Long-Term Comparative Efficacy and Safety of Risdiplam and Nusinersen in Children with Type 1 Spinal Muscular Atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disease characterized by a loss of motor neurons and progressive muscle weakness. Children with untreated type 1 SMA never sit independently and require increasing levels of ventilatory support as the disease progresses. Without intervention, and lacking ventilatory support, death typically occurs before the age of 2 years. There are currently no head-to-head trials comparing available treatments in SMA. Indirect treatment comparisons are therefore needed to provide information on the relative efficacy and safety of SMA treatments for healthcare decision-making. METHODS: The long-term efficacy and safety of risdiplam versus nusinersen in children with type 1 SMA was evaluated using indirect treatment comparison methodology to adjust for differences between population baseline characteristics, to reduce any potential bias in the comparative analysis. An unanchored matching-adjusted indirect comparison was conducted using risdiplam data from 58 children in FIREFISH (NCT02913482) and published aggregate nusinersen data from 81 children obtained from the ENDEAR (NCT02193074) and SHINE (NCT02594124) clinical trials with at least 36 months of follow-up. RESULTS: Children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death, an 81% reduction in the rate of death or permanent ventilation, and a 57% reduction in the rate of serious adverse events compared with children treated with nusinersen. Children treated with risdiplam also had a 45% higher rate of achieving a Hammersmith Infant Neurological Examination, Module 2 motor milestone response and a 186% higher rate of achieving a ≥ 4-point improvement in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders compared with children treated with nusinersen. CONCLUSION: Long-term data supported risdiplam as a superior alternative to nusinersen in children with type 1 SMA. Video abstract available for this article. Video abstract (MP4 184542 KB).

Risdiplam and nusinersen are two approved treatments for patients with type 1 spinal muscular atrophy (SMA). There are currently no head-to-head trials that compare the outcomes of these treatments in patients. This study conducted a statistical comparison of the efficacy and safety of risdiplam and nusinersen in children with type 1 SMA who received treatment for at least 36 months. Risdiplam data were collected from 58 children who participated in the FIREFISH trial (NCT02913482). Published combined data were collected from 81 children treated with nusinersen who participated in the ENDEAR (NCT02193074) and SHINE (NCT02594124) trials. Outcomes from the two studies were compared using matching-adjusted indirect comparison (MAIC) methodology. MAIC adjusts for differences in baseline characteristics between patients in two trials to make the populations more similar and reduce bias in the comparison. Results suggested that children with type 1 SMA treated with risdiplam had a 78% reduction in the rate of death and an 81% reduction in the rate of death or permanent ventilation compared with children treated with nusinersen. With risdiplam, children also had a higher rate of achieving motor function responses, and a longer time to the first serious adverse event compared with children treated with nusinersen. These results support risdiplam as a superior alternative to nusinersen in children with type 1 SMA over 36 months of follow-up. Access to long-term data beyond 36 months would allow for additional indirect comparisons between SMA treatments. These comparisons are key to guiding treatment decision-making in the absence of head-to-head trials.

A systematic review and meta-analysis of environmental contaminant exposure impacts on weight loss and glucose regulation during calorie-restricted diets in preclinical studies: Persistent organic pollutants may impede glycemic control.

Epidemiological evidence links chemical exposure with type 2 diabetes (T2DM) risk and prevalence. Chemical exposure may therefore also limit success of weight loss or restoration of glycemic control during calorie restricted diets. Few human studies examine this hypothesis. This systematic review and clustered meta-analysis examines preclinical evidence that exposure to anthropogenic environmental contaminants impedes weight loss and resumption of glycemic control during calorie restriction. Of five eligible papers from 212 unique citations, four used C57BL/6 mice and one used Sprague Dawley rats. In four the animals received high fat diets to induce obesity and impaired glycemic control. All examined persistent organic pollutants (POPs). Polychlorinated biphenyl (PCB) 77 exposure did not affect final mass (standardised mean difference (SMD) = -0.35 [-1.09, 0.39]; n = 5 (experiments); n = 3 (papers)), or response to insulin in insulin tolerance tests (SMD = -1.54 [-3.25, 0.16] n = 3 (experiments); n = 2 (papers)), but impaired glucose control in glucose tolerance tests (SMD = -1.30 [-1.96, -0.63]; n = 6 (experiments); n = 3 (papers)). The impaired glycemic control following perfluoro-octane sulphonic acid (PFOS) exposure and enhanced mass loss following dichlorodiphenyltrichloroethane (DDT) exposure have not been replicated. Animal studies thus suggest some chemical groups, especially PCB and PFOS, could impair glucose control management during calorie restriction, similar to conclusions from limited existing clinical studies. We discuss the research that is urgently required to inform weight management services that are now the mainstay prevention initiative for T2DM.

