Utilization of low- and high-value health care by individuals with and without cognitive impairment.

OBJECTIVES: Cognitive impairment and dementia have rising prevalence and impact the health care utilization and lives of older adults. Receipt of low-value (LV) care and underutilization of high-value (HV) care by individuals with these cognitive disorders may have negative consequences for patient health, health system efficiency, and societal welfare. Evidence on health care value among cognitively impaired individuals is limited; we thus ascertained receipt of LV and HV health care in older adults with normal cognition, cognitive impairment without dementia (CIND), and dementia. STUDY DESIGN: Retrospective cohort study of Health and Retirement Study data linked to Medicare claims (1996-2018). METHODS: We examined the association between cognitive decline and the receipt of 5 LV and 7 HV services vs individuals with no change in cognition. RESULTS: Receipt of LV care ranged from 4% to 13% regardless of cognitive status. Cognitive decline (from unimpaired to either CIND or dementia) was associated with decreased probability of receipt of 1 LV service (colorectal cancer screening at 85 years and older [5-percentage-point reduction; P = .047]) and 3 HV services (glucose-lowering drugs [7-percentage-point reduction; P = .029], statins [32-percentage-point reduction; P = .045], and antiresorptive therapy [61-percentage-point reduction; P = .019]). CONCLUSIONS: LV service receipt is wasteful and may be harmful, but it was not consistently associated with cognitive status. Lack of HV care for those with cognitive impairment could be a missed opportunity to improve well-being or reduce preventable adverse events. Our results suggest opportunities for improving the quality of care received by all older adults, including those with cognitive impairment.

Provider reported implementation barriers to hepatitis C elimination in Washington State.

BACKGROUND: Despite curative treatment options since 2014, only 12% of individuals in Washington State diagnosed with Hepatitis C (HCV) received treatment in 2018. Washington State agencies launched an elimination plan in 2019 to promote access to and delivery of HCV screening and treatment. The purpose of this study is to evaluate provider and health system barriers to successful implementation of HCV screening and treatment across Washington State. METHODS: This is a cross-sectional online survey of 547 physicians, nurse practitioners, physician assistants, and clinical pharmacists who provide care to adult patients in Washington State conducted in 2022. Providers were eligible if they worked in a primary care, infectious disease, gastroenterology, or community health settings. Questions assessed HCV screening and treating practices, implementation barriers, provider knowledge, observed stigma, and willingness to co-manage HCV and substance use disorder. Chi-squared or fishers exact tests compared characteristics of those who did and did not screen or treat. RESULTS: Provider adoption of screening for HCV was high across the state (96%), with minimal barriers identified. Fewer providers reported treating HCV themselves (28%); most (71%) referred their patients to another provider. Barriers identified by those not treating HCV included knowledge deficit (64%) and lack of organizational support (24%). The barrier most identified in those treating HCV was a lack of treating clinicians (18%). There were few (< 10%) reports of observed stigma in settings of HCV treatment. Most clinicians (95%) were willing to prescribe medication for substance use disorders to those that were using drugs including alcohol. CONCLUSION: Despite widespread screening efforts, there remain barriers to implementing HCV treatment in Washington State. Lack of treating clinicians and clinician knowledge deficit were the most frequently identified barriers to treating HCV. To achieve elimination of HCV by 2030, there is a need to grow and educate the clinician workforce treating HCV.

Short-chain fatty acids abrogate Japanese encephalitis virus-induced inflammation in microglial cells via miR-200a-3p/ZBTB20/IKßα axis.

