Endothelial mechanisms for inactivation of inflammation-induced hyperpermeability.

Microvascular hyperpermeability is a hallmark of inflammation. Many negative effects of hyperpermeability are due to its persistence beyond what is required for preserving organ function. Therefore, we propose that targeted therapeutic approaches focusing on mechanisms that terminate hyperpermeability would avoid the negative effects of prolonged hyperpermeability while retaining its short-term beneficial effects. We tested the hypothesis that inflammatory agonist signaling leads to hyperpermeability and initiates a delayed cascade of cAMP-dependent pathways that causes inactivation of hyperpermeability. We applied platelet-activating factor (PAF) and vascular endothelial growth factor (VEGF) to induce hyperpermeability. We used an Epac1 agonist to selectively stimulate exchange protein activated by cAMP (Epac1) and promote inactivation of hyperpermeability. Stimulation of Epac1 inactivated agonist-induced hyperpermeability in the mouse cremaster muscle and in human microvascular endothelial cells (HMVECs). PAF induced nitric oxide (NO) production and hyperpermeability within 1 min and NO-dependent increased cAMP concentration in about 15-20 min in HMVECs. PAF triggered phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in a NO-dependent manner. Epac1 stimulation promoted cytosol-to-membrane eNOS translocation in HMVECs and in myocardial microvascular endothelial (MyEnd) cells from wild-type mice, but not in MyEnd cells from VASP knockout mice. We demonstrate that PAF and VEGF cause hyperpermeability and stimulate the cAMP/Epac1 pathway to inactivate agonist-induced endothelial/microvascular hyperpermeability. Inactivation involves VASP-assisted translocation of eNOS from the cytosol to the endothelial cell membrane. We demonstrate that hyperpermeability is a self-limiting process, whose timed inactivation is an intrinsic property of the microvascular endothelium that maintains vascular homeostasis in response to inflammatory conditions.NEW & NOTEWORTHY Termination of microvascular hyperpermeability has been so far accepted to be a passive result of the removal of the applied proinflammatory agonists. We provide in vivo and in vitro evidence that 1) inactivation of hyperpermeability is an actively regulated process, 2) proinflammatory agonists (PAF and VEGF) stimulate microvascular hyperpermeability and initiate endothelial mechanisms that terminate hyperpermeability, and 3) eNOS location-translocation is critical in the activation-inactivation cascade of endothelial hyperpermeability.

Cannabidiol-associated hepatotoxicity: A systematic review and meta-analysis.

BACKGROUND: Findings of liver enzyme elevations in recent cannabidiol studies have raised concerns over liver safety. This study aimed to determine the association between cannabidiol use, liver enzyme elevation, and drug-induced liver injury (DILI). METHODS: In this systematic review and meta-analysis, a search of EMBASE, CENTRAL, CINAHL, Clinicaltrials.gov, Medline, medRxiv, and Web of Science of records up to February 2022 was conducted. Clinical trials initiating daily cannabidiol treatment with serial liver enzyme measures were included. The proportion of liver enzyme elevations and DILI were independently extracted from published reports. Pooled proportions and probability meta-analyses were conducted. RESULTS: Cannabidiol use was associated with an increased probability of liver enzyme elevation (N = 12 trials, n = 1229; OR = 5.85 95% CI = 3.84-8.92, p < 0.001) and DILI (N = 12 trials, n = 1229; OR = 4.82 95% CI = 2.46-9.45, p < 0.001) compared to placebo controls. In participants taking cannabidiol (N = 28 trials, n = 1533), the pooled proportion of liver enzyme elevations was 0.074 (95% CI 0.0448-0.1212), and DILI was 0.0296 (95% CI 0.0136-0.0631). High-dose CBD (≥1000 mg/day or ≥20 mg/kg/day) and concomitant antiepileptic drug use were identified as risk factors. No cases were reported in adults using cannabidiol doses <300 mg/day. No cases of severe DILI were reported. CONCLUSIONS: Cannabidiol-associated liver enzyme elevations and DILI meet the criteria of common adverse drug events. Clinicians are encouraged to screen for cannabidiol use and monitor liver function in patients at increased risk.

Developing Criteria for Health Economic Quality Evaluation Tool.

