Medium-chain fatty acids (MCFAs), particularly decanoic acid (C10) and octanoic acid (C8), have garnered attention in recent years for their potential antiepileptic properties. A previous study from our laboratory demonstrated that C10 targets the PPARγ nuclear receptor, increasing the activity of the antioxidant enzyme catalase and thereby possibly modulating peroxisomal content. Here, we examined markers of peroxisomal content and activity in response to C10 and C8 exposure in neuronal-like SH-SY5Y cells. SH-SY5Y were treated with 250 mM C10 or C8 for a period of 6 days. Following this, biochemical markers of peroxisomal content and function were assessed, including acyl-coA oxidase activity, peroxisomal gene expression and peroxisomal VLCFA β-oxidation. Our findings revealed that C10 treatment augments acyl-CoA oxidase 1 (ACOx1) activity by 129% in comparison to control cells. An exploration into genes related to peroxisomal biosynthesis showed 23% increased expression of PEX11α upon C10 exposure, implying peroxisomal proliferation. Furthermore, it was observed that C10 exposure not only elevated ACOx1 activity but also enhanced peroxisomal β-oxidation of docosanoic acid (C22). Our findings bolster the premise that C10 functions as a peroxisome proliferator, influencing peroxisomal content and function. Further investigations are required to fully understand the mechanistic details as to how this may be beneficial in epilepsy and the potential implications with regards to peroxisomal disease.

UNASSIGNED: To evaluate the cost-effectiveness of adjuvant nivolumab compared with surveillance for the treatment of patients with high-risk muscle-invasive urothelial carcinoma (MIUC) after radical resection from a US healthcare payer perspective and to investigate the impact of alternative modeling approaches on the cost-effectiveness results.
UNASSIGNED: A four-state, semi-Markov model consisting of disease free, local recurrence, distant recurrence, and death health states was developed to investigate the cost-effectiveness of nivolumab compared with surveillance over a 30-year time horizon. The model used data from the randomized CheckMate 274 trial (NCT02632409) and published literature to inform transitions among health states, and inputs on cost, utility, adverse event, and disease management. Scenario analyses were conducted to investigate the impact of model structure and key assumptions on the results. One-way deterministic and probabilistic sensitivity analysis were conducted to investigate the robustness of the results.
UNASSIGNED: Total expected costs were higher with nivolumab ($162,278) compared with surveillance ($63,027). Nivolumab was associated with improved survival (1.61 life-years gained compared with surveillance) and an incremental gain of 0.98 quality-adjusted life-years (QALYs). Although total treatment costs were higher for nivolumab, cost offsets were observed because of delayed or avoided recurrences and deaths experienced with nivolumab compared with observation. The incremental cost-effectiveness and cost-utility ratios were $61,462/life-year and $100,930/QALY.
UNASSIGNED: At the time of analysis, CheckMate 274 had limited follow-up on disease-free survival and no overall survival data. The limited evidence necessitated assumptions on modeling survival after each type of recurrence.
UNASSIGNED: Nivolumab is estimated to be a life-extending and cost-effective option for adjuvant treatment of MIUC for patients who are at high risk of recurrence after undergoing radical resection in the United States. Using a threshold of $150,000/QALY, the cost-effectiveness conclusions remained consistent across the scenario and sensitivity analyses conducted.

UNASSIGNED: To present alternative approaches related to both structural assumptions and data sources for the development of a decision analytic model for evaluating the cost-effectiveness of adjuvant nivolumab compared with surveillance in patients with high-risk muscle-invasive urothelial carcinoma (MIUC) after radical resection.
UNASSIGNED: Alternative approaches related to both structural assumptions and data sources are presented to address challenges and data gaps, as well as discussion of strengths and limitations of each approach. Specifically, challenges and considerations related to the following are presented: (1) selection of a modeling approach (partitioned survival model or state transition model) given the available evidence, (2) choice of health state structure (three- or four-state) to model disease progression and subsequent therapy, (3) modeling of outcomes from subsequent therapy using tunnel states to account for time-dependent transition probabilities or absorbing health states with one-off costs and outcomes applied, and (4) methods for modeling health-state transitions in a setting where treatment has curative intent and available survival data are immature.
UNASSIGNED: Multiple considerations must be taken into account when developing an economic model for new, emerging oncology treatments in early lines of therapy, all of which can affect the model\'s overall ability to estimate (quality-adjusted) survival benefits over a lifetime horizon. This paper identifies a series of key structural and analytic considerations regarding modeling of nivolumab treatment in the adjuvant MIUC setting. Several alternative approaches with regard to structure and data have been included in a flexible cost-effectiveness model so the impact of the alternative approaches on model results can be explored. The impact of these alternative approaches on cost-effectiveness results are presented in a companion article. Our findings may also help inform the development of future models for other treatments and settings in early-stage cancer.

