The effectiveness of a protocol without routine radiographs for follow-up of adolescent idiopathic scoliosis patients (CURVE): a study protocol.

BACKGROUND AND PURPOSE: Current follow-up protocols for adolescent idiopathic scoliosis (AIS) are based on consensus and consist of regular full-spine radiographs to monitor curve progression and surgical complications. Consensus exists to avoid inappropriate use of radiographs in children. It is unknown whether a standard radiologic follow-up (S-FU) approach is necessary or if a patient-empowered follow-up (PE-FU) approach can reduce the number of radiographs without treatment consequences. METHODS AND ANALYSES: A nationwide multicenter pragmatic randomized preference trial was designed for 3 follow-up subgroups (pre-treatment, post-brace, post-surgery) to compare PE-FU and S-FU. 812 patients with AIS (age 10-18 years) will be included in the randomized trial or preference cohorts. Primary outcome is the proportion of radiographs with a treatment consequence for each subgroup. Secondary outcomes consist of the proportion of patients with delayed initiation of treatment due to non-routine radiographic follow-up, radiation exposure, societal costs, positive predictive value, and interrelation of clinical assessment, quality of life, and parameters for initiation of treatment during follow-up. Outcomes will be analyzed using linear mixed-effects models, adjusted for relevant baseline covariates, and are based on intention-to-treat principle. Study summary: (i) a national, multicenter pragmatic randomized trial addressing the optimal frequency of radiographic follow-up in patients with AIS; (ii) first study that includes patient-empowered follow-up; (iii) an inclusive study with 3 follow-up subgroups and few exclusion criteria representative for clinical reality; (iv) preference cohorts alongside to amplify generalizability; (v) first study conducting an economic evaluation comparing both follow-up approaches.

Cost-effectiveness of the McGill interactive pediatric oncogenetic guidelines in identifying Li-Fraumeni syndrome in female patients with osteosarcoma.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a penetrant cancer predisposition syndrome (CPS) associated with the development of many tumor types in young people including osteosarcoma and breast cancer (BC). The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) decision-support tool provides a standardized approach to identify patients at risk of CPSs. METHODS: We conducted a cost-utility analysis, from the healthcare payer perspective, to compare MIPOGG-guided, physician-guided, and universal genetic testing strategies to detect LFS in female patients diagnosed at an age of less than 18 years with osteosarcoma. We developed a decision tree and discrete-event simulation model to simulate the clinical and cost outcomes of the three genetic referral strategies on a cohort of female children diagnosed with osteosarcoma, especially focused on BC as subsequent cancer. Outcomes included BC incidence, quality-adjusted life-years (QALYs), healthcare costs, and incremental cost-utility ratios (ICURs). We conducted probabilistic and scenario analyses to assess the uncertainty surrounding model parameters. RESULTS: Compared to the physician-guided testing, the MIPOGG-guided strategy was marginally more expensive by $105 (-$516; $743), but slightly more effective by 0.003 (-0.04; 0.045) QALYs. Compared to MIPOGG, the universal testing strategy was $1333 ($732; $1953) more costly and associated with 0.011 (-0.043; 0.064) additional QALYs. The ICUR for the MIPOGG strategy was $33,947/QALY when compared to the physician strategy; the ICUR for universal testing strategy was $118,631/QALY when compared to the MIPOGG strategy. DISCUSSION: This study provides evidence for clinical and policy decision-making on the cost-effectiveness of genetic referral strategies to identify LFS in the setting of osteosarcoma. MIPOGG-guided strategy was most likely to be cost-effective at a willingness-to-pay threshold value of $50,000/QALY.

Building a New Generation of Public Health Leaders Forged in a Public Health Crisis.

