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Per- and polyfluoroalkyl substances (PFAS) are a group of synthetic, highly fluorinated aliphatic compounds, commonly utilised in a wide variety of consumer products with diverse applications. Since the genesis of these compounds, a growing body of evidence has demonstrated adverse health effects associated with PFAS exposure. In a racially diverse cohort of 459 pregnant mothers, demographically weighted towards minority representation (black 44.4%, white 38.4%, other 17.2%), across three major populous cities of the US, PFAS profiling was performed. Nine distinct PFAS species were quantified using mass spectrometry in plasma samples collected during the third trimester. Multivariable logistic and linear regression analyses were conducted to interrogate the associations of PFAS with gestational and birth outcomes: gestational diabetes, preeclampsia, gestational age at delivery, low birth weight, birth weight-, birth length- and head circumference-for-gestational-age. Detectable levels for eight out of nine profiled PFAS species were found in the plasma of pregnant mothers with a median range of 0.1-2.70 ng ml -1 . Using a mixtures approach, we observe that increased quantile-based g-computation (Qg-comp) "total" PFAS levels were associated with increased newborn birth-weight-for-gestational-age ( β 1.28; 95% CI 1.07-1.52; FDR p 0.006). In study centre-stratified analyses, we observed a similar trend in Boston pregnant mothers, with Qg-comp total PFAS associated with higher newborn birth-weight-for-gestational-age ( β 1.39; 95% CI 1.01-1.92, FDR p 0.05). We additionally found elevated PFUA concentrations were associated with longer gestational terms in San Diego pregnant mothers ( β 0.60; 95% CI 0.18-1.02, FDR p 0.05). In this multi-city study, we detected lower levels of PFAS than in many previous US environmental studies, concordant with current US trends indicating environmental PFAS levels are falling, and we note geographical variation in the associations between PFAS levels and birth outcomes., Competing Interests: No authors declare no competing interests., (This journal is © The Royal Society of Chemistry.)

Exposure to per- and polyfluoroalkyl substances (PFAS) through the environment can lead to harmful health outcomes and the development of disease. However, little is known about how PFAS impact underlying biology that contributes to these adverse health effects. The metabolome represents the end product of cellular processes and has been used previously to understand physiological changes that lead to disease. In this study, we investigated whether exposure to PFAS was associated with the global, untargeted metabolome. In a cohort of 459 pregnant mothers and 401 children, we quantified plasma concentrations of six individual PFAS- PFOA, PFOS, PFHXS, PFDEA, and PFNA- and performed plasma metabolomic profiling by UPLC-MS. In adjusted linear regression analysis, we found associations between plasma PFAS and perturbations in lipid and amino acid metabolites in both mothers and children. In mothers, metabolites of 19 lipid pathways and 8 amino acid pathways were significantly associated with PFAS exposure at an FDR<0.05 threshold; in children, metabolites of 28 lipid pathways and 10 amino acid pathways exhibited significant associations at FDR<0.05 with PFAS exposure. Our investigation found that metabolites of the Sphingomyelin, Lysophospholipid, Long Chain Polyunsaturated Fatty Acid (n3 and n6), Fatty Acid- Dicarboxylate, and Urea Cycle showed the most significant associations with PFAS, suggesting these may be particular pathways of interest in the physiological response to PFAS. To our knowledge, this is the first study to characterize associations between the global metabolome and PFAS across multiple periods in the life course to understand impacts on underlying biology, and the findings presented here are relevant in understanding how PFAS disrupt normal biological function and may ultimately give rise to harmful health effects., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: To improve the diagnosis and survival of children living with HIV (CLWH), the World Health Organization recommends testing approaches beyond traditional infant HIV testing programmes. Information about undiagnosed HIV prevalence among children of varying ages in the general population is needed to guide innovative national/subnational case-finding and testing approaches., Methods: We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-Pediatric model to estimate the prevalence of undiagnosed HIV in 2-, 5- and 10-year-old children in South Africa, Côte d'Ivoire and Zimbabwe in 2018. We simulated cohorts of children born in 2008 (10-year-olds), 2013 (5-year-olds) and 2016 (2-year-olds). Country-/year-specific inputs for pregnant/breastfeeding women included: HIV prevalence (4.2-32.3%), HIV incidence (0.03-0.24%/month), knowledge of HIV status (27-89%) and antiretroviral drug coverage (36-95%). Paediatric inputs included early infant testing coverage (6-95%) and breastfeeding duration (0-20 months). We projected the proportion of surviving CLWH in whom HIV remained undiagnosed and the undiagnosed HIV prevalence among surviving children of each age in the general population. For children born in 2016, we projected survival and diagnosis of all CLWH through 2026. We conducted sensitivity analyses on model parameters., Results: In 2018, the projected proportion of surviving CLWH whose HIV remained undiagnosed in South Africa/Côte d'Ivoire/Zimbabwe was 44.2%/55.8%/52.9% among 2-year-old CLWH; 29.0%/37.8%/33.2% among 5-year-old CLWH; and 18.3%/25.4%/23.1% among 10-year-old CLWH. Projected general population undiagnosed HIV prevalence in South Africa/Côte d'Ivoire/Zimbabwe was 0.44%/0.32%/0.68% among 2-year-olds; 0.25%/0.17%/0.41% among 5-year-olds; and 0.24%/0.14%/0.38% among 10-year-olds. Among all CLWH born in 2016, 50-54% were projected to die without HIV diagnosis (and subsequently without treatment) within 10 years after birth; 80-85% of these deaths occurred in the first 2 years., Conclusions: Projected population-level undiagnosed HIV prevalence is low and sharply decreases after age 2, with more CLWH dying than being diagnosed. Despite low undiagnosed prevalence in the general population of older children, we project that a large proportion of CLWH remain undiagnosed, suggesting that innovative strategies targeting untested children of all ages outside of health facility settings should be prioritized. Programmes could consider routine testing of the general population of children below 2 in all settings and children of all ages in high-prevalence settings., (© 2022 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Background: In Ukraine, there is no established colorectal cancer screening program. We aimed to project the number of screening colonoscopies needed for implementation of various CRC screening strategies in Ukraine., Methods: We modified a previously developed Markov microsimulation model to reflect the natural history of adenoma and CRC progression among average-risk 50-74-year-olds. We simulated colonoscopies needed for the following screening strategies: no screening, fecal occult blood test yearly, FOBT yearly with flexible sigmoidoscopy every 5 years, FS every 5 years, fecal immunohistochemistry test (FIT) yearly, or colonoscopy every 10 years. Assuming 80% screening adherence, we estimated colonoscopies required at 1 and 5 years depending on the implementation rate. In one-way sensitivity analyses, we varied implementation rate, screening adherence, sensitivity, and specificity., Results: Assuming an 80% screening adherence and complete implementation (100%), besides a no screening strategy, the fewest screening colonoscopies are needed with an FOBT program, requiring on average 6,600 and 26,800 colonoscopies per 100,000 persons at 1 and 5 years post-implementation, respectively. The most screening colonoscopies are required with a colonoscopy program, requiring on average 76,600 and 101,000 colonoscopies per 100,000 persons at 1 and 5 years post-implementation, respectively. In sensitivity analyses, the biggest driver of number of colonoscopies needed was screening adherence., Conclusions: The number of colonoscopies needed and therefore the potential strain on the healthcare system vary substantially by screening test. These findings can provide valuable information for stakeholders on equipment needs when implementing a national screening program in Ukraine., (© 2022. The Author(s) under exclusive licence to Société Internationale de Chirurgie.)

