Patient-reported outcomes and daily activity assessed with a digital wearable device in patients with paroxysmal nocturnal hemoglobinuria treated with ravulizumab: REVEAL, a prospective, observational study.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic blood disorder. Symptoms such as fatigue can have a substantial impact on patients' physical activity levels, sleep, quality of life, and work productivity. Ravulizumab treatment can reduce thrombosis risk, improve survival and quality of life, and reduce fatigue in PNH, but information is limited on how it impacts sleep and physical activity. Here, data on resting heart rate, daily physical activity, and sleep in ravulizumab-treated patients with PNH were passively collected via a digital wearable activity-tracking device and patient-reported outcome (PRO) data were collected via weekly surveys in the same cohort. METHODS: REVEAL was a 32-week prospective observational cohort study in individuals with PNH receiving ravulizumab in the USA. A wrist-worn Fitbit™ collected data on resting heart rate, daily step count, and sleep duration from eligible patients. Patients also completed the following electronic weekly surveys: Functional Assessment of Chronic Illness Therapy (FACIT) - Fatigue, Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health, PROMIS Global Mental Health, PROMIS Sleep-Related Impairment and Sleep Disturbance, and Work Productivity and Activity Impairment Questionnaire - Specific Health Problem (WPAI-SHP). Data collected from the activity trackers and surveys were compared against US general population values reported in the literature. RESULTS: Twenty-eight ravulizumab-treated patients were included (median age: 34 years; 54% female). PRO scores were within US general population normative values, including FACIT-Fatigue (40.0), PROMIS Global Physical Health (51.0), Global Mental Health (51.0), Sleep-Related Impairment (50.0), and Sleep Disturbance (49.0). Similarly, mean resting heart rate (67 bpm), daily step count (7476), and sleep duration (7.7 h) were within the range of US general population values. Daily step count was positively correlated with PROMIS Global Physical and Mental Health scores. CONCLUSIONS: This was the first study to use digital monitoring technology to collect data on physical activity and sleep in patients with PNH. The findings indicate that ravulizumab treatment enables patients with PNH to achieve activity levels (heart rate, sleep duration, step count) and quality of life that are comparable to those of the US general population. A weak positive correlation was identified between patient-reported physical and mental health and daily physical activity levels.

Access to Disease-Modifying Alzheimer's Therapies: Addressing Possible Challenges Using Innovative Payment Models.

OBJECTIVES: Aduhelm is the first approved disease-modifying therapies (DMT) for Alzheimer disease (AD). Nevertheless, under current payment models, AD DMTs-especially because they treat broader populations-will pose challenges to patient access since costs may accrue sooner than benefits do. New payment approaches may be needed to address this difference in timing. METHODS: We use the Future Elderly Model that draws on nationally representative data sets such as the Health and Retirement Study to estimate the potential benefits because of hypothetical AD DMTs in 4 stylized treatment scenarios for patients with mild cognitive impairment or mild AD, and develop a payment model to estimate the accrual of net costs and benefits to private and public payers. RESULTS: The modeled AD DMTs result in clinical benefit of 0.30 to 0.55 quality-adjusted life-years gained per patient in the baseline treatment scenario and 0.13 to 0.24 quality-adjusted life-years gained per patient in the least optimistic scenario. Private payers may observe a net loss in patients at the age of 61 to 65 years under the status quo (payment upon treatment). Constant and deferred installment payment models resolve this issue. CONCLUSIONS: Innovative payment solutions, such as installment payments, may be required to address misaligned incentives that AD DMTs may create among patients younger than the age of 65 years and may help address concerns about the timing and magnitude of costs and benefits accrued to private payers.

Crosswalk between the Mini-Mental State Examination and the Telephone Interview for Cognitive Status (TICS-27/30/40).

BACKGROUND: We develop a crosswalk between the Mini-Mental State Examination (MMSE) and Telephone Interview for Cognitive Status (TICS)-27, TICS-30, and TICS-40 for adults 65 years and older. METHODS: We examined the scores of 1809 participants, with and without cognitive impairment, who completed the MMSE and the TICS assessment in the 2016 Health and Retirement Study and the 2016 Harmonized Cognitive Assessment Protocol study. Crosswalks between MMSE and TICS-27/30/40 were developed via equipercentile equating. RESULTS: We present crosswalks for MMSE and TICS-27/30/40 for the 65+ population representative of the US elderly. While monotonic, the pattern of the TICS-30 to MMSE crosswalk differs from the other two crosswalks (MMSE to TICS-27/40). CONCLUSION: Our analysis offers an empirical crosswalk between two commonly used cognitive measures-the MMSE and TICS. Our findings suggest the need for validated and robust measures that allow for the comparison of scores on different cognitive scales.