The COVID-19 pandemic presented wide-ranging leadership challenges to public health leaders and public health organizations. In its wake, as the necessity of reconstructing public health and modernizing the Centers for Disease Control and Prevention (CDC) is considered, we reviewed reports from the Commonwealth Fund and the CDC and other leadership-focused literature to identify common themes for a new generation of public health leaders. We posit that this new generation must have the ability to communicate (build and maintain trust and accountability); forge, facilitate, and promote partnerships; connect public health and health care systems; build information systems that provide accessible, actionable data; engage in systems and strategic thinking and action; center equity and inclusivity and understand structural racism as a fundamental driver and creator of health inequities; and achieve and maintain resilience and self-care. For each of the 7 abilities, we offer a description, assess what COVID-19 taught us about the necessity of the ability for public health leaders, and offer suggestions for developing (or honing) one's skill set, mindset, and tool set in this regard. (Am J Public Health. 2024;114(6):626-632. https://doi.org/10.2105/AJPH.2024.307633).

Financial hardship and neighborhood socioeconomic disadvantage in long-term childhood cancer survivors.

BACKGROUND: Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships. METHODS: We performed a cross-sectional analysis of data from the Childhood Cancer Survivor Study between 1970 and 1999 and self-reported financial information from 2017 to 2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material and financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear models estimated effect sizes between ADI and financial hardship adjusting for clinical factors and personal socioeconomic status. RESULTS: Analysis was restricted to 3475 long-term childhood cancer survivors and 923 sibling controls. Median ages at time of evaluation was 39 years (interquartile range [IQR] = 33-46 years and 47 years (IQR = 39-59 years), respectively. Survivors resided in areas with greater deprivation (ADI ≥ 50: 38.7% survivors vs 31.8% siblings; P < .001). One quintile increases in deprivation were associated with small increases in behavioral (second quintile, P = .017) and psychological financial hardship (second quintile, P = .009; third quintile, P = .014). Lower psychological financial hardship was associated with individual factors including greater household income (≥$60 000 income, P < .001) and being single (P = .048). CONCLUSIONS: Childhood cancer survivors were more likely to live in areas with socioeconomic deprivation. Neighborhood-level disadvantage and personal socioeconomic circumstances should be evaluated when trying to assist childhood cancer survivors with financial hardships.

The continued financial effect of COVID: Increasing costs for non-elective major lower extremity amputations.

Background: The COVID-19 pandemic necessitated changes in processes of care, which significantly impacted surgical care. This study evaluated the impact of these changes on patient outcomes and costs for non-elective major lower extremity amputations (LEA). Methods: The 2019-2021 Florida Agency for Health Care Administration database was queried for adult patients who underwent non-elective major LEA. Per-patient inflation-adjusted costs were collected. Patient cohorts were established based on Florida COVID-19 mortality rates: COVID-heavy (CH) included nine months with the highest mortality, COVID-light (CL) included nine months with the lowest mortality, and pre-COVID (PC) included nine months before COVID (2019). Outcomes included in-hospital patient outcomes and hospitalization cost. Results: 6132 patients were included (1957 PC, 2104 CH, and 2071 CL). Compared to PC, there was increased patient acuity at presentation, but morbidity (31%), mortality (4%), and length of stay (median 12 [8-17] days) were unchanged during CH and CL. Additionally, costs significantly increased during the pandemic; median total cost rose 9%, room costs increased by 16%, ICU costs rose by 15%, and operating room costs rose by 15%. When COVID-positive patients were excluded, cost of care was still significantly higher during CH and CL. Conclusions: Despite maintaining pre-pandemic standards, as evidenced by unchanged outcomes, the pandemic led to increased costs for patients undergoing non-elective major LEA. This was likely due to increased patient acuity, resource strain, and supply chain shortages during the pandemic. Key message: While patient outcomes for non-elective major lower extremity amputations remained consistent during the COVID-19 pandemic, healthcare costs significantly increased, likely due to increased patient acuity and heightened pressures on resources and supply chains. These findings underscore the need for informed policy changes to mitigate the financial impact on patients and healthcare systems for future public health emergencies.

Assessment of complementary health approaches use in pediatric oncology: Modification and preliminary validation of the "Which Health Approaches and Treatments Are You Using?" (WHAT) questionnaires.