UNASSIGNED: Two randomized clinical trials, REDUCE and RESPECT, demonstrated that patent foramen ovale (PFO) closure in combination with antithrombotic therapy was more effective for the prevention of recurrent ischemic stroke compared with antithrombotic therapy alone. The aim of this study was to determine the relative efficacy and safety of the PFO closure devices used in REDUCE (HELEX and CARDIOFORM Septal Occluders) compared with the device used in RESPECT (Amplatzer PFO Occluder).
UNASSIGNED: An unanchored matching-adjusted indirect comparison (MAIC) of the PFO closure arms of the REDUCE and RESPECT trials was performed using patient-level data from REDUCE weighted to match baseline characteristics from RESPECT. Comparisons of the following outcomes were made between the devices assessed in the trials: risk of recurrent ischemic stroke; recurrent ischemic stroke one year after randomization; any serious adverse event (SAE) related to the procedure or device; and atrial fibrillation or atrial flutter as an SAE related to the procedure or device.
UNASSIGNED: After conducting the MAIC, baseline characteristics were well-matched between the two trials. Compared to RESPECT, PFO closure using the devices from REDUCE resulted in a hazard ratio of 0.46 (95% confidence interval [CI] 0.15-1.43; p = 0.17) for the risk of recurrent stroke. For the recurrence of stroke after one year, SAE related to the procedure or device, and atrial fibrillation or atrial flutter as SAE related to the procedure or device, the MAIC resulted in a rate difference of -0.68 (95%CI -2.06 to 0.70; p = .34), -1.29 (95%CI -3.82 to 1.25; p = .32), and -0.19 (95%CI -1.16 to 0.78; p = .71), respectively. These findings were consistent across scenario analyses.
UNASSIGNED: This MAIC analysis found no statistically significant differences in efficacy and safety outcomes between PFO closure with the HELEX and CARDIOFORM Septal Occluders versus the Amplatzer PFO Occluder, as used in the REDUCE and RESPECT trials.
The individual efficacy and safety of medical devices used for patent foramen ovale (PFO) closure in patients with stroke of unknown origin has been demonstrated in two independent trials: REDUCE (using the HELEX Septal Occluder and the CARDIOFORM Septal Occluder) and RESPECT (using the Amplatzer PFO Occluder). In the absence of a direct head-to-head trial for these devices, indirect treatment comparisons offer an alternative to assess their relative efficacy and safety. This study used a matching-adjusted indirect comparison to demonstrate that there were no significant differences between the devices used for PFO closure in the REDUCE and RESPECT trials in terms of safety outcomes.

To meet unmet medical needs, middle-to-large molecules, including peptides and oligonucleotides, have emerged as new therapeutic modalities. Owing to their middle-to-large molecular sizes, middle-to-large molecules are not suitable for oral absorption, but there are high expectations around orally bioavailable macromolecular drugs, since oral administration is the most convenient dosing route. Therefore, extensive efforts have been made to create bioavailable middle-to-large molecules or develop absorption enhancement technology, from which some successes have recently been reported. For example, Rybelsus® tablets and Mycapssa® capsules, both of which contain absorption enhancers, were approved as oral medications for type 2 diabetes and acromegaly, respectively. The oral administration of Rybelsus and Mycapssa exposes their pharmacologically active peptides with molecular weights greater than 1000, namely, semaglutide and octreotide, respectively, into systemic circulation. Although these two medications represent major achievements in the development of orally absorbable peptide formulations, the oral bioavailability of peptides after taking Rybelsus and Mycapssa is still only around 1%. In this article, we review the approaches and recent advances of orally bioavailable middle-to-large molecules and discuss challenges for improving their oral absorption.