Systematic Literature Review of the Natural History of Spinal Muscular Atrophy: Motor Function, Scoliosis, and Contractures.

BACKGROUND AND OBJECTIVES: Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder associated with continuous motor function loss and complications, such as scoliosis and contractures. Understanding the natural history of SMA is key to demonstrating the long-term outcomes of SMA treatments. This study reviews the natural history of motor function, scoliosis, and contractures in patients with SMA. METHODS: Electronic databases were searched from inception to June 27, 2022 (Embase, MEDLINE, and Evidence-Based Medicine Reviews). Observational studies, case-control studies, cross-sectional studies, and case series reporting on motor function (i.e., sitting, standing, and walking ability), scoliosis, and contracture outcomes in patients with types 1-3 SMA were included. Data on study design, baseline characteristics, and treatment outcomes were extracted. Data sets were generated from studies that reported Kaplan-Meier (KM) curves and pooled to generate overall KM curves. RESULTS: Ninety-three publications were included, of which 68 reported on motor function. Of these, 10 reported KM curves (3 on the probability of sitting in patients with types 2 and 3 SMA and 8 on the probability of walking/ambulation in patients with type 3 SMA). The median time to loss of sitting (95% CI) was 14.5 years (14.1-31.5) for the type 2 SMA sitter population (their maximum ability was independent sitting). The median time to loss of ambulation (95% CI) was 13.4 years (12.5-14.5) for type 3a SMA (disease onset at age younger than 3 years) and 44.2 years (43.0-49.4) for type 3b SMA (disease onset at age 3 years or older). Studies including scoliosis and contracture outcomes mostly reported non-time-to-event data. DISCUSSION: The results demonstrate that a high degree of motor function loss is inevitable, affecting patients of all ages. In addition, data suggest that untreated patients with types 2 and 3 SMA remain at risk of losing motor milestones during late adulthood, and patients with types 3a and 3b SMA are at risk of loss of ambulation over time. These findings support the importance of stabilization of motor function development even at older ages. Natural history data are key for the evaluation of SMA treatments as they contextualize the assessment of long-term outcomes.

Cost-effectiveness of voretigene neparvovec in the treatment of patients with inherited retinal disease with RPE65 mutation in Switzerland.

OBJECTIVE: We aimed to evaluate the cost-effectiveness of voretigene neparvovec (VN) compared with standard of care (SoC) for patients with inherited retinal disease (IRD) caused by a biallelic RPE65-mutation. VN is a live, non-replicating adeno-associated virus serotype 2 (AAV2). SoC is best supportive care provided to patients with visual impairment. Patients under SoC may experience progressive vision loss leading to complete blindness. METHODS: We adapted a previously published Markov cohort model for IRD. An annual cycle length, life-long time horizon, discount rate of 3% for cost and health outcomes, and Swiss health system perspective were used. Data from a randomised controlled phase III trial of VN versus SoC (ClinicalTrials.gov: NCT00999609) were used to estimate transitions between health states in the first year, after which VN patients were assumed to remain for 39 subsequent years in the health state they were in at the end of the first year. After the 40th year for VN patients and 1st year for SoC patients, visual decline was modelled based on observational data on the natural progression of the disease. Quality-adjusted life years (QALYs) were calculated based on an external study which elicited clinicians' EQ-5D-5L-based utility estimates for IRD patients with a RPE65-mutation. Costs (Swiss Francs (CHF), year 2018-2019) included drug acquisition/ administration, adverse events, testing for sufficient viable retinal cells, and healthcare-related costs of blindness. Societal costs of blindness were added in a complementary analysis. Robustness of the model results were tested in sensitivity and scenario analyses. RESULTS: For the base-case, VN resulted in incremental costs per patient of CHF 764'402 (VN: CHF 901'654, SoC: CHF 137'252), incremental blindness-free years of 7.67 (VN: 28.32, SoC: 20.65) and incremental QALYs of 6.73 (VN: 18.35, SoC: 11.62), leading to an incremental cost-effectiveness ratio of CHF 113'526 per QALY gained. In probabilistic sensitivity analysis, the cost-effectiveness of VN was better than CHF 100,000 per QALY gained in 41% of iterations. For the scenario analysis in which a societal perspective was adopted and for which a 50% work-related productivity loss from blindness was assumed, incremental costs of CHF 423,837 and an ICER of CHF 62'947 per QALY gained were produced. The scenario assuming VN treatment effect lasts for 20 years produced an ICER of CHF 156'171 per QALY gained, whereas assuming a life-long VN treatment effect resulted in an ICER of CHF 96'384 per QALY gained. CONCLUSION: The incremental cost-effectiveness ratio of VN compared to the SoC was estimated to be CHF 113'526 and CHF 62'947 per QALY gained, respectively, from a Swiss healthcare system, and societal perspective assuming a 50% productivity loss.

