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.

Understanding differences between what alternate propensity score methods estimate.

BACKGROUND: Many approaches to propensity score methods are used in the applied health economics and outcomes research literature. Often this creates confusion when different approaches produce different results for the same data. OBJECTIVE: To present a conceptual overview based on a potential outcomes framework to demonstrate how more than 1 mean treatment effect parameter can be estimated using the propensity score methods and how the selection of appropriate methods should align with the scientific questions. METHODS: We highlight that more than 1 mean treatment effect parameter can be estimated using the propensity score methods. Using the potential outcomes framework and alternate data-generating processes, we discuss under what assumptions different mean treatment effect parameter estimates are supposed to vary. We tie these discussions with propensity score methods to show that different approaches may estimate different parameters. We illustrate these methods using a case study of the comparative effectiveness of apixaban vs warfarin on the likelihood of stroke among patients with a prior diagnosis of atrial fibrillation. RESULTS: Different mean treatment effect parameters take on different values when treatment effects are heterogeneous. We show that traditional propensity score approaches, such as blocking, weighting, matching, or doubly robust, can estimate different mean treatment effect parameters. Therefore, they may not produce the same results even when applied to the same data using the same covariates. We found significant differences in our case study estimates of mean treatment effect parameters. Still, once a mean treatment effect parameter is targeted, estimates across different methods are not different. This highlights the importance of first selecting the target parameter for analysis by aligning the interpretation of the target parameter with the scientific questions and then selecting the specific method to estimate this target parameter. CONCLUSIONS: We present a conceptual overview of propensity score methods in health economics and outcomes research from a potential outcomes framework. We hope these discussions will help applied researchers choose appropriate propensity score approaches for their analysis. DISCLOSURES: Dr Unuigbe's time was supported through an unrestricted postdoctoral fellowship from Pfizer to the University of Washington, Seattle.

Short-Chain Fatty Acids in the Microbiota-Gut-Brain Axis: Role in Neurodegenerative Disorders and Viral Infections.

The gut-brain axis (GBA) is the umbrella term to include all bidirectional communication between the brain and gastrointestinal (GI) tract in the mammalian body. Evidence from over two centuries describes a significant role of GI microbiome in health and disease states of the host organism. Short-chain fatty acids (SCFAs), mainly acetate, butyrate, and propionate that are the physiological forms of acetic acid, butyric acid, and propionic acid respectively, are GI bacteria derived metabolites. SCFAs have been reported to influence cellular function in multiple neurodegenerative diseases (NDDs). In addition, the inflammation modulating properties of SCFAs make them suitable therapeutic candidates in neuroinflammatory conditions. This review provides a historical background of the GBA and current knowledge of the GI microbiome and role of individual SCFAs in central nervous system (CNS) disorders. Recently, a few reports have also identified the effects of GI metabolites in the case of viral infections. Among these viruses, the flaviviridae family is associated with neuroinflammation and deterioration of CNS functions. In this context, we additionally introduce SCFA based mechanisms in different viral pathogenesis to understand the former's potential as agents against flaviviral disease.

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.

Long-Term Survival with Sickle Cell Disease: A Nationwide Cohort Study of Medicare and Medicaid Beneficiaries.

We report the first population-based period life table, the expected lifetime survival for Medicare and Medicaid beneficiaries with Sickle Cell Disease (SCD), and the disparities in survival by insurance types in the United States. We constructed a retrospective cohort of individuals with diagnosed SCD receiving Common Care (any real-world patterns of care except transplant) based on nationwide Medicare and Medicaid claims data (2008-2016), covering beneficiaries in all 50 states. We analyzed lifetime survival probabilities using Kaplan-Meier curves and projected life expectancies at various ages for all and stratified by sex and insurance types. Our analysis included 94,616 individuals with SCD that have not undergone any transplant. Life expectancy at birth was 52.6 years (95% CI: 51.9, 53.4). Compared to the adults covered by Medicaid only, those covered by Medicare for disabilities or end-stage renal disease and those dually insured by Medicare and Medicaid had significantly worse life expectancy. Similarly, for beneficiaries aged ≥65 years, these two insurance types were associated with significantly shorter life expectancy than those enrolled in Medicare old age and survivor's insurance. Our study underscores the persistent life expectancy shortfall for SCD patients, the burden of premature mortality during adulthood, and survival disparities by insurance status.