Japanese encephalitis virus (JEV), a member of the Flaviviridae family, is a leading cause of viral encephalitis in humans. Survivors of this infection often develop lifelong neurological sequelae. Short-chain fatty acids (SCFAs) produced in the gut are vital mediators of the gut-brain axis. We aimed to study microRNA-based mechanisms of SCFAs in an in vitro model of JEV infection. N9 microglial cells were pretreated with SCFA cocktail before JEV infection. Cytokine bead analysis, immunoblotting, and PCR were performed to analyze relevant inflammatory markers. microRNA sequencing was performed using Illumina Hiseq, and bioinformatics tools were used for differentially expressed (DE) miRNAs and weighted gene co-expression network analysis (WGCNA). microRNA mimic/inhibitor experiments and luciferase assay were performed to study miRNA-target interaction. A significant reduction in monocyte chemoattractant protein (MCP1) and tumor necrosis factor alpha (TNFα) along with reduced expression of phospho-nuclear factor kappa B (phospho-NF-κB) was observed in SCFA conditions. Significant attenuation of histone deacetylase activity and protein expression was recorded. miRNA sequencing revealed 160 DE miRNAs in SCFA + JEV-treated cells at 6 h post-infection. WGCNA revealed miR-200a-3p, a hub miRNA significantly upregulated in SCFA conditions. Transcription factor ZBTB20 was bioinformatically predicted and validated as a gene target for miR-200a-3p. Further miRNA mimic/inhibitor assay demonstrated that miR-200-3p regulated ZBTB20 along with Iκßα that possibly dampened NF-κB signal activation downstream. IMPORTANCE: The gut-brain axis plays a pivotal role in the physiological state of an organism. Gut microbiota-derived metabolites are known to play a role in brain disorders including neuroviral infections. Short-chain fatty acids (SCFAs) appear to quench inflammatory markers in Japanese encephalitis virus-infected microglial cells in vitro. Mechanistically, we demonstrate the interaction between miR-200a-3p and ZBTB20 in regulating the canonical nuclear factor kappa B (NF-κB) signaling pathway via transcriptional regulation of Iκßα. Findings of this study pave the way to a better understanding of SCFA mechanisms that can be used to develop strategies against viral neuroinflammation.

Insights into the interaction and inhibitory action of palmatine on lysozyme fibrillogenesis: Spectroscopic and computational studies.

Interaction under amyloidogenic condition between naturally occurring protoberberine alkaloid palmatine and hen egg white lysozyme was executed by adopting spectrofluorometric and theoretical molecular docking and dynamic simulation analysis. In spetrofluorometric method, different types of experiments were performed to explore the overall mode and mechanism of interaction. Intrinsic fluorescence quenching of lysozyme (Trp residues) by palmatine showed effective binding interaction and also yielded different binding parameters like binding constant, quenching constant and number of binding sites. Synchronous fluorescence quenching and 3D fluorescence map revealed that palmatine was able to change the microenvironment of the interacting site. Fluorescence life time measurements strongly suggested that this interaction was basically static in nature. Molecular docking result matched with fluorimetric experimental data. Efficient drug like interaction of palmatine with lysozyme at low pH and high salt concentration prompted us to analyze its antifibrillation potential. Different assays and microscopic techniques were employed for detailed analysis of lysozyme amyloidosis.Thioflavin T(ThT) assay, Congo Red (CR) assay, 8-anilino-1-naphthalenesulfonic acid (ANS) assay, Nile Red (NR) assay, anisotropy and intrinsic fluorescence measurements confirmed that palmatine successfully retarded and reduced lysozyme fibrillation. Dynamic light scattering (DLS) and atomic force microscopy (AFM) further reiterated the excellent antiamyloidogenic potency of palmatine.

Tackling Challenges in Assessing the Economic Value of Tumor-Agnostic Therapies: A Cost-Effectiveness Analysis of Pembrolizumab as a Case Study.

OBJECTIVES: Assessing the value of tumor-agnostic drugs (TAD) is challenging given the potential variability in treatment effects, trials with small sample sizes, different standards of care (SoC), and lack of comparative data from single-arm basket trials. Our study developed and applied novel methods to assess the value of pembrolizumab compared with SoC to inform coverage decisions. METHODS: We developed a partitioned survival model to evaluate the cost-utility of pembrolizumab for previously treated patients with 8 advanced or metastatic microsatellite instability-high or mismatch repair-deficient cancers from a US commercial payer perspective. Efficacy of pembrolizumab was based on data from trials directly or with adjustment using Bayesian hierarchical models. Eight chemotherapy-based external control arms were constructed from the TriNetX electronic health record databases. Tumor-specific health-state utility values were applied. All costs were adjusted to 2022 US dollars. RESULTS: At a lifetime horizon, pembrolizumab was associated with increased effectiveness compared with chemotherapies in colorectal (quality-adjusted life years [QALYs]: +0.64, life years [LYs]: +0.64), endometrial (QALYs: +3.79, LYs: +5.47), and small intestine cancers (QALYs: +1.73, LYs: +2.48), but not for patients with metastatic gastric, cholangiocarcinoma, pancreatic, ovarian, and brain cancers. Incremental cost-effectiveness ratios varied substantially across tumor types. Pembrolizumab was found to be cost-effective in treating colorectal and endometrial cancers (incremental cost-effectiveness ratios: $121 967 and $139 257, respectively), and not cost-effective for other assessed cancers at a $150 000 willingness-to-pay/QALY threshold, compared with SoC chemotherapies. CONCLUSIONS: The cost-effectiveness of TADs can vary by cancers. Using analytic tools such as external controls and Bayesian hierarchical models can tackle several challenges in assessing the value of TADs and uncertainties from basket trials.