Accuracy in Facial Trustworthiness Impressions: Kernel of Truth or Modern Physiognomy? A Meta-Analysis.

Being able to identify trustworthy strangers is a critical social skill. However, whether such impressions are accurate is debatable. Critically, the field currently lacks a quantitative summary of the evidence. To address this gap, we conducted two meta-analyses. We tested whether there is a correlation between perceived and actual trustworthiness across faces, and whether perceivers show above-chance accuracy at assessing trustworthiness. Both meta-analyses revealed significant, modest accuracy (face level, r = .14; perceiver level, r = .27). Perceiver-level effects depended on domain, with aggressiveness and sexual unfaithfulness having stronger effects than agreeableness, criminality, financial reciprocity, and honesty. We also applied research weaving to map the literature, revealing potential biases, including a preponderance of Western studies, a lack of "cross-talk" between research groups, and clarity issues. Overall, this modest accuracy is unlikely to be of practical utility. Moreover, we strongly urge the field to improve reporting standards and generalizability of the results.

Preferences and Utilities for Treatment Attributes in Type 2 and Non-ambulatory Type 3 Spinal Muscular Atrophy in the United Kingdom.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disease that affects motor neurons, resulting in progressive skeletal muscle weakness and atrophy. OBJECTIVE: The aim was to understand the value patients with SMA and caregivers place on treatment attributes and to estimate health utilities for SMA treatment outcomes from a general public sample. METHODS: Two discrete choice experiments were designed to elicit treatment preferences and health utilities, respectively. Patients with Type 2 and non-ambulatory Type 3 SMA, caregivers of patients with SMA and a general public sample in the UK completed the surveys. Patients and caregiver participants were recruited through patient associations. General public participants were recruited via a survey recruitment panel. Attributes included motor function, breathing function, treatment administration, treatment reactions, eyesight monitoring, contraception (patients only) and overall survival (general public only). Clustered conditional logit models were used to estimate treatment preferences, and marginal rates of substitution were used to estimate disutilities. RESULTS: Adult patients (n = 84) were twice as likely to choose a treatment with improved (vs. stable) motor and breathing function and four to five times less likely to choose a treatment with deteriorated (vs. stable) motor and breathing function as a treatment outcome. Caregivers (n = 83) were three to nine times more likely to choose improved and two to four times less likely to choose deteriorated (vs. stable) motor and breathing function. Both patients and caregivers preferred oral over intrathecal treatment. Treatment reactions, eyesight monitoring or contraception had no significant effect on patient choices. Conversely, caregivers preferred avoidance of treatment reactions. General public data (n = 506) yielded disutilities for unable to sit (- 0.408), need for > 16 h daily mechanical breathing support (- 0.304) and intrathecal therapy (- 0.071). CONCLUSIONS: Study results show the importance of motor and breathing function to patients and caregivers, and an oral treatment preference. Disutilities (decrements to utility) were substantial for SMA disease outcomes and care aspects.

Systematic Literature Review to Assess Economic Evaluations in Spinal Muscular Atrophy (SMA).