The application of large-scale metabolomic profiling provides new opportunities for realizing the potential of omics-based precision medicine for asthma. By leveraging data from over 14,000 individuals in four distinct cohorts, this study identifies and independently replicates 17 steroid metabolites whose levels were significantly reduced in individuals with prevalent asthma. Although steroid levels were reduced among all asthma cases regardless of medication use, the largest reductions were associated with inhaled corticosteroid (ICS) treatment, as confirmed in a 4-year low-dose ICS clinical trial. Effects of ICS treatment on steroid levels were dose dependent; however, significant reductions also occurred with low-dose ICS treatment. Using information from electronic medical records, we found that cortisol levels were substantially reduced throughout the entire 24-hour daily period in patients with asthma who were treated with ICS compared to those who were untreated and to patients without asthma. Moreover, patients with asthma who were treated with ICS showed significant increases in fatigue and anemia as compared to those without ICS treatment. Adrenal suppression in patients with asthma treated with ICS might, therefore, represent a larger public health problem than previously recognized. Regular cortisol monitoring of patients with asthma treated with ICS is needed to provide the optimal balance between minimizing adverse effects of adrenal suppression while capitalizing on the established benefits of ICS treatment., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: We compared the cost-effectiveness of pediatric provider-initiated HIV testing and counseling (PITC) vs no PITC in a range of clinical care settings in South Africa., Methods: We used the Cost-Effectiveness of Preventing AIDS Complications Pediatric model to simulate a cohort of children, aged 2-10 years, presenting for care in 4 settings (outpatient, malnutrition, inpatient, tuberculosis clinic) with varying prevalence of undiagnosed HIV (1.0%, 15.0%, 17.5%, 50.0%, respectively). We compared "PITC" (routine testing offered to all patients; 97% acceptance and 71% linkage to care after HIV diagnosis) with no PITC. Model outcomes included life expectancy, lifetime costs, and incremental cost-effectiveness ratios (ICERs) from the health care system perspective and the proportion of children with HIV (CWH) diagnosed, on antiretroviral therapy (ART), and virally suppressed. We assumed a threshold of $3200/year of life saved (YLS) to determine cost-effectiveness. Sensitivity analyses varied the age distribution of children seeking care and costs for PITC, HIV care, and ART., Results: PITC improved the proportion of CWH diagnosed (45.2% to 83.2%), on ART (40.8% to 80.4%), and virally suppressed (32.6% to 63.7%) at 1 year in all settings. PITC increased life expectancy by 0.1-0.7 years for children seeking care (including those with and without HIV). In all settings, the ICER of PITC vs no PITC was very similar, ranging from $710 to $1240/YLS. PITC remained cost-effective unless undiagnosed HIV prevalence was <0.2%., Conclusions: Routine testing improves HIV clinical outcomes and is cost-effective in South Africa if the prevalence of undiagnosed HIV among children exceeds 0.2%. These findings support current recommendations for PITC in outpatient, inpatient, tuberculosis, and malnutrition clinical settings., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Bibliometric analyses show gender bias against women in scientific publications and citations. We hypothesized that a metric of an individual senior author's inclusivity of women as first authors in critical care publications would predict gender inequality., Methods: Using PubMed and Web of Science, we conducted a bibliometric analysis of original research publications in critical care from 2008 to 2018 in 11 specialty and general journals. Gender for first and senior authors was assigned by a gender determination application, and manually if needed. For all senior authors we defined the novel Female First Author Index (FFA-index) = #Female first authors in publications by an individual senior author/Total # publications by that senior author. We produced a novel interactive web-based application using the R package Shiny to increase potential utilization of the FFA-index., Results: Of 7370 publications, 30.4% had female first authors and 15.5% had female senior authors. After adjustment for impact factor, journal, year of publication, number of authors, country, and gender determination accuracy, female senior authorship was associated with a 1.9-fold increase in female first authorship [OR = 1.85 (95% CI 1.62, 2.11); p < 0.001] compared with male senior authorship. The mean (SD) FFA-index for all individual senior authors was 30.5 (42.9); with a significant difference in FFA-index between male and female senior authors (27.6 versus 42.5, respectively; p < 0.001). The interactive web-based application (FFA-index App) produces the same FFA-index output as our study results., Conclusions: Female representation at prominent authorship positions in critical care publications is still far from achieving gender parity. By creating an authorship index score, we propose a frame of reference for the advancement of female first authorship.