Evaluating Policies of Expanding Versus Restricting First-Line Treatment Choices: A Cost-Effectiveness Analysis Framework.

OBJECTIVES: Healthcare payers often implement coverage policies that restrict the utilization of costly new first-line treatments. Cost-effectiveness analysis can be conducted to inform these decisions by comparing the new treatment with an existing one. However, this approach may overlook important factors such as treatment effect heterogeneity and endogenous treatment selection, policy implementation costs, and diverse patient preferences across multiple treatment options. We aimed to develop a cost-effectiveness analysis framework that considers these real-world factors, facilitating the evaluation of alternative policies related to expanding or restricting first-line treatment choices. METHODS: We introduced a metric of incremental cost-effectiveness ratio (ICER) that compares an expanded choice set (CS) including the new first-line treatment with a restricted CS excluding the new treatment. ICER(CS) accounts for treatment selection influenced by heterogeneous treatment effects and policy implementation costs. We examined a basic scenario with 2 standard first-line treatment choices and a more realistic scenario involving diverse preferences toward multiple choices. To illustrate the framework, we conducted a retrospective evaluation of including versus excluding abiraterone acetate plus prednisone (AAP) (androgen deprivation therapy [ADT] + AAP) as a first-line treatment for metastatic hormone-sensitive prostate cancer. RESULTS: The traditional ICERs for ADT + AAP versus ADT alone and ADT+ docetaxel were $104 269 and $206 324/quality-adjusted life-year, respectively. The ICER(CS) for comparing an expanded CS with ADT + AAP with a restricted CS without ADT + AAP was $123 179/quality-adjusted life-year. CONCLUSIONS: The proposed framework provides decision makers with policy-relevant tools, enabling them to assess the cost-effectiveness of alternative policies of expanding versus restricting patients' and physicians' first-line treatment choices.

Isolating the Drivers of Racial Inequities in Prostate Cancer Treatment.

BACKGROUND: Black individuals in the United States are less likely than White individuals to receive curative therapies despite a 2-fold higher risk of prostate cancer death. While research has described treatment inequities, few studies have investigated underlying causes. METHODS: We analyzed a cohort of 40,137 Medicare beneficiaries (66 and older) linked to the Surveillance Epidemiology and End Results (SEER) cancer registry who had clinically significant, non-metastatic (cT1-4N0M0, grade group 2-5) prostate cancer (diagnosed 2010-2015). Using the Kitagawa-Oaxaca-Blinder decomposition, we assessed the contributions of patient health and health care delivery on the racial difference in localized prostate cancer treatments (radical prostatectomy or radiation). Patient health consisted of comorbid diagnoses, tumor characteristics, SEER site, diagnosis year, and age. Health care delivery was captured as a prediction model with these health variables as predictors of treatment, reflecting current treatment patterns. RESULTS: A total of 72.1% and 78.6% of Black and White patients received definitive treatment, respectively, a difference of 6.5 percentage points. An estimated 15% [95% confidence interval (CI): 6-24] of this treatment difference was explained by measured differences in patient health, leaving the remaining estimated 85% (95% CI: 74-94) attributable to a potentially broad range of health care delivery factors. Limitations included insufficient data to explore how specific health care delivery factors, including structural racism and social determinants, impact differential treatment. CONCLUSIONS: Our results show the inadequacy of patient health differences as an explanation of the treatment inequity. IMPACT: Investing in studies and interventions that support equitable health care delivery for Black individuals with prostate cancer will contribute to improved outcomes.

Temporal effect of imatinib adherence on time to remission in chronic myeloid leukemia patients.

INTRODUCTION: Adherence to imatinib in chronic myeloid leukemia (CML) patients is estimated to be as low as 70% despite its clinical benefit, and our understanding of the impact of nonadherence in this population is limited. This study presents a novel application of the Alternating Conditional Estimation (ACE) algorithm in newly diagnosed CML patients to map the full dose-response curve (DRC) and determine how the strength of this curve varies over time. METHODS: We applied the ACE algorithm alongside a backward elimination procedure to detect the presence of time dependence and nonlinearity in the relationship between imatinib adherence and time-to-remission. An extended Cox model allowing for the flexible modeling of identified effects via unpenalized B-splines was subsequently fit and assessed. RESULTS: The substantial improvement in model fit associated with the extended Cox approach suggests that traditional Cox proportional hazards model assumptions do not hold in this setting. Results indicate that the DRC for imatinib is non-linearly increasing, with an attenuated effect above a 74% adherence rate. The strength of this effect on remission varied over time and was strongest in the initial months of treatment, reaching a peak around 90 days post-initiation (log hazard ratio: 2.12, 95% confidence interval: 1.47 to 2.66). CONCLUSION: Most patients that achieved remission did so by 4 months (120 days) with consistently high adherence, suggesting that this could be a critical time and duration for realizing treatment benefit and patient monitoring. Findings regarding the relationship between adherence and remission can additionally help guide the design of future studies.