BACKGROUND: Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease that affects individuals with a broad age range. SMA is typically characterised by symmetrical muscle weakness but is also associated with cardiac defects, life-limiting impairments in respiratory function and bulbar function defects that affect swallowing and speech. Despite the advent of three innovative disease-modifying therapies (DMTs) for SMA, the cost of DMTs in addition to the costs of standard of care can be a barrier to treatment access for patients. Health Technology Assessment (HTA) decision makers evaluate the cost effectiveness of a new treatment before making a reimbursement decision. OBJECTIVE: The primary objective was to conduct a systematic literature review (SLR) to identify the modelling approaches used in economic evaluations that assess current approved treatments in SMA, with a secondary objective to widen the scope and identify economic evaluations assessing other (non-SMA) neuromuscular disorders. METHODS: An SLR was performed to identify available economic evaluations associated with any type of SMA (Type 1, 2, 3 and/or 4). Economic evaluations associated with other (non-SMA) neuromuscular disorders were identified but not further analysed. Electronic searches were conducted in Embase, MEDLINE, Evidence-Based Medicine Reviews and EconLit via the Ovid platform in August 2019, and were supplemented by searches of the grey literature (reference lists, conference proceedings, global HTA body websites and other relevant sources). Eligibility criteria were based on the population, interventions, comparators and outcomes (PICO) framework. Quality assessment of full publications was conducted with reference to a published checklist. RESULTS: Nine publications covering eight unique studies met all eligibility criteria for inclusion in the SLR, including four conference abstracts, two peer-reviewed original research articles and three HTA submissions (conducted in Canada, the US and the UK). Evaluations considered patients with early infantile-onset (most likely to develop Type 1 or Type 2 SMA), later-onset SMA and both infantile- and later-onset SMA. Data for the identified economic models were collected from literature reviews and relatively short-term clinical trials. Several intent-to-treat clinical trial populations were used in the studies, which resulted in variation in cycle length and different outcome measures to determine clinical efficacy. The results of the quality assessment on the five full-text, peer-reviewed publications found that they generally provided clear descriptions of objectives, modelling methods and results. However, key decisions, such as choice of economic evaluation, model type and choice of variables for sensitivity analysis, were often not adequately justified. CONCLUSIONS: This SLR highlights the need for economic evaluations in SMA to better align in modelling approaches with respect to (i) consistency in model structure and use of motor function milestones as health states; (ii) consensus on measuring quality of life to estimate utilities; (iii) consistency in data collection by registries; and (iv) consensus on SMA-type classification and endpoints that determine intervention efficacy. Future economic evaluations should also incorporate the review group critiques of previous HTA submissions relating to data inputs and approaches to modelling and should include patient data reflective of the SMA population being modelled. Economic evaluations would also be improved with inclusion of long-term efficacy and safety data from clinical trials and valid patient and caregiver utility data.

Systematic Literature Review to Assess the Cost and Resource Use Associated with Spinal Muscular Atrophy Management.

BACKGROUND: Spinal muscular atrophy (SMA) is a severe neuromuscular disease that is inherited in an autosomal recessive manner with an estimated incidence of 1 in 10,000 live births. The traditional classification of SMA includes five types (Types 0-4 SMA) based on patient age at disease onset and the highest motor milestone achieved. Spinal muscular atrophy leads to progressive muscle denervation, skeletal muscle atrophy and loss of motor function and ambulation, though phenotypes vary along a disease continuum. Regardless of disease severity, or access to treatment, a multidisciplinary approach to care is required to ease the burden of disease. To date, limited global data exist regarding the cost and resource use associated with SMA management. OBJECTIVE: We planned to perform a systematic literature review to identify studies on cost and healthcare resource use associated with SMA. METHODS: A comprehensive search was conducted in 2019 using several electronic databases in addition to supplementary sources and updated in 2021 in order to capture recently published studies. Electronic searches performed in Embase, MEDLINE, Evidence-Based Medicine Reviews and EconLit via the Ovid platform were supplemented by searches of the grey literature (reference lists, conference proceedings, global Health Technology Assessment body websites and other relevant sources). Study eligibility criteria were based on the population, interventions, comparators and outcomes (PICO) framework. Quality assessment of full-text publications was evaluated with reference to a published checklist. To accommodate heterogeneity across studies including countries, currencies, populations, time units and methods of reporting used, costs were reported in Euros in 2019. RESULTS: A total of 51 publications, comprising 49 unique studies of patients with SMA that met all eligibility criteria were included in the final selection. The publications comprised data from 14 countries and seven additional studies that reported multi-national data. Because of the heterogeneity between the different types of SMA, data were frequently reported separately for individuals with Type 1 or early-onset SMA and for Types 2, 3, and 4 SMA or later-onset SMA. Generally, direct medical costs and resource use were reported to be highest for patients with Type 1 SMA, decreasing incrementally for patients with Type 2 and Type 3 disease. Where cost categories were similar, direct costs were much lower in Europe than in the USA. Indirect costs were primarily associated with informal care, which was a substantial burden on patients and families in terms of both cost and time. Cost drivers were generally found to be dependent on SMA type. CONCLUSIONS: Long-term robust studies are required to fully elucidate the economic burden of SMA. Considering that motor function can vary broadly, especially in Type 2 SMA, it would be beneficial to understand how costs and resource use are affected by different degrees of ambulation. Reporting data in terms of achieved motor function could also mitigate the challenges of comparing global data studies of small populations. Global, regional, and/or local data collection platforms and disease registry networks could play an important role in helping to address current data gaps.