Introduction: Uptake of early infant HIV diagnosis (EID) varies widely across sub-Saharan African settings. We evaluated the potential clinical impact and cost-effectiveness of universal maternal HIV screening at infant immunization visits, with referral to EID and maternal antiretroviral therapy (ART) initiation., Methods: Using the CEPAC-Pediatric model, we compared two strategies for infants born in 2017 in Côte d'Ivoire (CI), South Africa (SA), and Zimbabwe: (1) existing EID programmes offering six-week nucleic acid testing (NAT) for infants with known HIV exposure (EID), and (2) EID plus universal maternal HIV screening at six-week infant immunization visits, leading to referral for infant NAT and maternal ART initiation (screen-and-test). Model inputs included published Ivoirian/South African/Zimbabwean data: maternal HIV prevalence (4.8/30.8/16.1%), current uptake of EID (40/95/65%) and six-week immunization attendance (99/74/94%). Referral rates for infant NAT and maternal ART initiation after screen-and-test were 80%. Costs included NAT ($24/infant), maternal screening ($10/mother-infant pair), ART ($5 to 31/month) and HIV care ($15 to 190/month). Model outcomes included mother-to-child transmission of HIV (MTCT) among HIV-exposed infants, and life expectancy (LE) and mean lifetime per-person costs for children with HIV (CWH) and all children born in 2017. We calculated incremental cost-effectiveness ratios (ICERs) using discounted (3%/year) lifetime costs and LE for all children. We considered two cost-effectiveness thresholds in each country: (1) the per-capita GDP ($1720/6380/2150) per year-of-life saved (YLS), and (2) the CEPAC-generated ICER of offering 2 versus 1 lifetime ART regimens (e.g. offering second-line ART; $520/500/580/YLS)., Results: With EID, projected six-week MTCT was 9.3% (CI), 4.2% (SA) and 5.2% (Zimbabwe). Screen-and-test decreased total MTCT by 0.2% to 0.5%, improved LE by 2.0 to 3.5 years for CWH and 0.03 to 0.07 years for all children, and increased discounted costs by $17 to 22/child (all children). The ICER of screen-and-test compared to EID was $1340/YLS (CI), $650/YLS (SA) and $670/YLS (Zimbabwe), below the per-capita GDP but above the ICER of 2 versus 1 lifetime ART regimens in all countries., Conclusions: Universal maternal HIV screening at immunization visits with referral to EID and maternal ART initiation may reduce MTCT, improve paediatric LE, and be of comparable value to current HIV-related interventions in high maternal HIV prevalence settings like SA and Zimbabwe., (© 2021 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Objective: Autoimmune encephalitis (AE) is a highly treatable neurologic condition that can cause psychosis. Screening for AE is not currently recommended in routine workup for first-episode psychosis (FEP), owing partly to the high cost of testing for AE-associated neuronal autoantibodies., Methods: This study used a decision-analytic model to estimate the cost-effectiveness of routine serum screening for AE compared with clinically targeted screening in patients with FEP. Model parameters drawn from prior published literature included the prevalence of neuronal autoantibodies in FEP (4.5%), serum autoantibody panel cost (US $291), remission probability with antipsychotics (0.58), and remission probability with immunotherapy for patients diagnosed with AE (0.85). Outcomes included quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs), assessed over a 5-year horizon from the US health care sector and societal perspectives. ICER thresholds of $50,000/QALY to $150,000/QALY were used to define cost-effectiveness. The analysis was conducted between June 2018 and January 2020., Results: Routine screening led to mean QALY gains of 0.008 among all patients and 0.174 among the subgroup of patients with neuronal autoantibodies. Mean costs increased by $780 from a societal perspective and $1,150 from a health care sector perspective, resulting in ICERs of $99,330/QALY and $147,460/QALY, respectively. Incorporating joint input data uncertainty, the likelihood routine screening has an ICER ≤ $150,000/QALY was 55% from a societal perspective and 37% from a health care sector perspective. The model parameter with the greatest contribution to overall uncertainty was the effectiveness of immunotherapy relative to antipsychotics., Conclusions: Routine screening for AE in patients with FEP may be cost-effective in the United States. As further immunotherapy effectiveness data become available, a more definitive recommendation to perform routine screening could be warranted., (© Copyright 2020 Physicians Postgraduate Press, Inc.)