Protocol of the Comparison of Intravesical Therapy and Surgery as Treatment Options (CISTO) study: a pragmatic, prospective multicenter observational cohort study of recurrent high-grade non-muscle invasive bladder cancer.

BACKGROUND: Bladder cancer poses a significant public health burden, with high recurrence and progression rates in patients with non-muscle-invasive bladder cancer (NMIBC). Current treatment options include bladder-sparing therapies (BST) and radical cystectomy, both with associated risks and benefits. However, evidence supporting optimal management decisions for patients with recurrent high-grade NMIBC remains limited, leading to uncertainty for patients and clinicians. The CISTO (Comparison of Intravesical Therapy and Surgery as Treatment Options) Study aims to address this critical knowledge gap by comparing outcomes between patients undergoing BST and radical cystectomy. METHODS: The CISTO Study is a pragmatic, prospective observational cohort trial across 36 academic and community urology practices in the US. The study will enroll 572 patients with a diagnosis of recurrent high-grade NMIBC who select management with either BST or radical cystectomy. The primary outcome is health-related quality of life (QOL) at 12 months as measured with the EORTC-QLQ-C30. Secondary outcomes include bladder cancer-specific QOL, progression-free survival, cancer-specific survival, and financial toxicity. The study will also assess patient preferences for treatment outcomes. Statistical analyses will employ targeted maximum likelihood estimation (TMLE) to address treatment selection bias and confounding by indication. DISCUSSION: The CISTO Study is powered to detect clinically important differences in QOL and cancer-specific survival between the two treatment approaches. By including a diverse patient population, the study also aims to assess outcomes across the following patient characteristics: age, gender, race, burden of comorbid health conditions, cancer severity, caregiver status, social determinants of health, and rurality. Treatment outcomes may also vary by patient preferences, health literacy, and baseline QOL. The CISTO Study will fill a crucial evidence gap in the management of recurrent high-grade NMIBC, providing evidence-based guidance for patients and clinicians in choosing between BST and radical cystectomy. The CISTO study will provide an evidence-based approach to identifying the right treatment for the right patient at the right time in the challenging clinical setting of recurrent high-grade NMIBC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03933826. Registered on May 1, 2019.

How does a local instrumental variable method perform across settings with instruments of differing strengths? A simulation study and an evaluation of emergency surgery.

Local instrumental variable (LIV) approaches use continuous/multi-valued instrumental variables (IV) to generate consistent estimates of average treatment effects (ATEs) and Conditional Average Treatment Effects (CATEs). There is little evidence on how LIV approaches perform according to the strength of the IV or with different sample sizes. Our simulation study examined the performance of an LIV method, and a two-stage least squares (2SLS) approach across different sample sizes and IV strengths. We considered four 'heterogeneity' scenarios: homogeneity, overt heterogeneity (over measured covariates), essential heterogeneity (unmeasured), and overt and essential heterogeneity combined. In all scenarios, LIV reported estimates with low bias even with the smallest sample size, provided that the instrument was strong. Compared to 2SLS, LIV provided estimates for ATE and CATE with lower levels of bias and Root Mean Squared Error. With smaller sample sizes, both approaches required stronger IVs to ensure low bias. We considered both methods in evaluating emergency surgery (ES) for three acute gastrointestinal conditions. Whereas 2SLS found no differences in the effectiveness of ES according to subgroup, LIV reported that frailer patients had worse outcomes following ES. In settings with continuous IVs of moderate strength, LIV approaches are better suited than 2SLS to estimate policy-relevant treatment effect parameters.

Racial Disparities in the Ascertainment of Cancer Recurrence in Electronic Health Records.