The permeation enhancers (PEs) sodium caprate (C10) and sodium N-[8-(2-hydroxybenzoyl) amino] caprylate (SNAC) have been utilized for the intestinal and gastric delivery of macromolecules, respectively. However, the potential of C10 for the gastric delivery of a peptide and the ability of SNAC to deliver other peptides to the stomach beyond semaglutide have not been investigated. In this study, we have developed and evaluated C10 and SNAC-containing erodible tablets for the gastricdelivery of a glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GIP/GLP1) dual agonist peptide (LY) in cynomolgus monkeys. We also evaluated the impact of release rates on the in vivo performance of C10 and SNAC. Furthermore, we compared the oral exposure of the LY peptide and semaglutide with different proteolytic stabilities using a SNAC erodible tablet. Additionally, we investigated the mechanism of action of SNAC for improving gastric absorption of the LY peptide via tissue distribution in monkey. C10 and SNAC tablets released the peptide and PE by erosion from the tablet surface with 100 % release within 60 min at pH 6.8. Following a single oral administration to monkeys, C10 and SNAC erodible tablets at 300 mg exhibited similar LY mean absolute oral bioavailability of 5.7 % and 4.2 %, respectively. The C10 immediate release capsule (500 mg) with faster dissolution profile (10 min) showed a decrease in the LY oral bioavailability; however, a faster dissolution profile (15 min) with erodible SNAC tablet resulted in a relatively higher LY oral bioavailability compared to the slow-release erodible tablets (60 min). Using SNAC as the PE, the combination of slow-release tablet design and LY peptide with higher pepsin stability resulted in about 4-fold higher mean oral bioavailability in the monkeys than semaglutide (4.2 % vs 1.2 %, respectively). In the monkey gastric tissue, SNAC was found to reduce tight junction protein levels and increase the peptide uptake into the gastric epithelium suggesting its permeation enhancing mechanism via both paracellular and transcellular pathways. Taking these data altogether, the enhanced proteolytic stability of the LY peptide combined with the optimal erodible tablets enabled the gastric delivery of the LY peptide with a higher oral bioavailability than semaglutide.

UNASSIGNED: To assess the public health impact and cost effectiveness of gender-neutral vaccination (GNV) versus female-only vaccination (FOV) with human papillomavirus (HPV) vaccination in Japan.
UNASSIGNED: We modeled the public health impact and cost effectiveness of GNV versus FOV to prevent HPV-associated diseases in Japan over the next 100 years. We used one-way sensitivity analyses to examine the impact of varying key model input parameters and conducted scenario analyses to explore the effects of varying the vaccination coverage rate (VCR) of each cohort.
UNASSIGNED: In the base-case analysis, GNV averted additional cancer cases (17,228 female/6,033 male) and deaths (1,892 female/1,849 male) compared to FOV. When all HPV-associated diseases were considered, GNV had an incremental cost-effectiveness ratio of ¥4,732,320 (US$35,987)/quality-adjusted life year gained compared to FOV. The model was most sensitive to the discount rate and the disutility associated with HPV-related diseases. GNV had greater relative public health benefits when the female VCR was lower and was cost effective at a female VCR of 30%.
UNASSIGNED: Immediate implementation of GNV would reduce the disease burden and mortality associated with HPV in Japan, and would be cost effective compared to FOV if the female VCR remains low (30%).
Human papillomavirus (HPV) is a common sexually transmitted infection and, in Japan, the prevalence of HPV infection and the incidence of its associated diseases are high among both men and women. In the present manuscript we modeled the public health impact and cost effectiveness of gender-neutral vaccination versus female-only vaccination to prevent HPV-associated diseases in Japan over the next 100 years and found that immediate implementation of a gender-neutral vaccination strategy would reduce the burden and mortality associated with HPV in Japan.

This paper discusses the econometric model of causal policy analysis and two alternative frameworks that are popular in statistics and computer science. By employing the alternative frameworks uncritically, economists ignore the substantial advantages of an econometric approach, resulting in less informative analyses of economic policy. We show that the econometric approach to causality enables economists to characterize and analyze a wider range of policy problems than alternative approaches.