Objective: This study aimed to estimate the cost-effectiveness of esketamine, a novel intranasally dosed antidepressant, for patients in the United States with treatment-resistant depression., Methods: A decision-analytic model parameterized with efficacy data from phase 3 randomized trials of esketamine was used to simulate the effects of treatment with esketamine versus oral antidepressants over a 5-year horizon, from both societal and health care sector perspectives. Outcomes included remission and response of depression, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness ratios (ICERs) for esketamine. Value-based prices were calculated, defined as the per-dose price at which esketamine would become cost-effective given cost-effectiveness thresholds of $50,000/QALY, $100,000/QALY, and $150,000/QALY. Uncertainty in these outcomes was assessed with probabilistic sensitivity analyses. Key model parameters included the efficacy of esketamine versus oral antidepressants (relative risk of 1.39 for remission; 1.32 for response) and the monthly cost of esketamine ($5,572 for month 1; $1,699-$2,244 thereafter)., Results: Over 5 years, esketamine was projected to increase time in remission from 25.3% to 31.1% of life-years, resulting in a gain of 0.07 QALYs. Esketamine increased societal costs by $16,617 and health care sector costs by $16,995. Base case ICERs were $237,111/QALY (societal) and $242,496/QALY (health care sector). Probabilistic sensitivity analysis showed a greater than 95% likelihood that esketamine's ICER would be above $150,000/QALY. At a cost-effectiveness threshold of $150,000/QALY, esketamine's value-based price was approximately $140/dose (versus a current price of $240/dose)., Conclusions: Esketamine is unlikely to be cost-effective for management of treatment-resistant depression in the United States unless its price falls by more than 40%.

Background: Healthcare payers in the United States are increasingly tying provider payments to quality and value using pay-for-performance policies. Cost-effectiveness analysis quantifies value in healthcare but is not currently used to design or prioritize pay-for-performance strategies or metrics. Acute ischemic stroke care provides a useful application to demonstrate how simulation modeling can be used to determine cost-effective levels of financial incentives used in pay-for-performance policies and associated challenges with this approach., Methods and Results: Our framework requires a simulation model that can estimate quality-adjusted life years and costs resulting from improvements in a quality metric. A monetary level of incentives can then be back-calculated using the lifetime discounted quality-adjusted life year (which includes effectiveness of quality improvement) and cost (which includes incentive payments and cost offsets from quality improvements) outputs from the model. We applied this framework to an acute ischemic stroke microsimulation model to calculate the difference in population-level net monetary benefit (willingness-to-pay of $50 000 to $150 000/quality-adjusted life year) accrued under current Medicare policy (stroke payment not adjusted for performance) compared with various hypothetical pay-for-performance policies. Performance measurement was based on time-to-thrombolytic treatment with tPA (tissue-type plasminogen activator). Compared with current payment, equivalent population-level net monetary benefit was achieved in pay-for-performance policies with 10-minute door-to-needle time reductions (5057 more acute ischemic stroke cases/y in the 0-3-hour window) incentivized by increasing tPA payment by as much as 18% to 44% depending on willingness-to-pay for health., Conclusions: Cost-effectiveness modeling can be used to determine the upper bound of financial incentives used in pay-for-performance policies, although currently, this approach is limited due to data requirements and modeling assumptions. For tPA payments in acute ischemic stroke, our model-based results suggest financial incentives leading to a 10-minute decrease in door-to-needle time should be implemented but not exceed 18% to 44% of current tPA payment. In general, the optimal level of financial incentives will depend on willingness-to-pay for health and other modeling assumptions around parameter uncertainty and the relationship between quality improvements and long-run quality-adjusted life expectancy and costs.

Background. Metamodels can simplify complex health policy models and yield instantaneous results to inform policy decisions. We investigated the predictive validity of linear regression metamodels used to support a real-time decision-making tool that compares infant HIV testing/screening strategies. Methods. We developed linear regression metamodels of the Cost-Effectiveness of Preventing AIDS Complications Pediatric (CEPAC-P) microsimulation model used to predict life expectancy and lifetime HIV-related costs/person of two infant HIV testing/screening programs in South Africa. Metamodel performance was assessed with cross-validation and Bland-Altman plots, showing between-method differences in predicted outcomes against their means. Predictive validity was determined by the percentage of simulations in which the metamodels accurately predicted the strategy with the greatest net health benefit (NHB) as projected by the CEPAC-P model. We introduced a zone of indifference and investigated the width needed to produce between-method agreement in 95% of the simulations. We also calculated NHB losses from "wrong" decisions by the metamodel. Results. In cross-validation, linear regression metamodels accurately approximated CEPAC-P-projected outcomes. For life expectancy, Bland-Altman plots showed good agreement between CEPAC-P and the metamodel (within 1.1 life-months difference). For costs, 95% of between-method differences were within $65/person. The metamodels predicted the same optimal strategy as the CEPAC-P model in 87.7% of simulations, increasing to 95% with a zone of indifference of 0.24 life-months ( ∼ 7 days). The losses in health benefits due to "wrong" choices by the metamodel were modest (range: 0.0002-1.1 life-months). Conclusions. For this policy question, linear regression metamodels offered sufficient predictive validity for the optimal testing strategy as compared with the CEPAC-P model. Metamodels can simulate different scenarios in real time, based on sets of input parameters that can be depicted in a widely accessible decision-support tool., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Cervical cancer screening is effective in reducing mortality, but adherence is generally low. We aimed to investigate the cost-effectiveness of a stepwise intervention to promote adherence to cervical cancer screening in Portugal., Methods: We developed a decision tree model to compare the cost-effectiveness of four competing interventions to increase adherence to cervical cancer screening: (i) a written letter (standard-of-care); (ii) automated short message service text messages (SMS)/phone calls/reminders; (iii) automated SMS/phone calls/reminders + manual phone calls; (iv) automated SMS/phone calls/reminders + manual phone calls + face-to-face interviews. The main outcome measure was cost per quality-adjusted life year (QALY) measured over a 5-year time horizon. Costs were calculated from the societal and provider perspectives., Results: From the societal perspective, the optimal strategy was automated SMS/phone calls/reminders, below a threshold of €8171 per QALY; above this and below €180 878 per QALY, the most cost-effective strategy was automated SMS/phone calls/reminders + manual phone calls and above this value automated SMS/phone calls/reminders + manual phone calls + face-to-face interviews. From the provider perspective, the ranking of the three strategies in terms of cost-effectiveness was the same, for thresholds of €2756 and €175 463 per QALY, respectively., Conclusions: Assuming a willingness-to-pay threshold of one time the national gross domestic product (€22 398/QALY), automated SMS/phone calls/reminders + manual phone calls is a cost-effective strategy to promote adherence to cervical cancer screening, both from the societal and provider perspectives., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Objective: The aim of this study was to evaluate the cost-effectiveness of retrograde voiding trials in the management of postoperative voiding dysfunction., Methods: We developed a disease simulation model to assess under which conditions routine retrograde voiding trial is the optimal strategy in terms of cost per quality-adjusted life-year and cost per case of chronic voiding dysfunction avoided. We varied the incidence of voiding dysfunction between 2% and 60%. We discounted future costs and utilities at 3% annually. We conducted 1- and 2-way sensitivity analyses on uncertain model parameters., Results: The lifetime analysis showed that when the incidence of postoperative voiding dysfunction exceeded 12.2%, retrograde voiding trials were cost-effective, assuming a willingness-to-pay (WTP) for health of $100,000/quality-adjusted life-year. When the incidence exceeded 31.1%, retrograde voiding trials became the dominant strategy (less costly and more effective). For a simple hysterectomy with voiding dysfunction incidence of approximately 10%, lifetime cost is $230,069/case of chronic voiding dysfunction avoided; for a midurethral sling with voiding dysfunction incidence of approximately 20%, lifetime cost is $60,449/case avoided. Sensitivity analyses showed that WTP for health, the incidence of presentation to the emergency department (ED) for urinary retention and the incidence of chronic urinary retention following treatment in the ED had the greatest impact on the cost-effectiveness results., Conclusions: Routine retrograde voiding trials following pelvic surgery can be cost-effective compared with expectant management when the incidence of voiding dysfunction exceeds 12.2%. These results were sensitive to WTP for health, incidence of ED visits for urinary retention, and incidence of chronic urinary retention following ED visits.