Medicare's hospital readmissions reduction program and the rise in observation stays.

OBJECTIVE: To evaluate whether Medicare's Hospital Readmissions Reduction Program (HRRP) is associated with increased observation stay use. DATA SOURCES AND STUDY SETTING: A nationally representative sample of fee-for-service Medicare claims, January 2009-September 2016. STUDY DESIGN: Using a difference-in-difference (DID) design, we modeled changes in observation stays as a proportion of total hospitalizations, separately comparing the initial (acute myocardial infarction, pneumonia, heart failure) and subsequent (chronic obstructive pulmonary disease) target conditions with a control group of nontarget conditions. Each model used 3 time periods: baseline (15 months before program announcement), an intervening period between announcement and implementation, and a 2-year post-implementation period, with specific dates defined by HRRP policies. DATA COLLECTION/EXTRACTION METHODS: We derived a 20% random sample of all hospitalizations for beneficiaries continuously enrolled for 12 months before hospitalization (N = 7,162,189). PRINCIPAL FINDINGS: Observation stays increased similarly for the initial HRRP target and nontarget conditions in the intervening period (0.01% points per month [95% CI -0.01, 0.3]). Post-implementation, observation stays increased significantly more for target versus nontarget conditions, but the difference is quite small (0.02% points per month [95% CI 0.002, 0.04]). Results for the COPD analysis were statistically insignificant in both policy periods. CONCLUSIONS: The increase in observation stays is likely due to other factors, including audit activity and clinical advances.

A Framework for a Health Economic Evaluation Model for Patients with Sickle Cell Disease to Estimate the Value of New Treatments in the United States of America.

BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder associated with lifelong morbidity and increased risk of mortality that affects approximately 100,000 individuals in the United States (US), primarily of African-American descent. Due to these complications, individuals with SCD typically incur high healthcare costs. With a number of costly but potentially curative SCD therapies on the horizon, understanding the progression of SCD and economic burden to insurers and patients is vital. OBJECTIVE: The aim is to develop a framework to understand the progression and costs of SCD that could be used to estimate how new treatments can impact the progression and costs of the disease. METHODS: We detail how we will create a simulation model that represents the natural history of a population and allows for the characterization of the impact of novel therapies on the disease, associated costs, and outcomes in comparison to current management. CONCLUSION: In this report, we describe a conceptual approach to modeling SCD to determine the relative clinical and economic impact of new gene therapies compared to conventional therapies with a goal of providing a flexible approach that could inform the clinical management of SCD for patients, payers, and policy makers.

Emerging pediatric visceral leishmaniasis in Kashmir valley: A report of three cases.

Visceral leishmaniasis is the most severe form of leishmaniasis. There has been an increase in number of cases in the sub-Himalayan regions of India in the past few years. Here we present three pediatric cases diagnosed with visceral leishmaniasis from the region.

Real-world calibration and transportability of the Disease Recovery Evaluation and Modification (DREaM) randomized clinical trial in adult Medicaid beneficiaries with recent-onset schizophrenia.