PURPOSE: There is growing interest in using computable phenotypes or proxies to identify important clinical outcomes, such as cancer recurrence, in rich electronic health records data. However, the race/ethnicity-specific accuracies of these proxies remain unclear. We examined whether the accuracy of a proxy for colorectal cancer (CRC) recurrence differed by race/ethnicity and the possible mechanisms that drove the differences. METHODS: Using data from a large integrated health care system, we identified a stratified random sample of 282 Black/African American (AA), Hispanic, and non-Hispanic White (NHW) patients with CRC who received primary treatment. Patient 5-year recurrence status was estimated using a utilization-based proxy and evaluated against the true recurrence status obtained using detailed chart review and by race/ethnicity. We used covariate-adjusted probit regression models to estimate the associations between race/ethnicity and misclassification. RESULTS: The recurrence proxy had excellent overall accuracy (positive predictive value [PPV] 89.4%; negative predictive value 96.5%; mean difference in timing 1.96 months); however, accuracy varied by race/ethnicity. Compared with NHW patients, PPV was 14.9% lower (95% CI, 2.53 to 28.6) among Hispanic patients and 4.3% lower (95% CI, -4.8 to 14.8) among Black/AA patients. The proxy disproportionately inflated the 5-year recurrence incidence for Hispanic patients by 10.6% (95% CI, 4.2 to 18.2). Compared with NHW patients, proxy recurrences for Hispanic patients were almost three times as likely to have been misclassified as positive (adjusted risk ratio 2.91 [95% CI, 1.21 to 8.31]). Higher false positives among racial/ethnic minorities may be related to higher prevalence of noncancerous lung-related problems and substantial delays in primary treatment because of insufficient patient-provider communication and abnormal treatment patterns. CONCLUSION: Using a proxy with worse accuracy among racial/ethnic minority patients to estimate population health may misdirect resources and support erroneous conclusions around treatment benefit for these patients.

Quantifying the value of older adult-specific clinical trials: Post-lumpectomy irradiation among older adults with early-stage breast cancer.

INTRODUCTION: Although there is increasing interest in conducting cancer clinical trials in older adults, the benefit of such trials is unclear. We aimed to quantify the real-world clinical and economic effects of two phase 3 trials (CALGB 9343 and PRIME II) which showed that post-lumpectomy radiation therapy (RT) improves loco-regional recurrence but makes no improvement in overall survival among older women with early-stage breast cancer (ESBC). MATERIALS AND METHODS: We developed a health-transition model to quantify the incremental clinical and economic outcomes between scenarios with vs. without older adult-specific trial results from a societal perspective between 2004 and 2018. The transition probabilities in the model were mainly derived from the 10-year results of CALGB 9343. The total number of the affected patient population in the US and the change in the probability of omitting post-lumpectomy RT due to the CALGB 9343 and PRIME II results were derived from a retrospective analysis of the SEER registry data for patients with ESBC. Sensitivity analyses were conducted to calculate the 95% credible interval (CR) of the incremental clinical and economic outcomes between the two scenarios. RESULTS: Between 2004 and 2018, 32,936 (95% CR: 31,512, 34,357) fewer patients received post-lumpectomy RT among those aged 70 years or older diagnosed with ESBC in the US and there was a decrease cost of $419 M USD (95% CR: -$238 M, -$689 M) in scenarios with vs. without older adult-specific trial results. The difference in projected life years (1083 years, 95% CI: -2542, 7985) and QALYs (866 years, 95% CI: -2561, 7780) were not significant. At a willingness-to-pay threshold of $100 k/QALY, the probability of older adult-specific trial results generating a positive net monetary benefit was 98%. DISCUSSION: The CALGB 9343 and PRIME II trial results were associated with a substantial cost-saving in the US society. Our results suggest that older adult-specific clinical trials that demonstrate no survival benefit of an intervention in older adults could be correlated with a significant monetary benefit. Further case studies are needed for different types of older adult-specific trials to understand the value of older adult-specific trials comprehensively.

How does cumulative evidence from older adult-specific trials influence clinical practice? A difference-in-differences analysis in early-stage breast cancer.

BACKGROUND: Despite increasing focus on conducting cancer clinical trials in older adults, it is unclear whether such evidence influences practice patterns. We aimed to estimate the impact of cumulative evidence from older adult-specific trial results from the CALGB 9343 and PRIME II trials that found post-lumpectomy irradiation has little benefit among older adults with early-stage breast cancer (ESBC). METHODS: Patients diagnosed with ESBC between 2000 and 2018 were identified from the SEER registry data. We examined the incremental immediate effect, incremental average yearly effect, and cumulative effect of a series of CALGB 9343 and PRIME II results on the utilization level of post-lumpectomy irradiation. We conducted difference-in-differences analyses, comparing those aged 70 or older vs. <65 years old. RESULTS: The initial 5-year CALGB 9343 results in 2004 led to a significant immediate (-0.038, 95% CI: -0.064, -0.012) and average yearly decrease (-0.008, 95% CI: -0.013, -0.003) in the probability of irradiation use among those aged 70 or older compared to those below 65 years of age. 11-year CALGB 9343 results in 2010 significantly accelerated the average yearly effect by 1.7 percentage points (95% CI: -0.030, -0.004). The other later results did not significantly change the time trend. The cumulative effect of all results between 2004 and 2018 was -26.3 percentage points (95% CI: -0.29, -0.24). CONCLUSION: Cumulative evidence from older adult-specific trials in ESBC led to decreasing use of irradiation over time among elderly patients. The rate of decrease after the initial results was accelerated by long-term follow-up results.