Background: Colorectal cancer is one of the most common cancers worldwide and is associated with high mortality when detected at a later stage. There is a paucity of studies from low and middle income countries to support the cost-effectiveness of colorectal cancer screening. We aim to analyze the cost-effectiveness of colorectal cancer screening compared to no screening in Ukraine, a lower-middle income country., Methods: We developed a deterministic Markov cohort model to assess the cost-effectiveness of three colorectal cancer screening strategies [fecal occult blood test (FOBT) every year, flexible sigmoidoscopy with FOBT every 5 years, and colonoscopy every 10 years] compared to no screening. We modeled outcomes in terms of cost per quality-adjusted life-years (QALYs) over a lifetime time horizon. We performed sensitivity analyses on treatment adherence, test characteristics and costs. Analyses were conducted from the perspective of the Ministry of Health of Ukraine., Results: The base-case lifetime cost-effectiveness analysis showed that all three screening strategies were cost saving compared to no screening, and among the three strategies, colonoscopy every 10 years was the dominant strategy compared to no screening with standard adherence to treatment. When decreased adherence to treatment was modeled, colonoscopy every 10 years was the most cost-effective strategy with an incremental cost-effectiveness ratio of $843 per QALY compared with no screening., Conclusion: Our findings indicate that colorectal cancer screening can save money and improve health compared to no screening in Ukraine. Colonoscopy every 10 years is superior to the other screening modalities evaluated in this study. This knowledge can be used to concentrate efforts on developing a national screening program in Ukraine.

Background: Targeting low-dose computed tomography (LDCT) for lung cancer screening to persons at highest risk for lung cancer mortality has been suggested to improve screening efficiency., Objective: To quantify the value of risk-targeted selection for lung cancer screening compared with National Lung Screening Trial (NLST) eligibility criteria., Design: Cost-effectiveness analysis using a multistate prediction model., Data Sources: NLST., Target Population: Current and former smokers eligible for lung cancer screening., Time Horizon: Lifetime., Perspective: Health care sector., Intervention: Risk-targeted versus NLST-based screening., Outcome Measures: Incremental 7-year mortality, life expectancy, quality-adjusted life-years (QALYs), costs, and cost-effectiveness of screening with LDCT versus chest radiography at each decile of lung cancer mortality risk., Results of Base-Case Analysis: Participants at greater risk for lung cancer mortality were older and had more comorbid conditions and higher screening-related costs. The incremental lung cancer mortality benefits during the first 7 years ranged from 1.2 to 9.5 lung cancer deaths prevented per 10 000 person-years for the lowest to highest risk deciles, respectively (extreme decile ratio, 7.9). The gradient of benefits across risk groups, however, was attenuated in terms of life-years (extreme decile ratio, 3.6) and QALYs (extreme decile ratio, 2.4). The incremental cost-effectiveness ratios (ICERs) were similar across risk deciles ($75 000 per QALY in the lowest risk decile to $53 000 per QALY in the highest risk decile). Payers willing to pay $100 000 per QALY would pay for LDCT screening for all decile groups., Results of Sensitivity Analysis: Alternative assumptions did not substantially alter our findings., Limitation: Our model did not account for all correlated differences between lung cancer mortality risk and quality of life., Conclusions: Although risk targeting may improve screening efficiency in terms of early lung cancer mortality per person screened, the gains in efficiency are attenuated and modest in terms of life-years, QALYs, and cost-effectiveness., Primary Funding Source: National Institutes of Health (U01NS086294).

