementia risk increased post-3 years. ConclusionThis study reveals a lower long-term dementia risk in MM survivors compared to non-MM individuals. Further prospective studies are needed to confirm these findings and explore the underlying mechanisms.

Antifibrotics and mortality in idiopathic pulmonary fibrosis: external validity and avoidance of immortal time bias

Background and objectivePooled analyses of previous randomized controlled trials reported that antifibrotics improved survival in patients with idiopathic pulmonary fibrosis (IPF), but the results were only based on short-term outcome data from selected patients who met strict criteria. Observational studies/meta-analyses also suggested that antifibrotics improve survival, but these studies failed to control for immortal time bias that considerably exaggerates drug effects. Therefore, whether antifibrotics truly improve long-term survival in patients with IPF in the real world remains undetermined and requires external validity.MethodsWe used data from the Japanese National Claims Database to estimate the intention-to-treat effect of antifibrotics on mortality. To address immortal time bias, we employed models treating antifibrotic initiation as a time-dependent covariate and target trial emulation (TTE), both incorporating new-user designs for antifibrotics and treating lung transplantation as a competing event.ResultsOf 30,154 patients with IPF, 14,525 received antifibrotics. Multivariate Fine–Gray models with antifibrotic initiation as a time-dependent covariate revealed that compared with no treatment, nintedanib (adjusted hazard ratio [aHR], 0.85; 95% confidence interval [CI], 0.81–0.89) and pirfenidone (aHR, 0.89; 95% CI, 0.86–0.93) were associated with reduced mortality. The TTE model also replicated the associations of nintedanib (aHR, 0.69; 95% CI, 0.65–0.74) and pirfenidone (aHR, 0.81; 95% CI, 0.78–0.85) with reduced mortality. Subgroup analyses confirmed this association regardless of age, sex, and comorbidities, excluding certain subpopulations.ConclusionsThe results of this large-scale real-world analysis support the generalizability of the association between antifibrotics and improved survival in various IPF populations.

Construction of a nomogram with IrAE and clinic character to predict the survival of advanced G/GEJ adenocarcinoma patients undergoing anti-PD-1 treatment.

This study aimed to develop and validate a survival prediction model and nomogram to predict survival in patients with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma undergoing treatment with anti-programmed cell death 1 receptor (PD-1). This model incorporates immune-related adverse events (irAEs) alongside common clinical characteristics as predictive factors. A dataset comprising 255 adult patients diagnosed with advanced G/GEJ adenocarcinoma was assembled. The irAEs affecting overall survival (OS) to a significant degree were identified and integrated as a candidate variable, together with 12 other candidate variables. These included gender, age, Eastern cooperative oncology group performance status (ECOG PS) score, tumor stage, human epidermal growth factor receptor 2 (HER2) expression status, presence of peritoneal and liver metastases, year and line of anti-PD-1 treatment, neutrophil-to-lymphocyte ratio (NLR), controlling nutritional status (CONUT) score, and Charlson comorbidity index (CCI). To mitigate timing bias related to irAEs, landmark analysis was employed. Variable selection was performed using the least absolute shrinkage and selection operator (LASSO) regression to pinpoint significant predictors, and the variance inflation factor was applied to address multicollinearity. Subsequently, a Cox regression analysis utilizing the forward likelihood ratio method was conducted to develop a survival prediction model, excluding variables that failed to satisfy the proportional hazards (PH) assumption. The model was developed using the entire dataset, then internally validated through bootstrap resampling and externally validated with a cohort from another Hospital. Furthermore, a nomogram was created to delineate the predictive model. After consolidating irAEs from the skin and endocrine systems into a single protective irAE category and applying landmark analysis, variable selection was conducted for the prognostic prediction model along with other candidate variables. The finalized model comprised seven variables: ECOG PS score, tumor stage, HER2 expression status in tumor tissue, first-line anti-PD-1 treatment, peritoneal metastasis, CONUT score, and protective irAE. The overall concordance index for the model was 0.66. Calibration analysis verified the model's accuracy in aligning predicted outcomes with actual results. Clinical decision curve analysis indicated that utilizing this model for treatment decisions could enhance the net benefit regarding 1- and 2-year survival rates for patients. This study developed a prognostic prediction model by integrating common clinical characteristics of irAEs and G/GEJ adenocarcinoma. This model exhibits good clinical practicality and possesses accurate predictive ability for overall survival OS in patients with advanced G/GEJ adenocarcinoma.

A Comprehensive Analysis of 10-Yard Sprint Reliability in Male and Female Youth Athletes.

Wannouch, YJ, Leahey, SR, Whitworth-Turner, CM, Oliver, JL, YH, KC, Laffer, JC, and Leicht, AS. A comprehensive analysis of 10-yard sprint reliability in male and female youth athletes. J Strength Cond Res 38(9): e477-e488, 2024-This study investigates the inter-week test-retest reliability of 9.14 meter (10 yard) sprint times in youth athletes. Although essential for assessing athletic ability and training efficacy, the critical and comprehensive examination of both relative and absolute reliability indices for short-distance sprints has been insufficient in youth contexts. One hundred ninety-eight youth athletes (128 males and 70 females) underwent 2 sprint attempts across 2 separate trials 24 hours apart and within 7 days of each other. The sprints were measured using dual-beam timing gates to capture split times for 0-4.57 meter (0-5 yards), 4.57-9.14 meter (5-10 yards), and 0-9.14 meter (0-10 yards). The minimal mean difference between the best sprint times across trials was 0.02 ± 0.13 seconds for males and 0.003 ± 0.14 seconds for females. No significant mean differences were found between trials for either gender (males: p = 0.0875; females: p = 0.8752), suggesting no systematic bias in sprint times. The SEM was 0.092 seconds for males and 0.099 seconds for females, with a corresponding SEMCV% of 4.6 and 4.8%. The overall coefficient of variation was 9.8% for males and 8.9% for females. Intraclass correlation coefficient values suggested that the sprint times across trials were reliable (males: 0.80; females: 0.76). The minimal detectable change was 0.25 seconds for males, 0.27 seconds for females. Cohen's d indicated trivial effects (<0.2) for males (0.154) and females (0.021). Minimal mean differences, a low SEM , and consistent ICC values demonstrate that the 0-9.14 meter sprint is a reliable assessment in youth athletes.