Associating Health-Related Quality-of-Life Score with Time Uses to Inform Productivity Measures in Cost-Effectiveness Analysis.

BACKGROUND: The Second Panel on Cost Effectiveness in Health and Medicine recommended that cost-effectiveness analyses (CEA) explicitly incorporate the valuation of productive time from a societal perspective. We developed a new approach to capture productivity impacts in CEA without direct evidence on these impacts by associating varying levels of health-related quality-of-life (HrQoL) score with different time uses in the United States. METHODS: We conceptualized a framework that estimates the association between HrQoL score with productivity through time uses. We used the American Time-Use Survey (ATUS) from year 2012-2013, when data on a Well-Being Module (WBM) was additionally collected alongside ATUS. The WBM measured the quality of life (QoL) score using a visual analog scale. To operationalize our conceptual framework, we employed an econometric approach that addressed three technical issues in the observed data: (i) distinction between overall QoL and HrQoL, (ii) correlation across different categories of time use and the share structure of time-use data, and (iii) reverse causality between time uses and HrQoL score in a cross-sectional setting. Furthermore, we developed a metamodel-based algorithm to summarize the numerous estimates from the primary econometric model efficiently. Finally, we illustrated the use of our algorithm to calculate productivity and time spent seeking care costs in an empirical CEA of a prostate cancer treatment. RESULTS: We provide the estimates of the metamodel algorithm. Incorporating these estimates into the empirical CEA reduced the incremental cost-effectiveness ratio by 27%. CONCLUSION: Our estimates can facilitate the inclusion of productivity and time spent seeking care in CEA as recommended by the Second Panel.

Can we predict trial failure among older adult-specific clinical trials using trial-level factors?

INTRODUCTION: Conducting older adult-specific clinical trials can help overcome the lack of clinical evidence for older adults due to their underrepresentation in clinical trials. Understanding factors contributing to the successful completion of such trials can help trial sponsors and researchers prioritize studies and optimize study design. We aimed to develop a model that predicts trial failure among older adult-specific cancer clinical trials using trial-level factors. MATERIALS AND METHODS: We identified phase 2-4 interventional cancer clinical trials that ended between 2008 and 2019 and had the minimum age limit of 60 years old or older using Aggregate Analysis of ClinicalTrials.gov data. We defined trial failure as closed early for reasons other than interim results or toxicity or completed with a sample of <85% of the targeted size. Candidate trial-level predictors were identified from a literature review. We evaluated eight types of machine learning algorithms to find the best model. Model fitting and testing were performed using 5-fold nested cross-validation. We evaluated the model performance using the area under receiver operating characteristic curve (AUROC). RESULTS: Of 209 older adult-specific clinical trials, 87 were failed trials per the definition of trial failure. The model with the highest AUROC in the validation set was the least absolute shrinkage and selection operator (AUROC in the test set = 0.70; 95% confidence interval [CI]: 0.53, 0.86). Trial-level factors included in the best model were the study sponsor, the number of participating centers, the number of modalities, the level of restriction on performance score, study location, the number of arms, life expectancy restriction, and the number of target size. Among these factors, the number of centers (odds ratio [OR] = 0.83, 95% CI: 0.71, 0.94), study being in non-US only vs. US only (OR = 0.32, 95% CI: 0.12, 0.82), and life expectancy restriction (OR = 2.17, 95% CI: 1.04, 4.73) were significantly associated with the trial failure. DISCUSSION: We identified trial-level factors predictive of trial failure among older adult-specific clinical trials and developed a prediction model that can help estimate the risk of failure before a study is conducted. The study findings could aid in the design and prioritization of future older adult-specific clinical trials.

Bone marrow-derived extracellular vesicles modulate the abundance of infiltrating immune cells in the brain and exert an antiviral effect against the Japanese encephalitis virus.