Objectives: To quantify the potential value of new research in patients treated with thrombolytic treatment (tissue-type plasminogen activator [tPA]) in the 4.5- to 6.0-hour time window after stroke onset and to determine the optimal size of a future trial using value of information analysis., Methods: Expected value of partial perfect and sample information (EVPPI and EVSI) analyses were conducted using a probabilistic Markov model. Data for modified Rankin Scale (mRS) distributions in patients 4.5 to 6.0 hours since stroke onset for tPA (n = 576) and placebo (n = 543) were obtained from pooled randomized controlled trials. EVSI was quantified with net monetary benefit (assuming willingness to pay for health as $100,000/QALY). We calculated discounted population-level EVSI by multiplying per-person EVSI by the annual number of eligible patients with stroke in the United States and assuming a 10-year time frame of treatment use. Study costs were based on administrative costs and the costs of tPA., Results: The base-case lifetime cost-effectiveness analysis showed that tPA was dominated by placebo in this patient group. EVPPI for mRS distributions was $1003 per person. On the basis of EVSI, the optimal sample size of a new trial collecting data on tPA efficacy in these patients would be 5600 across study arms with expected population-level societal returns (EVSI minus study costs) of $68.7 million., Conclusions: Expanding research attention to the 4.5- to 6.0-hour time window for tPA treatment of patients with acute ischemic stroke is justified because the expected returns are substantial. Even a relatively large trial in which more information on treatment efficacy on the basis of mRS scores is collected would represent good value for information., (Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Mathematical simulation models are commonly used to inform health policy decisions. These health policy models represent the social and biological mechanisms that determine health and economic outcomes, combine multiple sources of evidence about how policy alternatives will impact those outcomes, and synthesize outcomes into summary measures salient for the policy decision. Calibrating these health policy models to fit empirical data can provide face validity and improve the quality of model predictions. Bayesian methods provide powerful tools for model calibration. These methods summarize information relevant to a particular policy decision into (1) prior distributions for model parameters, (2) structural assumptions of the model, and (3) a likelihood function created from the calibration data, combining these different sources of evidence via Bayes' theorem. This article provides a tutorial on Bayesian approaches for model calibration, describing the theoretical basis for Bayesian calibration approaches as well as pragmatic considerations that arise in the tasks of creating calibration targets, estimating the posterior distribution, and obtaining results to inform the policy decision. These considerations, as well as the specific steps for implementing the calibration, are described in the context of an extended worked example about the policy choice to provide (or not provide) treatment for a hypothetical infectious disease. Given the many simplifications and subjective decisions required to create prior distributions, model structure, and likelihood, calibration should be considered an exercise in creating a reasonable model that produces valid evidence for policy, rather than as a technique for identifying a unique theoretically optimal summary of the evidence.

Background: The prevalence of ductal carcinoma in situ (DCIS) and the marked variability in patterns of care highlight the need for comparative effectiveness research. We sought to quantify the tradeoffs among alternative management strategies for DCIS with respect to disease outcomes and breast preservation., Methods: We developed a disease simulation model integrating data from the published literature to simulate the clinical events after six treatments (lumpectomy alone, lumpectomy with radiation, lumpectomy with radiation and tamoxifen, lumpectomy with tamoxifen, and mastectomy with and without breast reconstruction) for women with newly diagnosed DCIS. Outcomes included disease-free, invasive disease-free, and overall survival and breast preservation., Results: For a cohort of 1 million simulated women aged 45 years at diagnosis, both mastectomy and lumpectomy with radiation and tamoxifen were associated with a 12-month improvement in overall survival relative to lumpectomy alone. Adding radiation therapy to lumpectomy resulted in a 6-month improvement in overall survival but decreased long-term breast-preservation outcomes (likelihood of lifetime breast preservation = 0.781 vs 0.843 for lumpectomy alone). This decrement with radiation therapy was mitigated by the addition of tamoxifen (likelihood of lifetime breast preservation = 0.846)., Conclusions: Overall survival benefits of the six management strategies for DCIS are within 1 year, suggesting that treatment decisions can be informed by the patient's preference for breast preservation and disutility for recurrence. Our delineation of personalized outcomes for each strategy can help patients understand the implications of their treatment choice, so their decisions may reflect their own personal values and help improve the quality of care for patients with DCIS.

This article reviews the current evidence on the cost-effectiveness of psychotherapy for personality disorders (PDs). Although the evidence is still scarce, several well-designed cost-effectiveness studies provide insight into the question - how cost effective is it to reimburse therapies for PDs? This article further argues that the implementation costs and effects should be an integral part of cost-effectiveness analyses to enhance the dissemination of treatment recommendations. Moreover, cost-effectiveness analyses are important in working towards a more patient-centered approach in psychotherapy research that could potentially help accelerate the implementation and adoption of cost-effective care for PDs.