OBJECTIVE: Complementary Health Approaches (CHA) are commonly used by children with cancer; however, a few health care providers (HCPs) inquire about the use of CHA. A standardized questionnaire could facilitate such clinical discussions. We aimed to adapt and determine the face and content validity of the "Which Health Approaches and Treatments are you using?" (WHAT) child and parent-report questionnaires in pediatric oncology. METHODS: An electronic Delphi survey that included children with cancer (8-18 years), parents, and HCPs and CHA researchers was conducted to reach consensus on the content of the WHAT questionnaires in pediatric oncology. Children and parents from the Hospital for Sick Children (SickKids), and HCPs and researchers from the International Society of Pediatric Oncology and Pediatric Complementary and Alternative Medicine Research and Education Network completed the survey. To determine the face and content validity of the questionnaires, two iterative cycles of individual interviews were conducted with purposive samples of children (8-18 years), parents, and HCPs from SickKids. RESULTS: Consensus was reached on all domains and items of the original WHAT questionnaires after one Delphi cycle (n = 61). For face and content validity testing, the first cycle of interviews (n = 19) revealed that the questionnaires were mostly comprehensive and relevant. However, the paper-based format of the original WHAT was not user-friendly, and generic items were vague and not aimed at facilitating clinical dialogues about CHA use. The WHAT questionnaires were then modified into electronic cancer-specific self- and proxy-report questionnaires including 13 and 15 items, respectively. The second cycle (n = 21) showed no need for further changes. CONCLUSIONS: The modified electronic cancer-specific WHAT questionnaires showed adequate face and content validity. The next step is to determine inter-rater reliability, construct validity, and feasibility of administration of the modified WHAT questionnaires in pediatric oncology.

Engagement of private health care facilities in TB management in Lusaka district of Zambia: lessons learned and achievements.

BACKGROUND: Globally, at least 3 million TB patients are missed every year. In Zambia, the TB treatment coverage increased from 66% in 2020 to 92% in 2022. Involvement of all levels of health care service delivery is critical to finding all the missing TB patients. METHODS: A survey was undertaken in 15 private facilities in Lusaka district of Zambia using a structured tool administered by project team and a district health team member. Data collected during the survey was analysed and results were used to determine the type of TB services that were offered as well as barriers and enablers to TB service provision. This was followed by a set of interventions that included; training and mentorship on active case finding and systematic TB screening, increased diagnostic capacity, provision of national recording and reporting tools and provision of TB medication through linkage with the National TB program (NTP). We report findings from the baseline survey and changes in presumptive TB identification and notification following interventions. RESULTS: Major barriers to TB service delivery were the high cost of TB diagnostic testing and treatment in facilities where services were not supported by the National TB program; the mean cost was 33 (SD 33) and 93 (SD 148) for GeneXpert testing and a full course of treatment respectively. Pre-intervention, presumptive TB identification appeared to increase monthly by 4 (P = 0.000, CI=[3.00-5.00]). The monthly trends of presumptive TB identification during the intervention period increased by 5.32 (P = 0.000, [CI 4.31-6.33. Pre-intervention, the notification of TB appeared to decrease every month by -4.0 (P = 0.114, CI=[-9.00-0.10]) followed by an immediate increase in notifications of 13.94 TB patients (P = 0.001, CI [6.51, 21.36] in the first month on intervention. The monthly trends of notification during the intervention period changed by 0.34 (P = 0.000 [CI 0.19-0.48]). Private facility contribution to TB notification increased from 3 to 7%. CONCLUSION: Engagement and inclusion of private health facilities in TB service provision through a systems strengthening approach can increase contribution to TB notification by private health facilities.

Variant functional assessment in Drosophila by overexpression: what can we learn?

The last decade has been highlighted by the increased use of next-generation DNA sequencing technology to identify novel human disease genes. A critical downstream part of this process is assigning function to a candidate gene variant. Functional studies in Drosophila melanogaster, the common fruit fly, have made a prominent contribution in annotating variant impact in an in vivo system. The use of patient-derived knock-in flies or rescue-based, "humanization", approaches are novel and valuable strategies in variant testing but have been recently widely reviewed. An often-overlooked strategy for determining variant impact has been GAL4/upstream activation sequence-mediated tissue-defined overexpression in Drosophila. This mini-review will summarize the recent contribution of ectopic overexpression of human reference and variant cDNA in Drosophila to assess variant function, interpret the consequence of the variant, and in some cases infer biological mechanisms.