Mesenchymal stem cells (MSCs) have regenerative capacity and have reported a beneficial effect on the Japanese encephalitis virus (JEV) in an encephalitis model. However, the MSCs do not cross the blood-brain barrier and have other disadvantages limiting their therapeutic utility scope. Recently, there has been a shift in concept from a cell-based to a cell-free approach using MSCs-derived extracellular vesicles (MSC-EVs). The MSC-EVs retain regenerative and immunomodulatory capacity as their parental cells. However, the role of MSC-EVs in limiting JEV pathology remains elusive. In this study, we have used Bone marrow (BM)-derived EV (BM-EVs) and assessed their effect on JEV replication and pathogenesis in primary neuronal stem cells and a murine model. The in vitro and in vivo studies suggested that BM-derived EVs delay JEV-induced symptoms and death in mice, improve the length of survival, accelerate neurogenesis in primary neuronal stem cells, reduce JEV-induced neuronal death, and attenuate viral replication. BM-EVs treatment upregulated interferon-stimulated genes. Flow cytometry analysis revealed a reduction in the frequency of macrophages. At the same time, CD4+ T cells and neutrophils were significantly augmented, accompanied by the alteration of cytokine expression with the administration of BM-EVs, reinforcing the immunomodulatory role of EVs during JEV-induced encephalitis. In conclusion, our study describes the beneficial role of BM-EVs in limiting JEV pathology by attenuating virus replication, enhancing antiviral response, and neurogenesis in primary neuronal stem cells. However, BM-EVs do not seem to protect BBB integrity and alter immune cell infiltration into the treated brain.

Does Clinical Evidence of Heterogeneity Impact Treatment Selection? A Case Study of Abiraterone for Metastatic Prostate Cancer.

BACKGROUND: Two pivotal randomized controlled trials (RCTs) demonstrate that abiraterone acetate + prednisone (AAP) combined with androgen deprivation therapy (ADT) significantly extends the survival of men with metastatic hormone-sensitive prostate cancer (mHSPC) compared with ADT alone. Their subgroup analyses indicate that the survival benefit is significant for younger men but not older men. We aimed to assess whether publication of the RCTs was associated with differential real-world AAP utilization by age groups. METHODS: Using TriNetX electronic medical records data collected from 43 healthcare organizations across the United States, we performed a difference-in-differences event study among men with newly diagnosed mHSPC observed from June 2014 to June 2019. Eligible subjects were identified based on a comprehensive published algorithm. We analyzed the change in utilization rate of AAP before versus after publication of the RCTs among men aged <70 years versus ≥70 years, adjusting for demographic factors and clinical conditions. RESULTS: Our study included 6,888 men with newly diagnosed mHSPC with 12,738 observations, of whom 46% were aged <70 years. The prepublication trends of AAP utilization were similar between the age groups, whereas publication of the RCTs was associated with a 3.5% higher adjusted uptake rate of AAP among younger men (95% CI, 1.2%-5.8%) relative to older men. This estimate reflects an uptake rate nearly 3 times higher than would have been expected had younger men followed the same utilization trends as older men. The estimates remained consistent throughout the postpublication period. CONCLUSIONS: Our study suggests that publication of the RCTs was associated with faster uptake of AAP among younger versus older men with newly diagnosed mHSPC, despite the absence of clinical guidance for differential treatment selection. This finding highlights the importance of confirmatory studies among older men, considering the uncertainties of subgroup analyses in RCTs.

Remission and Relapse of Dyslipidemia After Vertical Sleeve Gastrectomy vs Roux-en-Y Gastric Bypass in a Racially and Ethnically Diverse Population.