Hedgehog signaling regulates dental papilla formation and tooth size during zebrafish odontogenesis.

BACKGROUND: Intercellular communication by the hedgehog cell signaling pathway is necessary for tooth development throughout the vertebrates, but it remains unclear which specific developmental signals control cell behavior at different stages of odontogenesis. To address this issue, we have manipulated hedgehog activity during zebrafish tooth development and visualized the results using confocal microscopy. RESULTS: We first established that reporter lines for dlx2b, fli1, NF-κB, and prdm1a are markers for specific subsets of tooth germ tissues. We then blocked hedgehog signaling with cyclopamine and observed a reduction or elimination of the cranial neural crest derived dental papilla, which normally contains the cells that later give rise to dentin-producing odontoblasts. Upon further investigation, we observed that the dental papilla begins to form and then regresses in the absence of hedgehog signaling, through a mechanism unrelated to cell proliferation or apoptosis. We also found evidence of an isometric reduction in tooth size that correlates with the time of earliest hedgehog inhibition. CONCLUSIONS: We hypothesize that these results reveal a previously uncharacterized function of hedgehog signaling during tooth morphogenesis, regulating the number of cells in the dental papilla and thereby controlling tooth size.

Cost-Effectiveness Analysis of PET-CT Surveillance After Treatment of Human Papillomavirus-Positive Oropharyngeal Cancer.

OBJECTIVE: To determine the cost-effectiveness of surveillance imaging with PET/CT scan among patients with human papillomavirus-positive oropharyngeal squamous cell carcinoma. STUDY DESIGN: Cost-effectiveness analysis. SETTING: Oncologic care centers in the United States with head and neck oncologic surgeons and physicians. METHODS: We compared the cost-effectiveness of 2 posttreatment surveillance strategies: clinical surveillance with the addition of PET/CT scan versus clinical surveillance alone in human papillomavirus-positive oropharyngeal squamous cell carcinoma patients. We constructed a Markov decision model which was analyzed from a third-party payer's perspective using 1-year Markov cycles and a 30-year time horizon. Values for transition probabilities, costs, health care utilities, and their studied ranges were derived from the literature. RESULTS: The incremental cost-effectiveness ratio for PET/CT with clinical surveillance versus clinical surveillance alone was $89,850 per quality-adjusted life year gained. Flexible fiberoptic scope exams during clinical surveillance would have to be over 51% sensitive or PET/CT scan cost would have to exceed $1678 for clinical surveillance alone to be more cost-effective. The willingness-to-pay threshold at which imaging surveillance was equally cost-effective to clinical surveillance was approximately $80,000/QALY. CONCLUSION: Despite lower recurrence rates of human papillomavirus-positive oropharyngeal cancer, a single PET/CT scan within 6 months after primary treatment remains a cost-effective tool for routine surveillance when its cost does not exceed $1678. The cost-effectiveness of this strategy is also dependent on the clinical surveillance sensitivity (flexible fiberoptic pharyngoscopy), and willingness-to-pay thresholds which vary by country.

Network Meta-analysis of Ravulizumab and Alternative Interventions for the Treatment of Neuromyelitis Optica Spectrum Disorder.