Systematic Literature Review to Identify Utility Values in Patients with Spinal Muscular Atrophy (SMA) and Their Caregivers.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder that has a substantial impact on health-related quality of life for patients with SMA and their caregivers. Utility values ('utilities') are used in health economic analyses to incorporate individual or societal perspectives regarding the desirability of health outcomes such as a certain health state or change in health states over time. OBJECTIVES: The primary objective of this systematic literature review (SLR) was to identify published utilities associated with patients with SMA and their caregivers and to determine the extent to which Health Technology Assessment (HTA) requirements of methods used to generate utilities are met. A secondary objective was to broaden the scope to identify utilities associated with other (non-SMA) neuromuscular disorders. METHODS: A comprehensive search to capture published utilities associated with patients with SMA and their caregivers was performed in 2019 and updated in 2021 using several electronic databases in addition to supplementary sources. As we anticipated that few published utilities associated with SMA would be identified, the search also captured utilities for other (non-SMA) neuromuscular disorders that may serve as useful surrogate values for studies of SMA and other rare diseases. Electronic searches were performed in Embase, MEDLINE, Evidence-Based Medicine Reviews, and EconLit via the Ovid platform and were supplemented by searches of the grey literature (reference lists, conference proceedings, global HTA body websites, and other relevant sources). Study eligibility criteria were based on the population, interventions, comparators, and outcomes (PICO) framework. The quality of the full-text publications was assessed using a checklist based on UK National Institute for Health and Care Excellence technical support documents. RESULTS: In total, 14 publications that reported SMA-related patient or caregiver utilities or disutilities met the eligibility criteria to be included in the SLR; the included studies demonstrate the substantial health-related quality-of-life burden of SMA on both patients with SMA and their caregivers. A variety of preference-based measures were used to derive utilities for patients with SMA and their caregivers. Different methods for collecting utility data included patient and proxy assessment of health states using questionnaires, vignette methodologies, structured forms of expert elicitation, and mapped data from results of clinical trials. A range of utilities was reported from both patient- and proxy-reported data, which reflects the degree of disability associated with early- and later-onset SMA. Methods for deriving utilities were assessed with respect to three reference cases from HTA bodies in the UK, the USA, and Canada. None of the 14 publications met the requirements of all three HTA bodies because of differing tariff requirements between countries; one study met the requirements of HTA bodies in Canada and the UK. Also, six studies did not report the method of valuation, which precluded analysis with respect to the HTA reference cases. CONCLUSIONS: This SLR provides a comprehensive repository of the currently available utilities relevant to patients with SMA and their caregivers. This SLR provides recommendations for establishing consensus on the approach to generating utility values for the SMA patient population and their caregivers for health economic decisions.

Cost-Effectiveness Analysis of Patiromer in Combination with Renin-Angiotensin-Aldosterone System Inhibitors for Chronic Kidney Disease in Sweden.

OBJECTIVES: Patients with chronic kidney disease (CKD) are commonly treated with renin-angiotensin-aldosterone system inhibitors (RAASi) in order to delay progression of renal disease. However, research has shown that RAASi in CKD patients increases hyperkalaemia (HK) prevalence, which leads to RAASi discontinuation or dose reduction with the loss of benefits on the kidney. Patiromer is a novel therapy for HK treatment and may enable patients to remain on their RAASi regimen. This study aimed to assess the cost-effectiveness of patiromer from a Swedish healthcare perspective. METHODS: A Markov model was developed to evaluate the economic outcomes of patiromer versus no patiromer in HK patients with stage 3-4 CKD taking RAASi. The model consisted of six health states reflecting disease progression and hospitalisations. The analysis mainly considered clinical data from the OPAL-HK trial and national costs. The main outcomes of interest were incremental costs (euro [EUR] 2016) and quality-adjusted life years (QALYs), discounted at 3%, and the incremental cost-effectiveness ratio (ICER). Extensive uncertainty analyses were performed. RESULTS: In comparison to no patiromer, a patiromer patient gained 0.14 QALYs and an incremental cost of EUR 6109 (Swedish krona [SEK] 57,850), yielding an ICER of EUR 43,307 (SEK 410,072)/QALY gained. The results were robust to a range of sensitivity analyses. At a willingness-to-pay threshold of EUR 52,804 (SEK 500,000)/QALY, patiromer had a 50% chance of being cost-effective. CONCLUSIONS: The results indicate that patiromer may demonstrate value for money in Swedish patients with stage 3-4 CKD, by enabling RAASi treatment. However, there is a considerable degree of uncertainty.

Evaluating the Cost-Effectiveness of Early Compared with Late or No Biologic Treatment to Manage Crohn's Disease using Real-World Data.