Protocol for the ONLOOP trial: pragmatic randomized trial evaluating a province-wide system of personalized reminders for evidence-based surveillance tests in adult survivors of childhood cancer in Ontario.

BACKGROUND: Childhood cancer treatment while often curative, leads to elevated risks of morbidity and mortality. Survivors require lifelong periodic surveillance for late effects of treatment, yet adherence to guideline-recommended tests is suboptimal. We created ONLOOP to provide adult survivors of childhood cancer with detailed health information, including summaries of their childhood cancer treatment and recommended surveillance tests for early detection of cardiomyopathy, breast cancer, and/or colorectal cancer, with personalized reminders over time. METHODS: This is an individually randomized, registry-based pragmatic trial with an embedded process and economic evaluation to understand ONLOOP's impact and whether it can be readily implemented at scale. All adult survivors of childhood cancer in Ontario overdue for guideline-recommended tests will be randomly assigned to one of two arms: (1) intervention or (2) delayed intervention. A letter of information and invitation will detail the ONLOOP program. Those who sign up will receive a personalized toolkit and a screening reminder 6 months later. With the participants' consent, ONLOOP will also send their primary care clinician a letter detailing the recommended tests and a reminder 6 months later. The primary outcome will be the proportion of survivors who complete one or more of the guideline-recommended cardiac, breast, or colon surveillance tests during the 12 months after randomization. Data will be obtained from administrative databases. The intent-to-treat principle will be followed. Based on our analyses of administrative data, we anticipate allocating at least 862 individuals to each trial arm, providing 90% power to detect an absolute increase of 6% in targeted surveillance tests completed. We will interview childhood cancer survivors and family physicians in an embedded process evaluation to examine why and how ONLOOP achieved success or failed. A cost-effectiveness evaluation will be performed. DISCUSSION: The results of this study will determine if ONLOOP is effective at helping adult survivors of childhood cancer complete their recommended surveillance tests. This study will also inform ongoing provincial programs for this high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov NCT05832138.

Utility of apical four-chamber longitudinal strain in the assessment of childhood cancer survivors: A multicenter study.

BACKGROUND: A previous multicenter study showed that longitudinal changes in standard cardiac functional parameters were associated with the development of cardiomyopathy in childhood cancer survivors (CCS). Evaluation of the relationship between global longitudinal strain (GLS) changes and cardiomyopathy risk was limited, largely due to lack of quality apical 2- and 3-chamber views in addition to 4-chamber view. We sought to determine whether apical 4-chamber longitudinal strain (A4LS) alone can serve as a suitable surrogate for GLS in this population. METHODS: A4LS and GLS were measured in echocardiograms with acceptable apical 2-, 3-, and 4-chamber views. Correlation was evaluated using Pearson and Spearman coefficients, and agreement was evaluated with Bland-Altman plots. The ability of A4LS to identify normal and abnormal values compared to GLS as the reference was evaluated. RESULTS: Among a total of 632 reviewed echocardiograms, we identified 130 echocardiograms from 56 patients with adequate views (38% female; mean age at cancer diagnosis 8.3 years; mean follow-up 9.4 years). Correlation coefficients between A4LS and GLS were .89 (Pearson) and .85 (Spearman), with Bland-Altman plot of GLS-A4LS showing a mean difference of -.71 ± 1.8. Compared with GLS as the gold standard, A4LS had a sensitivity of 86% (95% CI 79%-93%) and specificity of 82% (69%-95%) when using normal range cutoffs and 90% (82%-97%) and 70% (58%-81%) when using ±2 standard deviations. CONCLUSION: A4LS performs well when compared with GLS in this population. Given the more recent adoption of apical 2- and 3-chamber views in most pediatric echocardiography laboratories, A4LS is a reasonable stand-alone measurement in retrospective analyses of older study cohorts and echocardiogram biorepositories.

