Characteristics of health-state utilities used in cost-effectiveness analyses: a systematic review of published studies in Asia.

INTRODUCTION: Cost-utility analysis (CUA) is the preferred form of economic evaluation in many countries. As one of the key data inputs in cost-utility models, health state utility (HSU) has a crucial impact on CUA results. In the past decades, health technology assessment has been expanding rapidly in Asia, yet research examining the methodology and process used to generate cost-effectiveness evidence is scarce. The aim of this study was to examine the reporting of the characteristics of HSU data used in CUAs in Asia and how the characteristics have changed over time. METHODS: A systematic literature search was performed to identify published CUA studies targeting Asian populations. Information was extracted for both the general characteristics of selected studies and the characteristics of reported HSU data. For each HSU value identified, we extracted data for four key characteristics, including 1) estimation method; 2) source of health-related quality of life (HRQoL) data; 3) source of preference data; and 4) sample size. The percentage of nonreporting was calculated and compared over two time periods (1990-2010 vs 2011-2020). RESULTS: A total of 789 studies were included and 4,052 HSUs were identified. Of these HSUs, 3,351 (82.7%) were from published literature and 656 (16.2%) were from unpublished empirical data. Overall, the characteristics of HSU data were not reported in more than 80% of the studies. Of HSUs whose characteristics were reported, most of them were estimated using the EQ-5D (55.7%), Asian HRQoL data (91.9%), and Asian health preferences (87.7%); 45.7% of the HSUs was estimated with a sample of 100 or more individuals. All four characteristics showed improvements after 2010. CONCLUSION: Over the past two decades, there has been a significant increase in CUA studies targeting Asian populations. However, HSU's characteristics were not reported in most of the CUA studies, making it difficult to evaluate the quality and appropriateness of the HSUs used in those cost-effectiveness studies.

A Highly Selective and Sensitive Chemiluminescent Probe for Real-Time Monitoring of Hydrogen Peroxide in Cells and Animals.

Selective and sensitive molecular probes for hydrogen peroxide (H2 O2 ), which plays diverse roles in oxidative stress and redox signaling, are urgently needed to investigate the physiological and pathological effects of H2 O2 . A lack of reliable tools for in vivo imaging has hampered the development of H2 O2 mediated therapeutics. By combining a specific tandem Payne/Dakin reaction with a chemiluminescent scaffold, H2 O2 -CL-510 was developed as a highly selective and sensitive probe for detection of H2 O2 both in vitro and in vivo. A rapid 430-fold enhancement of chemiluminescence was triggered directly by H2 O2 without any laser excitation. Arsenic trioxide induced oxidative damage in leukemia was successfully detected. In particular, cerebral ischemia-reperfusion injury-induced H2 O2 fluxes were visualized in rat brains using H2 O2 -CL-510, providing a new chemical tool for real-time monitoring of H2 O2 dynamics in living animals.

Pregnane X Receptor Activation Attenuates Inflammation-Associated Intestinal Epithelial Barrier Dysfunction by Inhibiting Cytokine-Induced Myosin Light-Chain Kinase Expression and c-Jun N-Terminal Kinase 1/2 Activation.

The inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with a complex etiology. IBD is thought to arise in genetically susceptible individuals in the context of aberrant interactions with the intestinal microbiota and other environmental risk factors. Recently, the pregnane X receptor (PXR) was identified as a sensor for microbial metabolites, whose activation can regulate the intestinal epithelial barrier. Mutations in NR1I2, the gene that encodes the PXR, have been linked to IBD, and in animal models, PXR deletion leads to barrier dysfunction. In the current study, we sought to assess the mechanism(s) through which the PXR regulates barrier function during inflammation. In Caco-2 intestinal epithelial cell monolayers, tumor necrosis factor-α/interferon-γ exposure disrupted the barrier and triggered zonula occludens-1 relocalization, increased expression of myosin light-chain kinase (MLCK), and activation of c-Jun N-terminal kinase 1/2 (JNK1/2). Activation of the PXR [rifaximin and [[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenylidene]bis-phosphonic acid tetraethyl ester (SR12813); 10 µM] protected the barrier, an effect that was associated with attenuated MLCK expression and JNK1/2 activation. In vivo, activation of the PXR [pregnenolone 16α-carbonitrile (PCN)] attenuated barrier disruption induced by toll-like receptor 4 activation in wild-type, but not Pxr-/-, mice. Furthermore, PCN treatment protected the barrier in the dextran-sulfate sodium model of experimental colitis, an effect that was associated with reduced expression of mucosal MLCK and phosphorylated JNK1/2. Together, our data suggest that the PXR regulates the intestinal epithelial barrier during inflammation by modulating cytokine-induced MLCK expression and JNK1/2 activation. Thus, targeting the PXR may prove beneficial for the treatment of inflammation-associated barrier disruption in the context of IBD.