INTRODUCTION: Anti-aquaporin-4 antibody-positive (AQP4-Ab+) neuromyelitis optica spectrum disorder (NMOSD) is a complement-mediated autoimmune disease in which unpredictable and relapsing attacks on the central nervous system cause irreversible and accumulating damage. Comparative efficacy of new NMOSD therapies, such as ravulizumab, with established therapies is critical in making informed treatment decisions. METHODS: Efficacy of ravulizumab relative to established AQP4-Ab+ NMOSD treatments, such as eculizumab, inebilizumab, and satralizumab, was evaluated in a Bayesian network meta-analysis (NMA). Data were extracted from trials identified by a systematic literature review. The final evidence base consisted of 17 publications representing five unique and global studies (PREVENT, N-MOmentum, SAkuraSky, SAkuraStar, and CHAMPION-NMOSD). The primary endpoint was time-to-first relapse; other outcomes included annualized relapse rates (ARRs). RESULTS: For patients receiving monotherapy (monoclonal antibody only), ravulizumab was associated with a lower risk of relapse than inebilizumab (hazard ratio [HR] 0.09, 95% credible interval [CrI] 0.02, 0.57) or satralizumab (HR 0.08, 95% CrI 0.01, 0.55) and was comparable to eculizumab (HR 0.86, 95% Crl 0.16, 4.52). Ravulizumab + immunosuppressive therapy (IST) was associated with a lower risk of relapse than satralizumab + IST (HR 0.15, 95% CrI 0.03, 0.78); the comparison with eculizumab + IST suggested no difference. No patients treated with inebilizumab received background IST and were thus excluded from analysis. The ARR with ravulizumab monotherapy was 98% lower compared with inebilizumab (rate ratio [RR] 0.02, 95% Crl 0.00, 0.38) and satralizumab (RR 0.02, 95% Crl 0.00, 0.42) monotherapies. The ARR with ravulizumab ± IST showed the strongest treatment-effect estimates compared with other interventions. CONCLUSION: In the absence of head-to-head randomized controlled trials, NMA results suggest ravulizumab, a C5 inhibitor, is likely to be more effective in preventing NMOSD relapse in patients with AQP4-Ab+ NMOSD when compared with other treatments having different methods of action.

Anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, also called AQP4-Ab+ NMOSD, is a rare autoimmune disease that causes repeated episodes of symptoms such as blindness, arm/leg weakness, painful spasms, vomiting, and hiccups, among other symptoms. Each episode can cause nervous system damage to worsen, making it more difficult to recover back to regular abilities. Repeated episodes are likely to cause permanent damage, such as blindness and paralysis. Medical treatments that reduce episodes also reduce the damage and the chances symptoms will become permanent. One treatment, ravulizumab, is being studied to treat adults with AQP4-Ab+ NMOSD. This analysis looked at information from published clinical studies to compare ravulizumab with three other treatments (eculizumab, inebilizumab, and satralizumab) to determine how well each treatment reduced NMOSD episodes. There are no studies that have tested all four treatments in one study. Here, the treatments were compared by a method used to estimate the likelihood of a treatment being better than the others. While all four treatments successfully reduced episodes in their own studies, this analysis predicts that ravulizumab would likely be best in preventing episodes compared with inebilizumab or satralizumab when used alone or in combination with other immunosuppressive treatments. These findings, in consideration along with other relevant factors such as cost, safety, dosing delivery method, and frequency of treatment, may help doctors and patients decide what is the best treatment option for each individual patient to prevent attacks in adults with AQP4-Ab+ NMOSD.

Association of Intensive Lifestyle Intervention for Type 2 Diabetes With Labor Market Outcomes.

Importance: An intensive lifestyle intervention (ILI) has been shown to improve diabetes management and physical function. These benefits could lead to better labor market outcomes, but this has not been previously studied. Objective: To estimate the association of an ILI for weight loss in type 2 diabetes with employment, earnings, and disability benefit receipt during and after the intervention. Design, Setting, and Participants: This cohort study included participants with type 2 diabetes and overweight or obesity and compared an ILI with a control condition of diabetes support and education. Data for the original trial were accrued from August 22, 2001, to September 14, 2012. Trial data were linked with Social Security Administration records to investigate whether, relative to the control group, the ILI was associated with improvements in labor market outcomes during and after the intervention period. Difference-in-differences models estimating relative changes in employment, earnings, and disability benefit receipt between the ILI and control groups were used, accounting for prerandomization differences in outcomes for linked participants. Outcome data were analyzed from July 13, 2020, to May 17, 2023. Exposure: The ILI consisted of sessions with lifestyle counselors, dieticians, exercise specialists, and behavioral therapists on a weekly basis in the first 6 months, decreasing to a monthly basis by the fourth year, designed to achieve and maintain at least 7% weight loss. The control group received group-based diabetes education sessions 3 times annually during the first 4 years, with 1 annual session thereafter. Main Outcomes and Measures: Employment and receipt of federal disability benefits (Supplemental Security Income and Social Security Disability Insurance), earnings, and disability benefit payments from 1994 through 2018. Results: A total of 3091 trial participants were linked with Social Security Administration data (60.1% of 5145 participants initially randomized and 97.0% of 3188 of participants consenting to linkage). Among the 3091 with fully linked data, 1836 (59.4%) were women, and mean (SD) age was 58.4 (6.5) years. Baseline clinical and demographic characteristics were similar between linked participants in the ILI and control groups. Employment increased by 2.9 (95% CI, 0.3-5.5) percentage points for the ILI group relative to controls (P = .03) with no significant relative change in disability benefit receipt (-0.9 [95% CI, -2.1 to 0.3] percentage points; P = .13). Conclusions and Relevance: The findings of this cohort study suggest that an ILI to prevent the progression and complications of type 2 diabetes was associated with higher levels of employment. Labor market productivity should be considered when evaluating interventions to manage chronic diseases.