Background: Many interventions initiated within and financed from the health care sector are not necessarily primarily aimed at improving health. This poses important questions regarding the operationalisation of economic evaluations in such contexts., Aims of the Study: We investigated whether assessing cost-effectiveness using state-of-the-art methods commonly applied in health care evaluations is feasible and meaningful when evaluating interventions aimed at reducing youth delinquency., Methods: A probabilistic Markov model was constructed to create a framework for the assessment of the cost-effectiveness of systemic interventions in delinquent youth. For illustrative purposes, Functional Family Therapy (FFT), a systemic intervention aimed at improving family functioning and, primarily, reducing delinquent activity in youths, was compared to Treatment as Usual (TAU). "Criminal activity free years" (CAFYs) were introduced as central outcome measure. Criminal activity may e.g. be based on police contacts or committed crimes. In absence of extensive data and for illustrative purposes the current study based criminal activity on available literature on recidivism. Furthermore, a literature search was performed to deduce the model's structure and parameters., Results: Common cost-effectiveness methodology could be applied to interventions for youth delinquency. Model characteristics and parameters were derived from literature and ongoing trial data. The model resulted in an estimate of incremental costs/CAFY and included long-term effects. Illustrative model results point towards dominance of FFT compared to TAU., Discussion: Using a probabilistic model and the CAFY outcome measure to assess cost-effectiveness of systemic interventions aimed to reduce delinquency is feasible. However, the model structure is limited to three states and the CAFY measure was defined rather crude. Moreover, as the model parameters are retrieved from literature the model results are illustrative in the absence of empirical data., Implications for Health Care Provision and Use: The current model provides a framework to assess the cost-effectiveness of systemic interventions, while taking into account parameter uncertainty and long-term effectiveness., Implications for Health Policies: The framework of the model could be used to assess the cost-effectiveness of systemic interventions alongside (clinical) trial data. Consequently, it is suitable to inform reimbursement decisions, since the value for money of systemic interventions can be demonstrated using a decision analytic model., Implications for Further Research: Future research could be focussed on testing the current model based on extensive empirical data, improving the outcome measure and finding appropriate values for that outcome.

In adults, personality disorders are associated with a low quality of life and high societal costs. To explore whether these findings also apply to adolescents, 131 adolescent patients were recruited from a mental health care institute in The Netherlands. Axis I and Axis II disorders were diagnosed using semi-structured interviews. The EuroQol EQ-5D was used to measure quality of life and costs were measured by the Trimbos and Institute for Medical Technology Assessment Questionnaire on Costs Associated with Psychiatric Illness. The mean EQ-5D index value was 0.55. The mean direct medical cost in the year prior to treatment was €14,032 per patient. The co-occurrence of Axis I and Axis II disorders was a significant predictor of a low quality of life. Direct medical costs were higher for the depressive personality disorder. This study shows that the burden of disease among adolescents with personality pathology is high. This high burden provides evidence to suggest that further research and development of (cost-)effective treatment strategies for this population may be worthwhile.

Objectives: To quantify the trade-offs of alternative strategies in treating pediatric major depressive disorder with respect to the clinical benefit and risk of fatal and nonfatal suicidal behavior over a 5-year time horizon., Methods: We developed a disease simulation model integrating epidemiological and clinical data from the literature to simulate the effect of selective serotonin reuptake inhibitors (SSRIs), cognitive behavioral therapy (CBT), and a combination of both on a US pediatric population with major depressive disorder., Results: In a cohort of 1,000,000 simulated individuals (ages 10-24 years), the use of SSRIs was associated with the highest number of suicide-related events, while CBT was associated with the lowest number. Over a 5-year period, the strategy with the highest number of symptom-free weeks depended on assumptions made regarding treatment efficacy beyond the available clinical data., Conclusions: Considering the risk-benefit profile over a 5-year period, CBT offers a safer profile than combination treatment or SSRIs alone with respect to suicide deaths and attempts. Any additional benefits of SSRIs, either alone or in combination with CBT, must be weighed against the expected increase in suicides., (Copyright © 2012 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objective: In a budget-constrained health care system, decisions regarding resource allocation towards research and implementation are critical and can be informed by cost-effectiveness analysis. The objective of this study was to assess the societal value of conducting further research to inform reimbursement decisions and implementation of cost-effective psychotherapy for clusters B and C personality disorders (PDs)., Methods: Value of information and value of implementation analyses were conducted using previously developed cost-effectiveness models for clusters B and C PDs to evaluate the parameters that contribute to most of the decision uncertainty, and to calculate the population expected values of perfect information (pEVPI) and perfect implementation (pEVPIM)., Results: The pEVPI was estimated to be €425 million for cluster B PDs and €315 million for cluster C PDs, indicating that gathering additional evidence is expected to be cost-effective. The categories of parameters for which reduction of uncertainty would be most valuable were transition probabilities and health state costs. The pEVPIM was estimated to be €595 million for cluster B PDs and €1,372 million for cluster C PDs, suggesting that investing in implementation of cost-effective psychotherapy is likely to be worthwhile., Conclusions: The societal value of additional research on psychotherapy for clusters B and C PDs is substantial, especially when prioritizing information on transition probabilities and health state costs. Active implementation of cost-effective treatment strategies into clinical practice is likely to improve the efficiency of health care provision in The Netherlands., (Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

Objective: To conduct a formal economic evaluation of various dosages of psychotherapy for patients with avoidant, dependent, and obsessive-compulsive (ie, cluster C) personality disorders (Structured Interview for DSM-IV Personality criteria)., Method: We developed a decision-analytic model to assess the cost-effectiveness of 5 dosages of psychotherapy (ie, long-term outpatient psychotherapy, short-term and long-term day hospital psychotherapy, and short-term and long-term inpatient psychotherapy) over a 5-year time horizon in terms of cost per recovered patient-year and cost per quality-adjusted life-year (QALY). Model parameters were estimated using data from 466 patients with cluster C personality disorders who were admitted to 6 specialist centers of psychotherapy in The Netherlands and assigned to 1 of the 5 treatment groups. Probabilistic analysis was conducted to explore the stability of results over uncertain data ranges. Analyses were conducted from both societal and payer perspectives., Results: From the societal perspective and below a threshold of € 2,637 (US $3,351.92) per recovered patient-year, short-term day hospital psychotherapy resulted in the highest level of benefit for its cost; above the threshold, short-term inpatient psychotherapy was the most cost-effective choice. In terms of cost per QALY, this switch point was at a threshold value of € 16,570 (US $21,062.29) per QALY. From the payer perspective, the optimal strategy changed from short-term day hospital psychotherapy to short-term inpatient psychotherapy at threshold values of € 9,874 (US $12,550.94) per recovered patient-year and € 66,302 (US $84,277.13) per QALY., Conclusions: This study indicates that short-term day hospital psychotherapy and short-term inpatient psychotherapy are the most cost-effective treatment strategies for patients with cluster C personality disorders. The ultimate selection depends on what cost-effectiveness threshold is considered acceptable and what perspective is adopted., (© Copyright 2011 Physicians Postgraduate Press, Inc.)