Importance: The comparative effectiveness of the most common operations in the long-term management of dyslipidemia is not clear. Objective: To compare 4-year outcomes associated with vertical sleeve gastrectomy (VSG) vs Roux-en-Y gastric bypass (RYGB) for remission and relapse of dyslipidemia. Design, Setting, and Participants: This retrospective comparative effectiveness study was conducted from January 1, 2009, to December 31, 2016, with follow-up until December 31, 2018. Participants included patients with dyslipidemia at the time of surgery who underwent VSG (4142 patients) or RYGB (2853 patients). Patients were part of a large integrated health care system in Southern California. Analysis was conducted from January 1, 2018, to December 31, 2021. Exposures: RYGB and VSG. Main Outcomes and Measures: Dyslipidemia remission and relapse were assessed in each year of follow-up for as long as 4 years after surgery. Results: A total of 8265 patients were included, with a mean (SD) age of 46 (11) years; 6591 (79.8%) were women, 3545 (42.9%) were Hispanic, 1468 (17.8%) were non-Hispanic Black, 2985 (36.1%) were non-Hispanic White, 267 (3.2%) were of other non-Hispanic race, and the mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) was 44 (7) at the time of surgery. Dyslipidemia outcomes at 4 years were ascertained for 2168 patients (75.9%) undergoing RYGB and 3999 (73.9%) undergoing VSG. Remission was significantly higher for those who underwent RYGB (824 [38.0%]) compared with VSG (1120 [28.0%]) (difference in the probability of remission, 0.10; 95% CI, 0.01-0.19), with no differences in relapse (455 [21.0%] vs 960 [24.0%]). Without accounting for relapse, remission of dyslipidemia after 4 years was 58.9% (1279) for those who underwent RYGB and 51.9% (2079) for those who underwent VSG. Four-year differences between operations were most pronounced for patients 65 years or older (0.39; 95% CI, 0.27-0.51), those with cardiovascular disease (0.43; 95% CI, 0.24-0.62), or non-Hispanic Black patients (0.13; 95% CI, 0.01-0.25) and White patients (0.13; 95% CI, 0.03-0.22). Conclusions and Relevance: In this large, racially and ethnically diverse cohort of patients who underwent bariatric and metabolic surgery in clinical practices, RYGB was associated with higher rates of dyslipidemia remission after 4 years compared with VSG. However, almost one-quarter of all patients experienced relapse, suggesting that patients should be monitored closely throughout their postoperative course to maximize the benefits of these operations for treatment of dyslipidemia.

A landscape analysis and discussion of value of gene therapies for sickle cell disease.

INTRODUCTION: Sickle cell disease (SCD) is a rare genetic disease with limited therapeutic options. Gene-based therapies are being investigated in clinical trials to evaluate their curative potential. The expected life-long benefits of one-time administration of genetically corrected stem cells present uncharted challenges in estimating value of these treatments. Our objective is to conduct a landscape analysis of clinical trials and prompt a discussion estimating the value of gene therapy as a therapeutic option for SCD. AREAS COVERED: We searched Clinicaltrials.gov to identify and characterize clinical trials in gene therapies for SCD. We report available results and discuss current concerns and elements of value necessary to consider as these products come to market. EXPERT OPINION: Gene therapies could represent a major advance in SCD treatment. Although clinical trials are ongoing, reports of serious adverse events have led to pause of these trials, emphasizing the need to prove long-term tolerability. Measured using the methods of health economic evaluation, we anticipate high up-front costs may be offset by potential life-long benefits of these treatments. During development and after treatment approval, attention should be focused on ensuring adequate availability and equitable access to emerging therapies in underserved areas and low-middle-income countries (LMIC).

Comparative effectiveness of gastric bypass and sleeve gastrectomy on predicted 10-year risk of cardiovascular disease 5 years after surgery.

BACKGROUND: Comparative evidence is needed when deciding which bariatric operation to undergo for long-term cardiovascular risk reduction. OBJECTIVES: The Effectiveness of Gastric Bypass vs. Gastric Sleeve for Cardiovascular Disease (ENGAGE CVD) study compared the effectiveness of vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) operations for reduction of the American College of Cardiology and the American Heart Association-predicted 10-year atherosclerotic cardiovascular disease (ASCVD) risk 5 years after surgery. SETTING: Data for this study came from a large integrated healthcare system in the Southern California region of the United States. This is one of the most ethnically diverse (64% non-White) bariatric populations in the literature. METHODS: The ENGAGE CVD cohort consisted of 22,095 patients who underwent VSG or RYGB from 2009-2016. The VSG and RYGB were compared using a local instrumental variable approach to address observed and unobserved confounding, as well as to conduct heterogeneity of treatment effects for patients of different age groups, baseline-predicted 10-year CVD risk using the ASCVD risk score, and those who had type 2 diabetes (T2D) at the time of surgery. RESULTS: Patients (2771 RYGB and 6256 VVSG) were primarily women (80.6%), Hispanic or non-Hispanic Black (63.7%), and 46 ± 10 years of age, with a body mass index of 43.40 ± 6.5 kg/m2. The predicted 10-year ASCVD risk at surgery was 4.1% for VSG and 5.1% for RYGB, decreasing to 2.6% for VSG and 2.8% for RYGB 1 year postoperatively. By 5 years after surgery, patients remained with relatively low risk levels (3.0% for VSG and 3.3% for RYGB) and there were no significant differences in predicted 10-year ASCVD risk between VSG and RYGB at any time. CONCLUSION: Predicted 10-year ASCVD risk was low in this population and remained low up to 5 years for those with diabetes, Black and Hispanic patients, and older adults. Literature reporting significant differences between VSG and RYGB in 10-year ASCVD risk may be a result of residual confounding.