Novel insights into systemic sclerosis using a sensitive computational method to analyze whole-genome bisulfite sequencing data.

BACKGROUND: Abnormal DNA methylation is thought to contribute to the onset and progression of systemic sclerosis. Currently, the most comprehensive assay for profiling DNA methylation is whole-genome bisulfite sequencing (WGBS), but its precision depends on read depth and it may be subject to sequencing errors. SOMNiBUS, a method for regional analysis, attempts to overcome some of these limitations. Using SOMNiBUS, we re-analyzed WGBS data previously analyzed using bumphunter, an approach that initially fits single CpG associations, to contrast DNA methylation estimates by both methods. METHODS: Purified CD4+ T lymphocytes of 9 SSc and 4 control females were sequenced using WGBS. We separated the resulting sequencing data into regions with dense CpG data, and differentially methylated regions (DMRs) were inferred with the SOMNiBUS region-level test, adjusted for age. Pathway enrichment analysis was performed with ingenuity pathway analysis (IPA). We compared the results obtained by SOMNiBUS and bumphunter. RESULTS: Of 8268 CpG regions of ≥ 60 CpGs eligible for analysis with SOMNiBUS, we identified 131 DMRs and 125 differentially methylated genes (DMGs; p-values less than Bonferroni-corrected threshold of 6.05-06 controlling family-wise error rate at 0.05; 1.6% of the regions). In comparison, bumphunter identified 821,929 CpG regions, 599 DMRs (of which none had ≥ 60 CpGs) and 340 DMGs (q-value of 0.05; 0.04% of all regions). The top ranked gene identified by SOMNiBUS was FLT4, a lymphangiogenic orchestrator, and the top ranked gene on chromosome X was CHST7, known to catalyze the sulfation of glycosaminoglycans in the extracellular matrix. The top networks identified by IPA included connective tissue disorders. CONCLUSIONS: SOMNiBUS is a complementary method of analyzing WGBS data that enhances biological insights into SSc and provides novel avenues of investigation into its pathogenesis.

Impact of non-binding FDA guidances on primary endpoint selection in Alzheimer's disease trials.

Introduction: The U.S. Food and Drug Administration (FDA)'s guidances help describe the agency's current thinking on regulatory issues and serve as a means of informal policymaking that is non-binding. This study examines the impact of two guidance documents for Alzheimer's disease (AD) trials. The first guidance in 2013 encouraged the use of cognitive/functional endpoints, while the second in 2018 modified such recommendation. Methods: Using pivotal trial data, we applied a regression discontinuity in time (RDiT) framework to examine trialist response to these guidance documents. Results were stratified by disease-modifying therapy (DMT) status, and controlled for disease staging, FDA registration status, and trial phase. Results: Among AD DMT trials, annual use of cognitive/functional composite endpoints significantly increased after the 2013 guidance (+12.9%, P < .001), and significantly decreased after the 2018 guidance (-19.9%, P = .022). Discussion: Although guidance documents do not set new legal standards or impose binding requirements, our findings indicate they are broadly followed by AD trialists.

Cost-effectiveness Analysis of Submandibular Gland Preservation With Sialendoscopy for the Management of Sialolithiasis.