Fluorescent Probe HKSOX-1 for Imaging and Detection of Endogenous Superoxide in Live Cells and In Vivo.

Superoxide anion radical (O2(•-)) is undoubtedly the most important primary reactive oxygen species (ROS) found in cells, whose formation and fate are intertwined with diverse physiological and pathological processes. Here we report a highly sensitive and selective O2(•-) detecting strategy involving O2(•-) cleavage of an aryl trifluoromethanesulfonate group to yield a free phenol. We have synthesized three new O2(•-) fluorescent probes (HKSOX-1, HKSOX-1r for cellular retention, and HKSOX-1m for mitochondria-targeting) which exhibit excellent selectivity and sensitivity toward O2(•-) over a broad range of pH, strong oxidants, and abundant reductants found in cells. In confocal imaging, flow cytometry, and 96-well microplate assay, HKSOX-1r has been robustly applied to detect O2(•-) in multiple cellular models, such as inflammation and mitochondrial stress. Additionally, our probes can be efficiently applied to visualize O2(•-) in intact live zebrafish embryos. These probes open up exciting opportunities for unmasking the roles of O2(•-) in health and disease.

Systematic review and network meta-analysis comparing the efficacy of fezolinetant with hormone and nonhormone therapies for treatment of vasomotor symptoms due to menopause.

IMPORTANCE: The neurokinin 3 receptor antagonist fezolinetant 45 mg/d significantly reduced frequency/severity of moderate to severe vasomotor symptoms (VMS) of menopause compared with placebo in two phase 3 randomized controlled trials. Its efficacy relative to available therapies is unknown. OBJECTIVE: We conducted a systematic review and Bayesian network meta-analysis to compare efficacy with fezolinetant 45 mg and hormone therapy (HT) and non-HT for VMS in postmenopausal women. EVIDENCE REVIEW: Using OvidSP, we systematically searched multiple databases for phase 3 or 4 randomized controlled trials in postmenopausal women with ≥7 moderate to severe VMS per day or ≥50 VMS per week published/presented in English through June 25, 2021. Mean change in frequency and severity of moderate to severe VMS from baseline to week 12 and proportion of women with ≥75% reduction in VMS frequency at week 12 were assessed using fixed-effect models. FINDINGS: The network meta-analysis included data from the pooled phase 3 fezolinetant trials plus 23 comparator publications across the outcomes analyzed (frequency, 19 [34 regimens]; severity, 6 [7 regimens]; ≥75% response, 9 [15 regimens]). Changes in VMS frequency did not differ significantly between fezolinetant 45 mg and any of the 27 HT regimens studied. Fezolinetant 45 mg reduced the frequency of moderate to severe VMS events per day significantly more than all non-HTs evaluated: paroxetine 7.5 mg (mean difference [95% credible interval {CrI}], 1.66 [0.63-2.71]), desvenlafaxine 50 to 200 mg (mean differences [95% CrI], 1.12 [0.10-2.13] to 2.16 [0.90-3.40]), and gabapentin ER 1800 mg (mean difference [95% CrI], 1.63 [0.48-2.81]), and significantly more than placebo (mean difference, 2.78 [95% CrI], 1.93-3.62]). Tibolone 2.5 mg (the only HT regimen evaluable for severity) significantly reduced VMS severity compared with fezolinetant 45 mg. Fezolinetant 45 mg significantly reduced VMS severity compared with desvenlafaxine 50 mg and placebo and did not differ significantly from higher desvenlafaxine doses or gabapentin ER 1800 mg. For ≥75% responder rates, fezolinetant 45 mg was less effective than tibolone 2.5 mg (not available in the United States) and conjugated estrogens 0.625 mg/bazedoxifene 20 mg (available only as 0.45 mg/20 mg in the United States), did not differ significantly from other non-HT regimens studied and was superior to desvenlafaxine 50 mg and placebo. CONCLUSIONS: The only HT regimens that showed significantly greater efficacy than fezolinetant 45 mg on any of the outcomes analyzed are not available in the United States. Fezolinetant 45 mg once daily was statistically significantly more effective than other non-HTs in reducing the frequency of moderate to severe VMS. RELEVANCE: These findings may inform decision making with regard to the individualized management of bothersome VMS due to menopause.

Evaluating the prediction performance of objective physical activity measures for incident Parkinson's disease in the UK Biobank.