BACKGROUND: The Disease Recovery Evaluation and Modification study (DREaM; NCT02431702) assessed the benefit of initiating paliperidone palmitate (PP), a long-acting injectable antipsychotic, in patients with recent-onset schizophrenia or schizophreniform disorder. OBJECTIVE: To determine whether reductions in psychiatric hospitalizations with early initiation of PP vs oral antipsychotic (OAP) therapy observed in a DREaM post hoc analysis are transportable to a real-world population of patients with recent-onset schizophrenia. METHODS: Patients enrolled in DREaM were randomized to receive OAP or PP for 9 months, after which OAP recipients were re-randomized to receive OAP or PP for another 9 months. We used this design to form treatment arms: OAP-OAP, OAP-PP, and PP-PP. Inclusion/exclusion criteria were used to identify a Medicaid Managed Care (MMC) OAP-treated cohort of 1,000 patients diagnosed with schizophrenia using IBM Truven databases from 2015 to 2019. The MMC cohort was combined with the subset of patients diagnosed with schizophrenia enrolled in DREaM from US sites (N = 45, 43, and 44 for OAP-OAP, OAP-PP, and PP-PP, respectively). Propensity scores for the MMC cohort were estimated using baseline variables identified via double-lasso regression. Estimated propensity scores were used to weight psychiatric hospitalizations in the DREaM OAP-OAP group and compared with observed MMC OAP cohort psychiatric hospitalizations. After the successful calibration of the DREaM OAP-OAP group, similar approaches were taken for the OAP-PP and PP-PP groups to transport DREaM effects to MMC data. RESULTS: Standardized mean differences in baseline covariates between DREaM treatment arms and MMC groups were substantially reduced after calibration. The 18-month cumulative numbers of psychiatric hospitalizations per patient (SE) were 0.83 (0.14) for the MMC cohort, 0.43 (0.14) for the unweighted OAP-OAP, and 0.80 (0.37) for the calibrated OAP-OAP. The difference between the calibrated OAP-OAP and MMC was not statistically significant (difference, 0.03 [95% CI = -0.67 to 0.81]), indicating successful calibration. The mean difference in 18-month cumulative psychiatric hospitalizations relative to the MMC cohort was -0.77 (95% CI = -1.08 to -0.47) for OAP-PP and -0.83 (95% CI = -1.15 to -0.60) for PP-PP. CONCLUSIONS: Our study demonstrates that results from the DREaM OAP-OAP group reflect psychiatric hospitalizations in a real-world population when calibrated using specific baseline characteristics. Transporting the DREaM effects, we find that using OAP-PP and PP-PP treatment strategies for patients with recent-onset schizophrenia in the MMC population could reduce psychiatric hospitalizations compared with the use of OAP. These findings, along with the potential reduction in associated costs, should be considered when assessing the value of PP formulations. DISCLOSURES: Dr Basu reports consulting fees through Salutis Consulting LLC related to this work. Dr Mavros is a former employee of the Janssen Pharmaceutical Companies of Johnson & Johnson, Inc, and holds stock in the company. Ms Benson, Dr Fu, Ms Patel, and Dr Brown are employees of Janssen Scientific Affairs, LLC, and hold stock in Johnson & Johnson. This research was funded by Janssen Scientific Affairs, LLC. The sponsor was involved in the study design; collection, analysis, and interpretation of data; and development and review of the manuscript. All authors had full access to the study data and take responsibility for data integrity and the accuracy of the analyses. All authors provided direction and comments on the manuscript, reviewed and approved the final version prior to submission, made the final decision about where to publish these data, and approved submission to this journal.

Evaluation of a Health Information Exchange for Linkage to Mental Health Care After an Emergency Department Visit.

Aligning with Washington State's goal of reducing unnecessary emergency department (ED) use and improving linkage to outpatient primary and behavioral health care, this study evaluated whether an Emergency Department Information Exchange (EDIE) improved linkage to care for Medicaid enrollees with mental health conditions. Follow-up with any physician at 30 days increased slightly, although mental health-specific follow-up declined over time. Difference-in-differences estimates revealed no effect of EDIE on linkage to care after an ED visit. Medicaid beneficiaries with mental health needs and high utilization of the ED likely require additional support to increase timely and appropriate follow-up care.