OBJECTIVE: To compare the cost-effectiveness of sialendoscopy with gland excision for the management of submandibular gland sialolithiasis. STUDY DESIGN: Cost-effectiveness analysis. SETTING: Outpatient surgery centers. METHODS: A Markov decision model compared the cost-effectiveness of sialendoscopy versus gland excision for managing submandibular gland sialolithiasis. Surgical outcome probabilities were found in the primary literature. The quality of life of patients was represented by health utilities, and costs were estimated from a third-party payer's perspective. The effectiveness of each intervention was measured in quality-adjusted life-years (QALYs). The incremental costs and effectiveness of each intervention were compared, and a willingness-to-pay ratio of $150,000 per QALY was considered cost-effective. One-way, multivariate, and probabilistic sensitivity analyses were performed to challenge model conclusions. RESULTS: Over 10 years, sialendoscopy yielded 9.00 QALYs at an average cost of $8306, while gland excision produced 8.94 QALYs at an average cost of $6103. The ICER for sialendoscopy was $36,717 per QALY gained, making sialendoscopy cost-effective by our best estimates. The model was sensitive to the probability of success and the cost of sialendoscopy. Sialendoscopy must meet a probability-of-success threshold of 0.61 (61%) and cost ≤$11,996 to remain cost-effective. A Monte Carlo simulation revealed sialendoscopy to be cost-effective 60% of the time. CONCLUSION: Sialendoscopy appears to be a cost-effective management strategy for sialolithiasis of the submandibular gland when certain thresholds are maintained. Further studies elucidating the clinical factors that determine successful sialendoscopy may be aided by these thresholds as well as future comparisons of novel technology.

The economics of alternative payment models for pharmaceuticals.

Pharmaceuticals are priced uniformly by convention, but vary in their degree of effectiveness for different disease indications. As more high-cost therapies have launched, the demand for alternative payment models (APMs) has been increasing in many advanced markets, despite their well-documented limitations and challenges to implementation. Among policy justifications for such contracts is the maximization of value given scarce resources. We show that while uniform pricing rules can handle variable effectiveness in efficient markets, market inefficiencies of other kinds create a role for different value-based pricing structures. We first present a stylized theoretical model of efficient interaction among drug manufacturers, payers, and beneficiaries. In this stylized setting, uniform pricing works well, even when treatment effects are variable. We then use this framework to define market failures that result in obstacles to uniform pricing. The market failures we identify include: (1) uncertainty of patient distribution, (2) asymmetric beliefs, (3) agency imperfection by payer, (4) agency imperfection by provider, and (5) patient behavior and treatment adherence. We then apply our insights to real-world examples of alternative payment models, and highlight challenges related to contract implementation.

Reconstruction After Salvage Total Laryngectomy: A Cost-effectiveness Analysis.

OBJECTIVE: To determine the most cost-effective reconstruction method after salvage total laryngectomy. STUDY DESIGN: Cost-effectiveness analysis. SETTING: Tertiary care hospitals with head and neck oncologic and reconstructive surgeons. SUBJECTS AND METHODS: We constructed a Markov-based decision model to compare reconstruction by primary closure to pectoralis flap and free flap after salvage total laryngectomy. The model simulated disease with transition probabilities and health utilities found in primary literature and estimated the average overall cost of each reconstructive method using Medicare billing codes. Effectiveness was compared using quality-adjusted life years (QALYs). One-way and probabilistic sensitivity analyses were performed to scrutinize the conclusions of our model. Reconstruction methods were compared using incremental cost-effectiveness ratios (ICERs). In the United States, less than $150,000 per QALY gained is considered cost-effective (2019 US dollars). RESULTS: Our base case analysis revealed that primary closure was less expensive ($44,370) and yielded more QALYs (0.91) than both pectoralis ($45,163, 0.81 QALYs) and free flap ($46,244, 0.85 QALYs), making it the most cost-effective option. Between flaps, free flap was cost-effective over pectoralis flap (ICER = $27,025/QALY gained). Sensitivity analyses showed primary closure as cost-effective 69% of the time over either flap. These conclusions were sensitive to the health utilities (quality of life) of each method of reconstruction. CONCLUSION: Tissue flaps to augment closure after salvage total laryngectomy are not always the most cost-effective reconstructive option. The long-term morbidity of flap surgery oftentimes outweighs the benefit of lowering fistula rates after surgery. Careful consideration must be taken when advising patients of their reconstructive options.