BACKGROUND: Parkinson's disease (PD) is the fastest-growing neurological condition with over 10 million cases worldwide. While age and sex are known predictors of incident PD, there is a need to identify other predictors. This study compares the prediction performance of accelerometry-derived physical activity (PA) measures and traditional risk factors for incident PD in the UK Biobank. METHODS: The study population consisted of 92,352 UK Biobank participants without PD at baseline (43.8% male, median age 63 years with interquartile range 43-69). 245 participants were diagnosed with PD by April 1, 2021 (586,604 person-years of follow-up). The incident PD prediction performances of 10 traditional predictors and 8 objective PA measures were compared using single- and multi-variable Cox models. Prediction performance was assessed using a novel, stable statistic: the repeated cross-validated concordance (rcvC). Sensitivity analyses were conducted where PD cases diagnosed within the first six months, one year, and two years were deleted. RESULTS: Single-predictor Cox regression models indicated that all PA measures were statistically significant (p-values < 0.0001). The highest-performing individual predictors were total acceleration (TA) (rcvC = 0.813) among PA measures, and age (rcvC = 0.757) among traditional predictors. The two-step forward-selection process produced a model containing age, sex, and TA (rcvC = 0.851). Adding TA to the model increased the rcvC by 9.8% (p-value < 0.0001). Results were largely unchanged in sensitivity analyses. CONCLUSIONS: Objective PA summaries have better single-predictor model performance than known risk factors and increase the prediction performance substantially when added to models with age and sex.

Health Care Resource Utilization and Costs for Patients with Spinal Muscular Atrophy: Findings from a Retrospective US Claims Database Analysis.

INTRODUCTION: Spinal muscular atrophy (SMA) is a neurogenic disorder associated with progressive loss of muscle function, respiratory failure, and premature mortality. This study aimed to describe and compare real-world health care resource utilization (HCRU) and costs for US patients with SMA treated with disease-modifying treatments, including onasemnogene abeparvovec, nusinersen, and/or risdiplam. METHODS: This study used claims and structured electronic medical record data from the HealthVerity claims database (January 1, 2017-March 31, 2021). Eligible patients were aged ≤ 2 years at index (treatment initiation or switch), diagnosed with SMA, had ≥ 1 pharmacy/medical claim for onasemnogene abeparvovec, nusinersen, and/or risdiplam, and continuous enrollment ≥ 1 month pre- and ≥ 2 months post-index. SMA-related HCRU and costs during the study period (> 12 months post-index) were compared between treatment groups before and after propensity score weighting. Costs were adjusted to 2021 USD. RESULTS: Of 74 included patients, 62 (83.8%) received nusinersen and 12 (16.2%) received onasemnogene abeparvovec (monotherapy, n = 9; onasemnogene abeparvovec after nusinersen [switching], n = 3). After weighting, nusinersen-treated patients had greater annual numbers of inpatient (mean 5.3 nusinersen vs. 1.8 onasemnogene abeparvovec) and emergency department (mean 3.0 nusinersen vs. 1.5 onasemnogene abeparvovec; p < 0.05) visits, and greater annual SMA-related medical costs (mean $78,446 nusinersen vs. $29,438 onasemnogene abeparvovec; mean difference $49,007, p < 0.05) than onasemnogene abeparvovec-treated patients. Onasemnogene abeparvovec-treated patients incurred greater SMA-treatment pharmacy costs than nusinersen-treated patients (mean $2,241,875 onasemnogene abeparvovec vs. $693,191 nusinersen; mean difference $1,548,684, p < 0.05). CONCLUSIONS: SMA is associated with substantial economic burden. Patients treated with onasemnogene abeparvovec had greater SMA treatment-related pharmacy costs but lower SMA-related HCRU and medical costs compared with patients receiving nusinersen monotherapy.

Spinal muscular atrophy (SMA) is a crippling neurodegenerative disease with symptoms of respiratory failure, muscle weakness and loss of function, and premature death. This study describes and compares real-world health care resource utilization (HCRU) and costs for US patients with SMA receiving current treatments (e.g., onasemnogene abeparvovec, nusinersen, risdiplam) using claims and electronic medical record data from a US claims database. Patients included (n = 74) in the study were ≤ 2 years old at treatment initiation/switching of treatments (index), had been diagnosed with SMA and had one or more pharmacy or medical claim for onasemnogene abeparvovec, nusinersen, or risdiplam, and were continuously enrolled for ≥ 1 month before and ≥ 2 months after index. SMA-related HCRU and costs during the study period (up to 12 months post-index) were compared between treatment groups before and after propensity score weighting, with costs adjusted to 2021 USD. Propensity score weighting allows better comparison between patients in treatment and comparison groups by assigning patients different "weights." This weighting allows investigators to be certain that differences in outcomes between patient groups are a result of a particular treatment. After weighting, nusinersen-treated patients had a greater number of inpatient and emergency department visits and greater SMA-related medical costs annually, whereas patients who received onasemnogene abeparvovec had greater pharmacy costs. Our study indicates the greater medical costs among patients receiving nusinersen were largely driven by invasive procedures, such as tracheostomy and gastrostomy, that required hospitalization, but the exact mechanism of greater HCRU/costs associated with nusinersen needs to be further assessed.