The downtrending cost of robotic bariatric surgery: a cost analysis of 47,788 bariatric patients.

The surgical robot is assumed to be a fixed, indirect cost. We hypothesized rising volume of robotic bariatric procedures would decrease cost per patient over time. Patients who underwent elective, initial gastric bypass (GB) or sleeve gastrectomy (SG) for morbid obesity were selected from Florida Agency for Health Care Administration database from 2017 to 2021. Inflation-adjusted cost per patient was collected. Cost-over-time ($/patient year) and change in cost-over-time were calculated for open, laparoscopic, and robotic cases. Linear regression on cost generated predictive parameters. Density plots utilizing area under the curve demonstrated cost overlap. Among 76 hospitals, 11,472 bypasses (223 open, 6885 laparoscopic, 4364 robotic) and 36,316 sleeves (26,596 laparoscopic, 9724 robotic) were included. Total cost for robotic was approximately 1.5-fold higher (p < 0.001) than laparoscopic for both procedures. For GB, laparoscopic had lower total ($15,520) and operative ($6497) average cost compared to open (total $17,779; operative $9273) and robotic (total $21,756; operative $10,896). For SG, laparoscopic total cost was significantly less than robotic ($10,691 vs. $16,393). Robotic GB cost-over-time increased until 2021, when there was a large decrease in cost (-$944, compared with 2020). Robotic SG total cost-over time fluctuated, but decreased significantly in 2021 (-$490 compared with 2020). While surgical costs rose significantly in 2020 for bariatric procedures, our study suggests a possible downward trend in robotic bariatric surgery as total and operative costs are decreasing at a higher rate than laparoscopic costs.

Incidence, Risk Factors, and Outcomes Associated With Permanent Pacemaker Implantation Following Tricuspid Valve Surgery.

BACKGROUND: Data regarding permanent pacemaker (PPM) implantation following tricuspid valve surgery (TVS) are limited. We sought to evaluate its incidence, risk factors, and outcomes. METHODS AND RESULTS: Medicare beneficiaries who underwent TVS from 2013 to 2020 were identified. Patients who underwent TVS for endocarditis were excluded. The primary exposure of interest was new PPM after TVS. Outcomes included all-cause mortality and readmission with endocarditis or heart failure on follow-up. Among the 13 294 patients who underwent TVS, 2518 (18.9%) required PPM placement. Risk factors included female sex (relative risk [RR], 1.26 [95% CI, 1.17-1.36], P<0.0001), prior sternotomy (RR, 1.12 [95% CI, 1.02-1.23], P=0.02), preoperative second-degree heart block (RR, 2.20 [95% CI, 1.81-2.69], P<0.0001), right bundle-branch block (RR, 1.21 [95% CI, 1.03-1.41], P=0.019), bifascicular block (RR, 1.43 [95% CI, 1.06-1.93], P=0.02), and prior malignancy (RR, 1.23 [95% CI, 1.01-1.49], P=0.04). Tricuspid valve (TV) replacement was associated with a significantly higher risk of PPM implantation when compared with TV repair (RR, 3.20 [95% CI, 2.16-4.75], P<0.0001). After a median follow-up of 3.1 years, mortality was not different in patients who received PPM compared with patients who did not (hazard ratio [HR], 1.02 [95% CI, 0.93-1.12], P=0.7). PPM placement was not associated with a higher risk of endocarditis but was associated with a higher risk of heart failure readmission (HR, 1.28 [95% CI, 1.14-1.43], P<0.001). CONCLUSIONS: PPM implantation frequently occurs after TVS, notably in female patients and patients undergoing TV replacement. Although mortality is not increased, it is associated with higher rates of heart failure rehospitalization.

A Medicare Physician Fee Schedule Analysis of Reimbursement Trends in Laryngology from 2000 to 2021.