BACKGROUND AND AIMS: We evaluated the cost-effectiveness of early [≤2 years after diagnosis] compared with late or no biologic initiation [starting biologics >2 years after diagnosis or no biologic use] for adults with Crohn's disease in Switzerland. METHODS: We developed a Markov cohort model over the patient's lifetime, from the health system and societal perspectives. Transition probabilities, quality of life, and costs were estimated using real-world data. Propensity score matching was used to ensure comparability between patients in the early [intervention] and late/no [comparator] biologic initiation strategies. The incremental cost-effectiveness ratio [ICER] per quality-adjusted life year [QALY] gained is reported in Swiss francs [CHF]. Sensitivity and scenario analyses were performed. RESULTS: Total costs and QALYs were higher for the intervention [CHF384 607; 16.84 QALYs] compared with the comparator [CHF340 800; 16.75 QALYs] strategy, resulting in high ICERs [health system: CHF887 450 per QALY; societal: CHF449 130 per QALY]. In probabilistic sensitivity analysis, assuming a threshold of CHF100 000 per QALY, the probability that the intervention strategy was cost-effective was 0.1 and 0.25 from the health system and societal perspectives, respectively. In addition, ICERs improved when we assumed a 30% reduction in biologic prices [health system: CHF134 502 per QALY; societal: intervention dominant]. CONCLUSIONS: Early biologic use was not cost-effective, considering a threshold of CHF100 000 per QALY compared with late/no biologic use. However, early identification of patients likely to need biologics and future drug price reductions through increased availability of biosimilars may improve the cost-effectiveness of an early treatment approach.

Economic evaluation of a novel genetic screening test for risk of venous thromboembolism compared with standard of care in women considering combined hormonal contraception in Switzerland.

AIM: The aim of this study was to assess the cost effectiveness of the Pill Protect (PP) genetic screening test for venous thromboembolism (VTE) risk compared with standard of care (SoC), for women considering combined hormonal contraceptives (CHCs) in Switzerland. METHODS: A two-part microsimulation model was developed to estimate VTE events, costs and quality-adjusted life years (QALYs) associated with the PP and SoC strategies. In the first portion of the model, a cohort of 1 million Swiss first-time seekers of a CHC were simulated. It was determined whether each women would receive a CHC or non-CHC by using prescribing patterns elicited from a modified Delphi study. These results formed the basis of the SoC strategy. For the PP strategy, a PP test was included and the results considered in addition to SoC practice. Each woman then entered a Markov model that captured morbidity and mortality over a lifetime. The risk of having a VTE was derived from the risk algorithm that underpins the PP test. The remaining model inputs relating to population characteristics, costs, health resource use, mortality and utilities were derived from published studies or national sources. The model was validated and calibrated to align with population-based studies. Extensive uncertainty analyses were conducted. RESULTS: From a Swiss health system perspective, the PP strategy in comparison with the SoC strategy generated an additional CHF 231, and gained 0.003 QALYs per woman, leading to an incremental cost-effectiveness ratio of CHF 76 610 per QALY gained. Assuming a threshold of CHF 100 000 per QALY gained, the PP strategy is likely to be cost effective. Our results were generally robust to variations in the parameter values. CONCLUSIONS: The PP test may be cost effective in Switzerland for screening women seeking CHCs for their risk of VTE based on the current evidence.

Is the elimination of 'sleeping sickness' affordable? Who will pay the price? Assessing the financial burden for the elimination of human African trypanosomiasis Trypanosoma brucei gambiense in sub-Saharan Africa.

INTRODUCTION: Programme to eliminate neglected tropical diseases (NTDs) have gained global recognition, and may allow for improvements to universal health coverage and poverty alleviation. It is hoped that elimination of human African trypanosomiasis (HAT) Trypanosoma brucei gambiense (Tbg) would assist in this goal, but the financial costs are still unknown. The objective of this analysis was to forecast the financial burden of direct costs of HAT Tbg to funders and society. METHODS: In order to estimate the total costs to health services and individuals: (1) potential elimination programmes were defined; (2) the direct costs of programmes were calculated; (3) the per case out-of-pocket payments (OOPs) by programme and financial risk protection indicators were estimated. The total estimated costs for control and elimination programme were reported up till 2020 in international dollars. The mean results for both direct programme costs and OOPs were calculated and reported along with 95% CIs. RESULTS: Across sub-Saharan Africa, HAT Tbg maintaining 'Control' would lead to a decline in cases and cost US$630.6 million. In comparison, the cost of 'Elimination' programme ranged from US$410.9 million to US$1.2 billion. Maintaining 'Control' would continue to cause impoverishment and financial hardship to households; while all 'Elimination' programme would lead to significant reductions in poverty. CONCLUSION: Overall, the total costs of either control or elimination programme would be near US$1 billion in the next decade. However, only elimination programme will reduce the number of cases and improve financial risk protection for households who are impacted by HAT Tbg.