Mimicking Clinical Trials Using Real-World Data: A Novel Method and Applications.

INTRODUCTION: Simulating individual-level trial data when only summary data are available is often useful for meta-analysis, forming external control arms and calibrating trial results to real-world data (RWD). The joint distribution of baseline characteristics in a trial is usually simulated by combining its summary data with RWD's correlations. However, RWD correlations may not be a perfect proxy for the trial. A misspecified correlation structure could bias any analysis in which the outcomes generating models are nonlinear or include effect modifiers. METHODS: We developed an iterative algorithm using copula and resampling, which was based on the estimated propensity score for the likelihood of enrollment in a trial given participants' characteristics. Validation was performed using Monte Carlo simulations under different scenarios in which the marginal and joint distributions of covariates differ between trial samples and RWD. Two applications were illustrated using an actual trial and the Surveillance, Epidemiology, and End Results-Medicare data. We calculated the standardized mean difference (SMD) to assess the generalizability of the trial and explored the feasibility of generating an external control by applying a parametric Weibull model trained in RWD to predict survival in the simulated trial cohort. RESULTS: Across all scenarios, approximated correlations derived from the algorithm were closer to the true correlations than the RWD's correlations. The algorithm also successfully reproduced the joint distribution of characteristics for the actual trial. A similar SMD was observed using simulated data and individual-level trial data. The 95% confidence intervals were overlapped between adjusted survival estimates from the simulated trial and actual trial Kaplan-Meier estimates. CONCLUSIONS: The algorithm could be a feasible way to simulate individual-level data when only summary data are available. Further research is needed to validate our approach with larger sample sizes. HIGHLIGHTS: The correlation structure is crucial to building the joint distribution of patient characteristics, and a misspecified correlation structure could potentially influence predicted outcomes.An iterative algorithm was developed to approximate a trial's correlation structure using published summary trial data and real-world data.The algorithm could be a feasible way to simulate individual-level trial data when only trial summary data are available.

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.

Accounting for the Growth of Observation Stays in the Assessment of Medicare's Hospital Readmissions Reduction Program.

Importance: Decreases in 30-day readmissions following the implementation of the Medicare Hospital Readmissions Reduction Program (HRRP) have occurred against the backdrop of increasing hospital observation stay use, yet observation stays are not captured in readmission measures. Objective: To examine whether the HRRP was associated with decreases in 30-day readmissions after accounting for observation stays. Design, Setting, and Participants: This retrospective cohort study included a 20% sample of inpatient admissions and observation stays among Medicare fee-for-service beneficiaries from January 1, 2009, to December 31, 2015. Data analysis was performed from November 2021 to June 2022. A differences-in-differences analysis assessed changes in 30-day readmissions after the announcement of the HRRP and implementation of penalties for target conditions (heart failure, acute myocardial infarction, and pneumonia) vs nontarget conditions under scenarios that excluded and included observation stays. Main Outcomes and Measures: Thirty-day inpatient admissions and observation stays. Results: The study included 8 944 295 hospitalizations (mean [SD] age, 78.7 [8.2] years; 58.6% were female; 1.3% Asian; 10.0% Black; 2.0% Hispanic; 0.5% North American Native; 85.0% White; and 1.2% other or unknown). Observation stays increased from 2.3% to 4.4% (91.3% relative increase) of index hospitalizations among target conditions and 14.1% to 21.3% (51.1% relative increase) of index hospitalizations for nontarget conditions. Readmission rates decreased significantly after the announcement of the HRRP and returned to baseline by the time penalties were implemented for both target and nontarget conditions regardless of whether observation stays were included. When only inpatient hospitalizations were counted, decreasing readmissions accrued into a -1.48 percentage point (95% CI, -1.65 to -1.31 percentage points) absolute reduction in readmission rates by the postpenalty period for target conditions and -1.13 percentage point (95% CI, -1.30 to -0.96 percentage points) absolute reduction in readmission rates by the postpenalty period for nontarget conditions. This reduction corresponded to a statistically significant differential change of -0.35 percentage points (95% CI, -0.59 to -0.11 percentage points). Accounting for observation stays more than halved the absolute decrease in readmission rates for target conditions (-0.66 percentage points; 95% CI, -0.83 to -0.49 percentage points). Nontarget conditions showed an overall greater decrease during the same period (-0.76 percentage points; 95% CI, -0.92 to -0.59 percentage points), corresponding to a differential change in readmission rates of 0.10 percentage points (95% CI, -0.14 to 0.33 percentage points) that was not statistically significant. Conclusions and Relevance: The findings of this study suggest that the reduction of readmissions associated with the implementation of the HRRP was smaller than originally reported. More than half of the decrease in readmissions for target conditions appears to be attributable to the reclassification of inpatient admission to observation stays.