Background: Recommendations on current clinical guidelines are informed by limited economic evidence., Aims: A formal economic evaluation of three modalities of psychotherapy for patients with cluster B personality disorders., Method: A probabilistic decision-analytic model to assess the cost-effectiveness of out-patient, day hospital and in-patient psychotherapy over 5 years in terms of cost per recovered patient-year and cost per quality-adjusted life-year (QALY). Analyses were conducted from both societal and payer perspectives., Results: From the societal perspective, the most cost-effective choice switched from out-patient to day hospital psychotherapy at a threshold of 12,274 euros per recovered patient-year; and from day hospital to in-patient psychotherapy at 113,298 euros. In terms of cost per QALY, the optimal strategy changed at 56,325 euros and 286,493 euros per QALY respectively. From the payer perspective, the switch points were at 9895 euros and 155,797 euros per recovered patient-year, and 43,427 euros and 561,188 euros per QALY., Conclusions: Out-patient psychotherapy and day hospital psychotherapy are the optimal treatments for patients with cluster B personality disorders in terms of cost per recovered patient-year and cost per QALY.

A generic quality of life measure was used to investigate the burden of disease in a large sample of patients with personality disorders. The 1,708 subjects included in this study were recruited from six different mental health care institutes in the Netherlands. The burden of disease was measured using the EuroQol EQ-5D. Personality disorders were diagnosed using the Structured Interview for DSM-IV Personality (SIDP-IV). The mean EQ-5D index value was 0.56. Primarily the total number of personality disorder diagnoses rather than the specific type determined the quality of life. Notably borderline personality disorder was not associated with the highest burden. The findings indicate that patients with personality disorders experience a high burden of disease, comparable to that of severe somatic illnesses. The results call into question the primary focus in literature on borderline personality disorder. The current study yields a strong argument in favor of reimbursing (effective) treatments for this patient population.

Objective: Some evidence suggests that personality disorders are associated with a high economic burden due to, for example, a high demand on psychiatric, health, and social care services. However, state-of-the-art cost studies for the broad range of personality disorder diagnoses are lacking. The present study examines the direct medical costs, as well as the indirect costs, of patients seeking mental health treatment with DSM-IV personality disorders., Method: The 1740 subjects included in this study were recruited from March 2003 to March 2006 from 6 different mental health care institutes in the Netherlands specializing in the psychotherapeutic treatment of personality disorders. The direct and indirect costs were assessed using the Trimbos and Institute for Medical Technology Assessment Questionnaire on Costs Associated with Psychiatric Illness. Personality disorders were diagnosed using the Structured Interview for DSM-IV Personality., Results: The mean total costs of the personality disorder group in the 12 months prior to treatment were 11,126 euros per patient. Two thirds (66.5%) of these costs consisted of direct medical costs, while the remaining costs were related to productivity losses. Borderline and obsessive-compulsive personality disorders were uniquely associated with increased mean total costs., Conclusions: Treatment-seeking patients with personality disorders pose a high economic burden on society, a burden substantially higher than that found in, for instance, depression or generalized anxiety disorder. These high societal costs present a strong argument in favor of prioritizing effective personality disorder treatments in reimbursement decisions.

Objective: Despite scientific evidence of effectiveness, psychotherapy for personality disorders is not yet fully deployed, nor is its reimbursement self-evident. Both clinicians and health care policy-makers increasingly rely on evidence-based medicine and health economics when determining a treatment of choice and reimbursement. This article aims to contribute to that understanding by applying these criteria on psychotherapy as a treatment for patients with personality disorder., Method: We have evaluated the available empirical evidence on effectiveness and cost-effectiveness, and integrated this with necessity of treatment as a moderating factor., Results: The effectiveness of psychotherapy for personality disorders is well documented with favourable randomized trial results, 2 metaanalyses, and a Cochrane review. However, the evidence does not yet fully live up to modern standards of evidence-based medicine and is mostly limited to borderline and avoidant personality disorders. Data on cost-effectiveness suggest that psychotherapy for personality disorders may lead to cost-savings. However, state-of-the-art cost-effectiveness data are still scarce. An encouraging factor is that the available studies indicate that patients with personality disorder experience a high burden of disease, stressing the necessity of treatment., Conclusions: When applying an integrated vision on outcome, psychotherapy can be considered not only an effective treatment for patients with personality disorder but also most likely a cost-effective and necessary intervention. However, more state-of-the-art research is required before clinicians and health care policy-makers can fully appreciate the benefits of psychotherapy for personality disorders. Considerable progress is possible if researchers focus their efforts on evidence-based medicine and cost-effectiveness research.

The burden of disease of 1,651 inpatients in the Netherlands who had complex personality problems and personality disorders and who were treated in specialized units that provide psychotherapy was compared with the burden of disease of patients with other mental and physical conditions. Patients completed the EuroQol EQ-5D, a generic quality-of-life questionnaire. The mean EQ-5D index score was .54 (possible scores range from -.59 to 1.00, with higher scores indicating fewer problems). This score reflects a burden of disease comparable with the burden in severe illnesses, such as Parkinson's disease (.58) or rheumatic disease (.53).