OBJECTIVE: The purpose of this study is to characterize Medicare reimbursement trends for laryngology procedures over the last two decades. METHODS: This analysis used CMS' Physician Fee Schedule (PFS) Look-Up Tool to determine the reimbursement rate of 48 common laryngology procedures, which were divided into four groups based on their practice setting and clinical use: office-based, airway, voice disorders, and dysphagia. The PFS reports the physician service reimbursement for "facilities" and global reimbursement for "non-facilities". The annual reimbursement rate for each procedure was averaged across all localities and adjusted for inflation. The compound annual growth rate (CAGR) of each procedure's reimbursement was determined, and a weighted average of the CAGR for each group of procedures was calculated using each procedure's 2020 Medicare Part B utilization. RESULTS: Reimbursement for laryngology procedure (CPT) codes has declined over the last two decades. In facilities, the weighted average CAGR for office-based procedures was -2.0%, for airway procedures was -2.2%, for voice disorders procedures was -1.4%, and for dysphagia procedures was -1.7%. In non-facilities, the weighted average CAGR for office-based procedures was -0.9%. The procedures in the other procedure groups did not have a corresponding non-facility reimbursement rate. CONCLUSION: Like other otolaryngology subspecialties, inflation-adjusted reimbursements for common laryngology procedures have decreased substantially over the past two decades. Because of the large number of physician participants and patient enrollees in the Medicare programs, increased awareness and further research into the implications of these trends on patient care is necessary to ensure quality in the delivery of laryngology care. LEVEL OF EVIDENCE: NA Laryngoscope, 134:247-256, 2024.

Job lock among survivors of childhood cancer and their spouses post Affordable Care Act implementation: A Childhood Cancer Survivor Study brief report.

It is unknown how common job lock (i.e., staying at job to maintain health insurance) remains among childhood cancer survivors after Affordable Care Act (ACA) implementation in 2010. We examined prevalence of and factors associated with job lock using a cross-sectional survey from the Childhood Cancer Survivor Study (3503 survivors; 942 siblings). Survivor, spousal, and any survivor/spouse job lock were more frequently reported by survivors than siblings. Survivor job lock/any job lock was associated with older age, low income, severe chronic conditions, and debt/inability to pay debt. Job lock remains more common among survivors than siblings after ACA implementation.

Evaluation of Flexible Parametric Relative Survival Approaches for Enforcing Long-Term Constraints When Extrapolating All-Cause Survival.

OBJECTIVES: Parametric models are used to estimate the lifetime benefit of an intervention beyond the range of trial follow-up. Recent recommendations have suggested more flexible survival approaches and the use of external data when extrapolating. Both of these can be realized by using flexible parametric relative survival modeling. The overall aim of this article is to introduce and contrast various approaches for applying constraints on the long-term disease-related (excess) mortality including cure models and evaluate the consequent implications for extrapolation. METHODS: We describe flexible parametric relative survival modeling approaches. We then introduce various options for constraining the long-term excess mortality and compare the performance of each method in simulated data. These methods include fitting a standard flexible parametric relative survival model, enforcing statistical cure, and forcing the long-term excess mortality to converge to a constant. We simulate various scenarios, including where statistical cure is reasonable and where the long-term excess mortality persists. RESULTS: The compared approaches showed similar survival fits within the follow-up period. However, when extrapolating the all-cause survival beyond trial follow-up, there is variation depending on the assumption made about the long-term excess mortality. Altering the time point from which the excess mortality is constrained enables further flexibility. CONCLUSIONS: The various constraints can lead to applying explicit assumptions when extrapolating, which could lead to more plausible survival extrapolations. The inclusion of general population mortality directly into the model-building process, which is possible for all considered approaches, should be adopted more widely in survival extrapolation in health technology assessment.

Shifting the Focus from Dissolution to Permeation: Introducing the Meso-fluidic Chip for Permeability Assessment (MCPA).