Do Research Groups Align on an Intervention's Value? Concordance of Cost-Effectiveness Findings Between the Institute for Clinical and Economic Review and Other Health System Stakeholders.

The Institute for Clinical and Economic Review (ICER) employs fixed cost-effectiveness (CE) thresholds that guide their appraisal of an intervention's long-term economic value. Given ICER's rising influence in the healthcare field, we undertook an assessment of the concordance of ICER's CE findings to the published CE findings from other research groups (i.e., "non-ICER" researchers including life science manufacturers, academics, and government institutions). Disease areas and pharmaceutical interventions for comparison were determined based on ICER evaluations conducted from 1 January 2015 to 31 December 2017. A targeted literature search was conducted for non-ICER CE publications using PubMed. Studies had to be conducted from the US setting, include the same disease characteristics (e.g., disease severity; treatment history), incorporate the same pharmaceutical interventions and comparison groups, and present incremental costs per quality-adjusted life-year (QALY) gained from the healthcare sector or payer perspective. Discordance was measured as the proportion of unique interventions that would have had more favorable valuations (i.e., low, intermediate, high value-for-money) if the CE findings from other research groups had been used for decision making instead of ICER's findings. More favorable valuations were defined as transitioning from low value (as determined by ICER) to intermediate or high value (as determined by other researchers) and from intermediate value (as determined by ICER) to high value (as determined by other researchers). Among the 13 non-ICER studies meeting inclusion criteria, six disease areas and 14 interventions were assessed. Of the 14 interventions, a more favorable valuation would have been recommended for ten therapies if the CE ratios from other research groups had been used for decision making instead of ICER's findings, representing a 71.4% (10/14) discordance rate. Moreover, these discrepancies were found in each of the evaluated disease areas, with the largest number of discordant valuations found in rheumatoid arthritis (five out of six interventions were discordant) followed by one valuation each in multiple sclerosis (one out of three), non-small cell lung cancer (one out of two), multiple myeloma (one out of one), high cholesterol (one out of one), and congestive heart failure (one out of one). Our findings indicate high discordance when comparing ICER's appraisals to the CE findings of non-ICER researchers. To understand the value of new interventions, the totality of evidence on the CE of an intervention-including results from ICER and non-ICER modeling efforts-should be considered when making coverage and reimbursement decisions.

Cost-effectiveness analysis of vagal nerve blocking for morbid obesity.

OBJECTIVES: To assess the lifetime cost-effectiveness of intermittent, reversible vagal nerve blocking (via the implantable weight loss device vBloc) therapy versus conventional therapy as treatment for patients who are class 2 obese with diabetes and for those who are class 3 obese with or without diabetes, who have found pharmacotherapy and behavioral therapies ineffective, but are not prepared or willing to undergo current bariatric surgical options. STUDY DESIGN: A cost-effectiveness model was designed to simulate weight loss, diabetes remission, and costs in patients with obesity undergoing vagal nerve blocking therapy versus conventional therapy. METHODS: The model compared 2 treatment arms, vagal nerve blocking therapy and conventional therapy, and for each treatment arm included 4 health states based on body mass index (BMI) class. Using Monte Carlo simulation, patients entered the model one at a time and could transition between health states by experiencing BMI change. The model focused on change in BMI and diabetes remission as predictors of healthcare costs, health-related quality of life, and survival. Inputs for vagal nerve blocking effectiveness were obtained from the ReCharge trial; however, remaining inputs were estimated from published literature. Incremental cost-effectiveness ratios (ICERs) were evaluated in terms of cost per quality-adjusted life-year (QALY) gained. RESULTS: ICERs for vagal nerve blocking versus conventional therapy in patients who were class 2 and class 3 obese were estimated to be $17,274 and $21,713 per QALY gained, respectively. Sensitivity analyses showed results to be robust to reasonable variation in model inputs, with the upper limit of ICERs remaining below $30,000 for all sensitivity analysis scenarios assessed. CONCLUSIONS: Vagal nerve blocking therapy provides a cost-effective alternative to conventional therapy in patients who are class 2 obese with diabetes and in those who are class 3 with or without diabetes.