UNASSIGNED: This study compared the psychometric properties of EQ-5D-5L and SF-6D to assess the interchangeability of both instruments in patients with a recent fracture presenting at a Fracture Liaison Service (FLS).
UNASSIGNED: Data from a prospective observational study in a Dutch FLS clinic were used. Over 3 years, subjects were interviewed at several time points using EQ-5D-5L and SF-36. Floor and ceiling effects were evaluated. Agreement was evaluated by intra-class correlation coefficients and visualized in Bland-Altman plots. Spearman\'s rank correlation coefficients were applied to assess convergent validity. Mann-Whitney U test or Kruskal-Wallis H test as well as effect size (ES) were used to explore known-groups validity. Responsiveness was explored using standardized response mean (SRM) and ES. For each measurement property, hypotheses on direction and magnitude of effects were formulated.
UNASSIGNED: A total of 499 patients were included. EQ-5D-5L had a considerable ceiling effect in comparison to SF-6D (21 vs. 1.2%). Moderate agreement between the (UK and Dutch) EQ-5D-5L and SF-6D was identified with intra-class correlation coefficients of 0.625 and 0.654, respectively. Bland-Altman plots revealed proportional bias as the differences in utilities between two instruments were highly dependent on the health states. High correlation between instruments was found (UK: rho = 0.758; Dutch: rho = 0.763). EQ-5D-5L and SF-6D utilities showed high correlation with physical component score but low correlation with mental component score of SF-36. Both instruments showed moderate discrimination (ES > 0.5) for subgroup by baseline fracture type, and moderate responsiveness (SRM > 0.5) in patients that sustained a subsequent fracture.
UNASSIGNED: Both EQ-5D-5L and SF-6D appeared to be valid utility instruments in patients with fractures attending the FLS. However, they cannot be used interchangeably given only moderate agreement was identified, and differences in utilities and ceiling effect were revealed. Comparable construct validity and responsiveness were indicated, and neither instrument was found to be clearly superior.
The EQ-5D and SF-36 as generic multi-domain questionnaires are widely used to measure the health-related quality-of-life (HRQoL) in a sample of the persons who suffer from the diseases or the general population. Their responses could be converted to patients or societal Health State Utility Values (HSUVs) with the range of 0 (“death”) to 1 (“full health”). A specific application of HSUV is to calculate quality-adjusted life years as the indicator of effectiveness to evaluate whether the cost of a new intervention is justified in terms of health gains through cost-utility analysis in health economics, the evidence can be further used to inform decision-making. However, different instruments differ in construct and valuation, potentially leading to different estimates for the person’s same “health state”, and healthcare decisions could be compromised when researchers or decision-makers are not aware of potential differences in HSUV. Therefore, it is important to gain insight into the specific psychometric properties of these instruments, and to understand whether instruments are interchangeable. Our study is based on data from a Dutch Fracture Liaison Service (FLS is a program for secondary fracture prevention), compared the psychometric properties and interchangeability of two instruments (EQ-5D-5L and SF-6D) in patients with a recent fracture presenting at the FLS, and suggested both instruments are valid in utility elicitation in our target population. However, they cannot be used interchangeably given only moderate agreement and differences in utilities. Neither instrument was found to be clearly superior given comparable construct and longitudinal validity, but different instruments values in different aspects of HRQoL assessment.

OBJECTIVE: To assess the accuracy of standard parametric survival models, spline models, and mixture cure models (MCMs) fitted to overall survival (OS) data available at the time of submission in the NICE HTA process compared with data subsequently made available.
METHODS: Standard parametric distributions, spline models, and MCMs were fitted to OS data presented in single technology appraisals (TAs) for immune-checkpoint inhibitors (ICIs) in cancer. For each TA, the estimated survival from the fitted models was compared with Kaplan-Meier (KM) data that were made available following the HTA submission using differences between point estimates and restricted area under the curve (AUC) at both the midpoint and the end of additional follow-up. Differences in interval AUC values (calculated for each 6-month period) were also assessed.
RESULTS: Standard parametric survival models and spline models were more likely to underestimate longer-term survival, irrespective of the measure used to assess model accuracy. MCMs were more likely to overestimate survival; however, this was improved in some cases by applying an additional hazard of mortality for \"statistically cured\" patients.
CONCLUSIONS: The accuracy of the models was assessed based on much shorter OS data than the period for which extrapolation is needed, which may impact conclusions regarding the most accurate models. The most recent TAs for ICIs have not been captured.
CONCLUSIONS: There are no definitive findings that unquestionably support the use of one specific extrapolation technique. Rather, each has the potential to provide accurate or inaccurate extrapolation to longer-term data in certain circumstances, but the added flexibility of more complex models can be justified for treatments, like ICIs, that have extended survival for patients across disease areas. The use of mortality adjustments for \"statistically cured\" patients allows decision-makers to explore more conservative scenarios in the face of high decision uncertainty.