In response to the growing ethical and environmental concerns associated with animal testing, numerous in vitro tools of varying complexity and biorelevance have been developed and adopted in pharmaceutical research and development. In this work, we present one of these tools, i.e., the Meso-fluidic Chip for Permeability Assessment (MCPA), for the first time. The MCPA combines an artificial barrier (PermeaPad®) with an organ-on-chip device (MIVO®) and real-time automated concentration measurements, to yield a sustainable, yet effortless method for permeation testing. The system offers three major physiological aspects, i.e., a biomimetic membrane, an optimal membrane interfacial area-to-donor-volume-ratio (A/V) and a physiological flow on the acceptor/basolateral side, which makes the MPCA an ideal candidate for mechanistic studies and excellent in vivo bioavailability predictions. We validated the method with a handful of assorted drug compounds in unstirred and stirred donor conditions, before exploring its applicability as a tool for dissolution/permeation testing on a BCS class III/I drug (pyrazinamide) crystalline adducts and BCS class II/IV (hydrocortisone) amorphous solid dispersions. The results were highly reproducible and clearly displayed the method's potential for evaluating the performance of enabling formulations, and possibly even predicting in vivo performance. We believe that, upon further development, the MCPA will serve as a useful in vitro tool that could push sustainability into pharmaceutics by refining, reducing and replacing animal testing in early-stage drug development.

Perils of Randomized Controlled Trial Survival Extrapolation Assuming Treatment Effect Waning: Why the Distinction Between Marginal and Conditional Estimates Matters.

OBJECTIVES: A long-term, constant, protective treatment effect is a strong assumption when extrapolating survival beyond clinical trial follow-up; hence, sensitivity to treatment effect waning is commonly assessed for economic evaluations. Forcing a hazard ratio (HR) to 1 does not necessarily estimate loss of individual-level treatment effect accurately because of HR selection bias. A simulation study was designed to explore the behavior of marginal HRs under a waning conditional (individual-level) treatment effect and demonstrate bias in forcing a marginal HR to 1 when the estimand is "survival difference with individual-level waning". METHODS: Data were simulated under 4 parameter combinations (varying prognostic strength of heterogeneity and treatment effect). Time-varying marginal HRs were estimated in scenarios where the true conditional HR attenuated to 1. Restricted mean survival time differences, estimated having constrained the marginal HR to 1, were compared with true values to assess bias induced by marginal constraints. RESULTS: Under loss of conditional treatment effect, the marginal HR took a value >1 because of covariate imbalances. Constraining this value to 1 lead to restricted mean survival time difference bias of up to 0.8 years (57% increase). Inflation of effect size estimates also increased with the magnitude of initial protective treatment effect. CONCLUSIONS: Important differences exist between survival extrapolations assuming marginal versus conditional treatment effect waning. When a marginal HR is constrained to 1 to assess efficacy under individual-level treatment effect waning, the survival benefits associated with the new treatment will be overestimated, and incremental cost-effectiveness ratios will be underestimated.

Financial hardship among siblings of long-term survivors of childhood cancer: A Childhood Cancer Survivor Study report.

BACKGROUND: Siblings of children with cancer may experience adverse household economic consequences, but their financial outcomes in adulthood are unknown. METHODS: A total of 880 siblings (aged 18-64 years) of adult-aged childhood cancer survivors were surveyed to estimate the prevalence of financial hardship by three established domains (behavioral, material, and psychological). For individual financial hardship items matching the contemporaneous National Health Interview Survey or Behavioral Risk Factor Surveillance System, siblings were compared with the general population by calculating adjusted prevalence odds ratios (ORs) to sample-weighted responses. Multivariable logistic regression models examined associations between sibling characteristics and each hardship domain and between sibling hardship and survivors' cancer/treatment characteristics. RESULTS: Behavioral, material, and psychological hardship was reported by 24%, 35%, and 28%, respectively. Compared with national survey respondents, siblings were more likely to report worries about medical bills (OR, 1.14; 95% confidence interval [CI], 1.06-1.22), difficulty affording nutritious foods (OR, 1.79; 95% CI, 1.54-2.07), and forgoing needed medical care (OR, 1.38; 95% CI, 1.10-1.73), prescription medications (OR, 2.52; 95% CI, 1.99-3.20), and dental care (OR, 1.34; 95% CI, 1.15-1.57) because of cost. Sibling characteristics associated with reporting financial hardship in one or more domains included female sex, older age, chronic health conditions, lower income, not having health insurance, high out-of-pocket medical expenditures, and nonmedical/nonhome debt. No survivor cancer/treatment characteristics were associated with sibling financial hardship. CONCLUSIONS: Adult siblings of childhood cancer survivors were more likely to experience financial hardship compared with the general population. Childhood cancer may adversely affect entire households, with potentially lasting implications.