Cost-Effectiveness Analysis of REBYOTA™ (Fecal Microbiota, Live-jslm [FMBL]) Versus Standard of Care for the Prevention of Recurrent Clostridioides difficile Infection in the USA.

INTRODUCTION: Recurrent Clostridioides difficile infection (rCDI) is common and associated with considerable clinical and economic consequences. REBYOTA™ (fecal microbiota, live-jslm [FMBL]) is a microbiota-based live biotherapeutic approved for the prevention of rCDI following antibiotic treatment for rCDI. We sought to evaluate cost-effectiveness of FMBL compared to standard of care (SOC) from a US third-party payer perspective among patients with one or more (≥ 1) recurrences. METHODS: A Markov model with a lifetime time horizon was developed. The model population included adult patients who had ≥ 1 recurrence after a primary CDI episode and had completed ≥ 1 round of antibiotics, or had ≥ 2 severe CDI episodes resulting in hospitalization within the last year. The model consisted of six health states with an 8-week model cycle: rCDI, absence of CDI after recurrence, colectomy, ileostomy, ileostomy reversal, and death. Drug costs and rCDI-related medical costs were estimated in 2022 US dollars and discounted at 3% annually. Deterministic sensitivity analyses were performed. RESULTS: Compared to SOC, FMBL at $9000/course resulted in an incremental cost-effectiveness ratio (ICER) of $18,727 per quality-adjusted life year (QALY) gained. The incremental cost was $5336 (FMBL $79,236, SOC $73,900) and the incremental effectiveness was 0.285 QALYs (FMBL 10.346, SOC 10.061). The cumulative drug acquisition and administration costs for the FMBL and SOC arms were $24,245 and $16,876, while rCDI-related medical costs for FMBL and SOC were $54,991 and $57,024, respectively. The ICER in the subgroup of patients at first recurrence was $13,727 per QALY gained. FMBL remained cost-effective across all sensitivity analyses. CONCLUSIONS: FMBL was found to be cost-effective compared to SOC for the prevention of rCDI with more benefits among patients at first recurrence, with an ICER far below the payer ICER threshold of $100,000. Patients treated with FMBL experienced higher total QALYs and reduced healthcare resource utilization, including reduced hospitalizations.

Budget Impact Analysis of REBYOTA™ (Fecal Microbiota, Live-jslm [FMBL]) for Preventing Recurrent Clostridioides difficile Infection in the US.

INTRODUCTION: Patients with Clostridioides difficile infection (CDI) often experience recurrences (rCDI), which are associated with high morbidity, mortality, and healthcare expenditures. REBYOTA™ (fecal microbiota, live-jslm [FMBL]) is a microbiota-based live biotherapeutic approved for the prevention of rCDI following antibiotic treatment for rCDI. We quantified the budget impact of FMBL during the first 3 years following introduction from a third-party US payer perspective. METHODS: A decision-tree model was used to estimate the budget impact of one-course FMBL by comparing costs under the scenario with FMBL to the scenario without FMBL (standard of care) in patients with one or more (≥ 1) recurrences after a primary episode of CDI and had completed ≥ 1 round of antibiotic treatments. Drug costs, rCDI-related medical costs, and budget impact over 1-3 years were estimated in 2022 US dollars. One-way sensitivity analyses were performed. RESULTS: For an insurance plan with a population size of 1,000,000, 468 patients per year were estimated to have ≥ 1 rCDI. The budget impact of one-course FMBL at $9000/course was cost-saving at an¼ average of -$0.0039 on a per-member-per-month (PMPM) basis, an average of -$8.30 on a per-treated-member-per-month (PTMPM) basis, and a total of -$139,865 on a plan level assuming 5%, 15%, and 20% of patients receive FMBL over 1-3 years, respectively. The scenario with FMBL entry was associated with higher drug costs (difference at $0.0474 PMPM; $101.26 PTMPM; $1,706,445 total plan) and lower rCDI-related medical costs (difference at -$0.0513 PMPM; -$109.56 PTMPM; -$1,846,309 total plan). The budget impact of FMBL in patients at first rCDI was cost-saving at -$0.0139 PMPM, -$84.78 PTMPM, corresponding to an annual savings of $500,022. CONCLUSIONS: FMBL has a cost-saving budget impact for a US payer, with higher initial drug costs being offset by savings in rCDI-related medical costs. Greater cost saving was found in patients at first recurrence.