Ethical Considerations for Global Health Decision-Making: Justice-Enhanced Cost-Effectiveness Analysis of New Technologies for Trypanosoma brucei gambiense.

We sought to assess formally the extent to which different control and elimination strategies for human African trypanosomiasis Trypanosoma brucei gambiense (Gambiense HAT) would exacerbate or alleviate experiences of societal disadvantage that traditional economic evaluation does not take into account. Justice-enhanced cost-effectiveness analysis (JE-CEA) is a normative approach under development to address social justice considerations in public health decision-making alongside other types of analyses. It aims to assess how public health interventions under analysis in comparative evaluation would be expected to influence the clustering of disadvantage across three core dimensions of well-being: agency, association and respect. As a case study to test the approach, we applied it to five strategies for Gambiense HAT control and elimination, in combination with two different other evaluations: a cost-effectiveness analysis and a probability of elimination analysis. We have demonstrated how JE-CEA highlights the ethical importance of adverse social justice impacts of otherwise attractive options and how it indicates specific modifications to policy options to mitigate such impacts. JE-CEA holds promise as an approach to help decision makers and other stakeholders consider social justice more fully, explicitly and systematically in evaluating public health programs.

A systematic review of cost-effectiveness analysis of screening interventions for assessing the risk of venous thromboembolism in women considering combined oral contraceptives.

Use of combined oral contraceptives (COCs) by women increases the risk of venous thromboembolism (VTE), which can have a major impact on an individuals' quality of life. VTE is also associated with an increase in healthcare costs. Our aim was to systematically review cost-effectiveness analyses (CEAs) considering any screening for risk of VTE in women using COCs. The quality of reporting in each study was assessed, a summary of results was prepared, and the key drivers of cost effectiveness in each of the eligible CEAs were identified. A search strategy using MeSH terms was performed in MEDLINE, Embase, the Centre for Review and Dissemination (CRD) database including the Economic Evaluation Database from the UK National Health Service, and Cochrane reviews. Two reviewers independently screened and determined the final articles, and a third reviewer resolved any discrepancies. Consolidated Health Economic Evaluation Reporting Standards was used to assess the quality of reporting in terms of perspective, effectiveness measures, model structure, cost, time-horizon and discounting. Four publications (three from Europe, one from the United States) were eligible for inclusion in the review. According to current criteria, relevant elements were sometimes not captured and the sources of epidemiological and effectiveness data used in the CEAs were of limited quality. The studies varied in terms of type of costs assessed, country settings, model assumptions and uncertainty around input parameters. Key drivers of CEAs were sensitivity and specificity of the test, incidence rate of VTE, relative risk of prophylaxis, and costs of the test. The reviewed studies were too dissimilar to draw a firm conclusion on cost-effectiveness analysis about universal and selective screening in high-risk groups. The new emerging diagnostic tools for identifying women at risk of developing VTE, that are more predictive and less costly, highlight the need for more studies that apply the latest evidence and utilize robust methods for cost-effectiveness analysis. This information is required to improve decision making for this pertinent issue within personalized medicine.

A dissociation in judgements of confidence in people with dandruff based on self-reports compared to reports from other observers.

OBJECTIVE: It is not clear how well evaluations made by other people correspond with self-evaluations of esteem or confidence. To address this question, we compared measurements of confidence in participants with and without dandruff. METHODS: Participants with dandruff were significantly different from healthy control participants on a quality of life measure of scalp dermatitis, but not on self-evaluations of esteem or confidence. To determine whether there were differences in the evaluation of confidence by others, both groups of participants were videoed while they prepared for or gave a presentation in an interview scenario. RESULTS: Raters, who were unfamiliar with the identities of the participants, evaluated confidence from the muted videos. In contrast to their self-evaluations, male participants with dandruff were rated as having lower confidence compared to participants who reported a healthy scalp. CONCLUSIONS: These findings reveal a difference between explicit and implicit measures of self-esteem in men compared to women with dandruff.

Seeing beyond 2020: an economic evaluation of contemporary and emerging strategies for elimination of Trypanosoma brucei gambiense.