Analysis of health inequities in transfers of admitted patients from an academic emergency department to partner community hospital.

BACKGROUND: Many academic medical centers (AMC) transfer patients who require admission but not tertiary care to partner community hospitals from their emergency departments (ED). These transfers alleviate ED boarding but may worsen existing healthcare disparities. We assessed whether disparities exist in the transfer of patients from one AMC ED to a community hospital General Medical Service. METHODS: We performed a retrospective cohort study on all patients screened for transfer between April 1 and December 31, 2021. During the screening process, the treating ED physician determines whether the patient meets standardized clinical criteria and a patient coordinator requests patient consent. We collected patient demographics data from the electronic health record and performed logistic regression at each stage of the transfer process to analyze how individual characteristics impact the odds of proceeding with transfer. RESULTS: 5558 patients were screened and 596 (11%) ultimately transferred. 1999 (36%) patients were Black or Hispanic, 698 (12%) had a preferred language other than English, and 956 (17%) were on Medicaid or uninsured. A greater proportion of Black and Hispanic patients were deemed eligible for interhospital transfer compared to White patients and a greater proportion of Hispanic patients completed transfer to the community hospital (p < 0.017 after Bonferroni correction). After accounting for other demographic variables, patients older than 50 (OR 1.21, 95% CI 1.04-1.40), with a preferred language other than English (OR 1.27, 95% CI 1.00-1.62), and from a priority neighborhood (OR 1.38, 95% CI 1.18-1.61) were more likely to be eligible for transfer, while patients who were male (OR 1.50, 95% CI 1.10-2.05) and younger than 50 (OR 1.85, 95% CI 1.20-2.78) were more likely to consent to transfer (p < 0.05). CONCLUSION: Health disparities exist in the screening process for our interfacility transfer program. Further investigation into why these disparities exist and mitigation strategies should be undertaken.

Post-Menopausal Quality of Life Claims: Overlooking the Requirements of Normal Science and Fundamental Measurement in ICER'S Cost-Effectiveness Assessment of Fezolinetant for Moderate to Severe Vasomotor Symptoms.

One of the signal failures in health technology assessment is the absence of consideration given, not only to the standards of normal science, but to those of fundamental measurement. A recent evidence report by the Institute for Clinical and Economic Review (ICER) is emblematic of this failure. Based on a simple linear regression model that translates aggregate scores from the ordinal Menopause-specific Quality of Life Questionnaire (MENQOL) to the ordinal EuroQol EQ-5D-5L, ICER has applied these scores to an assumption driven model simulation to produce preferences, QALYs and incremental cost-per-QALY claims for fezolinetant for moderate to severe symptoms associated with menopause. Unfortunately, the attempt to crosswalk multidimensional or multiattribute ordinal scores is mathematically impossible. The 'created' EQ-5D-5L preferences are, as a result, of no interest. The overall result is that the ICER modelled claims for cost-effectiveness fail the required standards for normal science and fundamental measurement. fundamental are impossible. This is unfortunate, although it might be possible to assess certain domains of the MENQOL for their approximation to an interval score with the application of the Rasch Rating Scale Model, this will not support quality of life claims. A preferred approach would be to consider an alternative latent trait for quality of life in menopause, applying Rasch Measurement Theory (RMT), to develop a polytomous instrument that has the required measurement properties. The purpose of this commentary is to point out, as a number of previous commentaries have done, that this framework for creating assumption driven simulated modelled claims has no role in decisions for product assessment, access to formulary and pricing. This commentary expands upon these previous commentaries in placing RMT is the context of a needed paradigm shift to support the evolution of objective knowledge. This is critical if we are to understand, from the individual's perspective, not only an accurate assessment of the burden of menopause but to see this as part of an on-going research program that has to rely on fundamental measurement.