Telehealth Reduces Missed Appointments in Pediatric Patients with Tuberculosis Infection.

Pediatric patients with untreated tuberculosis infection (TBI), also called latent TBI, are at risk of progression to active TB disease. The primary aim of this study was to identify factors associated with higher rates of missed appointments and failure to complete therapy for pediatric patients with TBI. A secondary aim was to determine the impact of the COVID-19 pandemic and the rise of telehealth on TBI missed appointment rates. We first performed a retrospective chart review of 129 pediatric patients referred to the free Yale Pediatric Winchester Chest Tuberculosis Clinic from 2016-2019. Associations between demographic/clinical variables and missed appointments/failure to complete therapy were analyzed using univariate and bivariate chi-square tests. Language, lack of primary provider, and distance to clinic were the main contributors to missed appointments and poor treatment adherence. There was an association between the number of missed appointments and failure to complete treatment (p = 0.050). A second cohort of 29 patients was analyzed from January-December 2021 when telehealth was offered for follow-up appointments. Of these follow-up visits, 54% were conducted via telehealth, and the clinic's missed appointment rate dropped significantly from 16.9% to 5.8% during this time frame (p = 0.037). These data demonstrate that telehealth is accepted as an alternative by patients for follow-up TBI visits.

HKOCl-3: a fluorescent hypochlorous acid probe for live-cell and in vivo imaging and quantitative application in flow cytometry and a 96-well microplate assay.

Ultra-selective and ultra-sensitive probes for hypochlorous acid (HOCl), one of the most poorly understood reactive oxygen species (ROS), are urgently needed to unravel the HOCl functions in important biological processes such as development and innate immunity. Based on a selective oxidative O-dearylation reaction of 2,6-dichlorophenol toward HOCl over other reactive oxygen species, we have developed a novel fluorescent probe HKOCl-3 for HOCl detection with ultra-selectivity, ultra-sensitivity and a rapid turn-on response. The functional robustness of HKOCl-3 for endogenous HOCl detection and imaging has been thoroughly scrutinized in multiple types of phagocytes and in vivo imaging of live intact zebrafish embryos. Furthermore, HKOCl-3 has been successfully applied to the detection of endogenous HOCl by a 96-well microplate assay and flow cytometry. Therefore, HKOCl-3 holds great promise as a versatile molecular tool that enables innovative investigation of HOCl biology and ROS-related diseases in multiple detection modalities.

The ADPKD genes pkd1a/b and pkd2 regulate extracellular matrix formation.

Mutations in polycystin1 (PKD1) account for the majority of autosomal dominant polycystic kidney disease (ADPKD). PKD1 mutations are also associated with vascular aneurysm and abdominal wall hernia, suggesting a role for polycystin1 in extracellular matrix (ECM) integrity. In zebrafish, combined knockdown of the PKD1 paralogs pkd1a and pkd1b resulted in dorsal axis curvature, hydrocephalus, cartilage and craniofacial defects, and pronephric cyst formation at low frequency (10-15%). Dorsal axis curvature was identical to the axis defects observed in pkd2 knockdown embryos. Combined pkd1a/b, pkd2 knockdown demonstrated that these genes interact in axial morphogenesis. Dorsal axis curvature was linked to notochord collagen overexpression and could be reversed by knockdown of col2a1 mRNA or chemical inhibition of collagen crosslinking. pkd1a/b- and pkd2-deficient embryos exhibited ectopic, persistent expression of multiple collagen mRNAs, suggesting a loss of negative feedback signaling that normally limits collagen gene expression. Knockdown of pkd1a/b also dramatically sensitized embryos to low doses of collagen-crosslinking inhibitors, implicating polycystins directly in the modulation of collagen expression or assembly. Embryos treated with wortmannin or LY-29400 also exhibited dysregulation of col2a1 expression, implicating phosphoinositide 3-kinase (PI3K) in the negative feedback signaling pathway controlling matrix gene expression. Our results suggest that pkd1a/b and pkd2 interact to regulate ECM secretion or assembly, and that altered matrix integrity may be a primary defect underlying ADPKD tissue pathologies.