BACKGROUND: Trypanosoma brucei (T b) gambiense is targeted to reach elimination as a public health problem by 2020 and full elimination by 2030. To achieve these goals, stakeholders need to consider strategies to accelerate elimination. Hence, we aimed to model several options related to current and emerging methods for case detection, treatment, and vector control across settings to assess cost-effectiveness and the probability of elimination. METHODS: Five intervention strategies were modelled over 30 years for low, moderate, and high transmission settings. Model parameters related to costs, efficacy, and transmission were based on available evidence and parameter estimation. Outcomes included disability-adjusted life-years (DALYs), costs, and long-term prevalence. Sensitivity analyses were done to calculate the uncertainty of the results. FINDINGS: To reach elimination targets for 2020 across all settings, approaches combining case detection, treatment, and vector control would be most effective. Elimination in high and moderate transmission areas was probable and cost-effective when strategies included vector control and novel methods, with incremental cost-effectiveness ratios (ICERs) ranging from US$400 to $1500 per DALY averted. In low transmission areas, approaches including the newest interventions alone or in combination with tiny targets (vector control) were cost-effective, with ICERs of $200 or $1800 per DALY averted, respectively, but only strategies including vector control were likely to lead to elimination. Results of sensitivity analyses showed that allowing for biennial surveillance, reducing vector control maintenance costs, or variations of active surveillance coverage could also be cost-effective options for elimination, depending on the setting. INTERPRETATION: Although various strategies might lead to elimination of T b gambiense, cost-effective approaches will include adoption of emerging technologies and, in some settings, increased surveillance or implementation of vector control. FUNDING: Bill & Melinda Gates Foundation.

The effect of dietary intervention on the metabolic and behavioural impairments generated by short term high fat feeding in the rat.

Previous studies have shown that rats fed a high calorie diet rich in saturated fat for 12weeks exhibit peripheral insulin resistance and impairments of behavioural flexibility when switched from an operant delayed matching to place (DMTP) schedule to a delayed non-matching to place (DNMTP) schedule. However, the metabolic changes evoked by feeding a high fat (HF) diet can be observed within two weeks of commencing the diet. The current study has confirmed that 4weeks exposure to an HF diet resulted in increased body weight, peripheral insulin resistance and plasma leptin. Studies performed during weeks 3 and 4 on the HF diet revealed suppressed lever pressing rates and impaired behavioural flexibility in the operant DMTP/DNMTP task. When animals fed the HF diet were then returned to a standard chow (SC) diet for 5weeks their weight and blood biochemistry no longer differed from those measured in animals that had never been exposed to the HF diet. The animals restored to the SC diet exhibited a clear ability to acquire the DNMTP schedule of reinforcement although these animals continued to lever press at a lower rate when compared with animals that received the SC diet throughout. The data suggest that exposure to an HF diet diminishes the motivation to respond for a reward and, thus, the capacity to adapt behavioural performance. This deficit was ameliorated, but not totally reversed, by the dietary intervention. If also true for humans, the results suggest that deficits in behavioural flexibility develop after only a short period on a high calorie diet but may be largely reversible through simple dietary intervention, at least in the early stages of deficit development. However, the putative effects of short-term exposure to an HF diet on behavioural motivation may persist for some time after switching to a healthier low fat diet and remain a problem for those seeking to adopt a healthier diet.

Antibody responses to surface antigens of Plasmodium falciparum gametocyte-infected erythrocytes and their relation to gametocytaemia.

An essential element for continuing transmission of Plasmodium falciparum is the availability of mature gametocytes in human peripheral circulation for uptake by mosquitoes. Natural immune responses to circulating gametocytes may play a role in reducing transmission from humans to mosquitoes. Here, antibody recognition of the surface of mature intra-erythrocytic gametocytes produced either by a laboratory-adapted parasite, 3D7, or by a recent clinical isolate of Kenyan origin (HL1204), was evaluated longitudinally in a cohort of Ghanaian school children by flow cytometry. This showed that a proportion of children exhibited antibody responses that recognized gametocyte surface antigens on one or both parasite lines. A subset of the children maintained detectable anti-gametocyte surface antigen (GSA) antibody levels during the 5 week study period. There was indicative evidence that children with anti-GSA antibodies present at enrolment were less likely to have patent gametocytaemia at subsequent visits (odds ratio = 0·29, 95% CI 0·06-1·05; P = 0·034). Our data support the existence of antigens on the surface of gametocyte-infected erythrocytes, but further studies are needed to confirm whether antibodies against them reduce gametocyte carriage. The identification of GSA would allow their evaluation as potential anti-gametocyte vaccine candidates and/or biomarkers for gametocyte carriage.