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.

Prevalence of comorbidities associated with sickle cell disease among non-elderly individuals with commercial insurance-A retrospective cohort study.

Sickle cell disease (SCD) is a severe monogenic disease associated with high morbidity and mortality and a disproportionate burden on Black communities. Few population-based studies have examined the prevalence of comorbidities among persons with SCD. We estimated the prevalence of comorbidities experienced by individuals with SCD enrolled in employer-based health insurance plans in the US over their non-elderly lifetimes (0-64 years of age) with a retrospective cohort design using Truven Health MarketScan commercial claims data from 2007-2018. ICD-9/10 codes were used to identify individuals with SCD using a previously published algorithm. For this cohort, comorbidities associated with SCD were identified across 3 age categories (<18, 18-45, 46-64 years-old), based on the CMS Chronic Comorbidities Warehouse or SCD-specific diagnosis codes, when applicable. The total number of SCD patients available for analysis in each age category was 7,502 (<18 years), 10,183 (18-45 years) and 4,459 (46-64 years). Across all ages, vaso-occlusive pain, infections (non-specific), and fever were the most common comorbidities. Vaso-occlusive pain and infection were the most prevalent conditions for persons age <18- and 18-45-year-olds, while in the 46-54-year-old age group, infection and cardiovascular including pulmonary hypertension were most prevalent. Compared to persons <18 years old, the prevalence of vaso-occlusive pain, fever, and acute chest syndrome claims declined in older populations. The comorbidity burden of SCD is significant across all age groups. SCD patients experience comorbidities of age such as chronic pain, cardio-vascular conditions including pulmonary hypertension and renal disease at far higher rates than the general population. Novel disease modifying therapies in development have the potential to significantly reduce the comorbidity burden of SCD.

Involvement of host microRNAs in flavivirus-induced neuropathology: An update.

Flaviviruses are a spectrum of vector-borne RNA viruses that cause potentially severe diseases in humans including encephalitis, acute-flaccid paralysis, cognitive disorders and foetal abnormalities. Japanese encephalitis virus (JEV), Zika virus (ZIKV), West Nile virus (WNV) and Dengue virus (DENV) are globally emerging pathogens that lead to epidemics and outbreaks with continued transmission to newer geographical areas over time. In the past decade, studies have focussed on understanding the pathogenic mechanisms of these viruses in a bid to alleviate their disease burden. MicroRNAs (miRNAs) are short single-stranded RNAs that have emerged as master-regulators of cellular gene expression. The dynamics of miRNAs within a cell have the capacity to modulate hundreds of genes and, consequently, their physiological manifestation. Increasing evidence suggests their role in host response to disease and infection including cell survival, intracellular viral replication and immune activation. In this review, we aim to comprehensively update published evidence on the role of miRNAs in host cells infected with the common neurotropic flaviviruses, with an increased focus on neuropathogenic mechanisms. In addition, we briefly cover therapeutic advancements made in the context of miRNA-based antiviral strategies.

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.