OBJECTIVES: Because existing publication guidelines and checklists have limitations when used to assess the quality of cost-effectiveness analysis, we developed a novel quality assessment tool for cost-effectiveness analyses, differentiating methods and reporting quality and incorporating the relative importance of different quality attributes. METHODS: We defined 15 quality domains from a scoping review and identified 72 methods and reporting quality attributes (36 each). After designing a best-worst scaling survey, we fielded an online survey to researchers and practitioners to estimate the relative importance of the attributes in February 2021. We analyzed the survey data using a sequential conditional logit model. The final tool included 48 quality attributes deemed most important for assessing methods and reporting quality (24 each), accompanied by a free and web-based scoring system. RESULTS: A total of 524 participants completed the methodology section, and 372 completed both methodology and reporting sections. Quality attributes pertaining to the "modeling" and "data inputs and evidence synthesis" domains were deemed most important for methods quality, including "structure of the model reflects the underlying condition and intervention's impact" and "model validation is conducted." Quality attributes pertaining to "modeling" and "Intervention/comparator(s)" domains were considered most important for reporting quality, including "model descriptions are detailed enough for replication." Despite its growing prominence, "equity considerations" were not deemed as important as other quality attributes. CONCLUSIONS: The Criteria for Health Economic Quality Evaluation tool allows users to differentiate methods and reporting as well as quantifies the relative importance of quality attributes. Alongside other considerations, it could help assess and improve the quality of cost-effectiveness evidence to inform value-based decisions.

Effect of the 2012 US Preventive Services Task Force Recommendations on Prostate-Specific Antigen Screening in a Medicare Advantage Population.

BACKGROUND: In 2012, the US Preventive Service Task Force revised its recommendations for prostate-specific antigen (PSA) screening from "insufficient evidence" to "do not recommend" for men aged 70-74 while maintaining "do not recommend" for men aged 75+. METHODS: Using the difference-in-difference approach, we evaluated whether the rate of change in the use of low-value PSA screening differed between the control group (men aged 75+, N=7,856,204 person-years) and the intervention group (men aged 70-74, N=5,329,192 person-years) enrolling in the Medicare Advantage plan without a history of prostate cancer within the OptumLabs Data Warehouse claims data (2009-2019). A generalized estimating equation logistic model was specified with independent variables: an intervention group indicator, a pre- and post-period (after 2012 Q2) indicator, index time, and interaction terms. We assumed a 12-month dissemination period. RESULTS: Before the revised recommendation in 2012, the trends did not significantly differ between the 2 age groups with the odds of receiving PSA screening decreasing by 1.2% (95% confidence interval [1.0, 1.4%]) per quarter. However, the odds of receiving PSA screening increased by 3.0% [2.8, 3.2%] per quarter across both groups since the revision. There was no significant additional change in the trend for those aged 70-74 (0.1% [-0.2, 0.5%]). CONCLUSIONS: Although the 2012 US Preventive Service Task Force's recommendations were expected to only change behaviors among men aged 70-74, our analysis found that men aged 70-74 and aged 75+ exhibited similar trends from 2009 to 2019, including the increased use of low-value PSA screening since 2016. Multifaceted efforts to discourage low-value PSA screening would be important for a sustained impact.

A Systematic Review of Economic Evaluations of COVID-19 Interventions: Considerations of Non-Health Impacts and Distributional Issues.

OBJECTIVES: This study aims to conduct a systematic review of economic evaluations of COVID-19 interventions and to examine whether and how these studies incorporate non-health impacts and distributional concerns. METHODS: We searched the National Institutes of Health's COVID-19 Portfolio as of May 20, 2021, and supplemented our search with additional sources. We included original articles, including preprints, evaluating both the health and economic effects of a COVID-19-related intervention. Using a pre-specified data collection form, 2 reviewers independently screened, reviewed, and extracted information about the study characteristics, intervention types, and incremental cost-effectiveness ratios (ICERs). We used an Impact Inventory to catalog the types of non-health impacts considered. RESULTS: We included 70 articles, almost half of which were preprints. Most articles (56%) included at least one non-health impact, but fewer (21%) incorporated non-economic consequences. Few articles (17%) examined subgroups of interest. After excluding negative ICERs, the median ICER for the entire sample (n = 243 ratios) was $67,000/quality-adjusted life-year (QALY) (interquartile range [IQR] $9000-$893,000/QALY). Interventions including a pharmaceutical component yielded a median ICER of $93,000/QALY (IQR $4000-$7,809,000/QALY), whereas interventions including a non-pharmaceutical component were slightly more cost-effective overall with a median ICER of $81,000/QALY (IQR $12,000-$1,034,000/QALY). Interventions reported to be highly cost-effective were treatment, public information campaigns, quarantining identified contacts/cases, canceling public events, and social distancing. CONCLUSIONS: Our review highlights the lack of consideration of non-health and distributional impacts among COVID-19-related economic evaluations. Accounting for non-health impacts and distributional effects is essential for comprehensive assessment of interventions' value and imperative for generating cost-effectiveness evidence for both current and future pandemics.

The Impact of Broader Value Elements on Cost-Effectiveness Analysis: Two Case Studies.

OBJECTIVES: This study aimed to explore the impact of including broader value elements in cost-effectiveness analyses by presenting 2 case studies, one on human papillomavirus (HPV) infection and one on early-stage Hodgkin's lymphoma (ESHL). METHODS: We identified broader value elements (eg, patient and caregiver time, spillover health effects, productivity) from the Second Panel's Impact Inventory and the ISPOR Special Task Force's value flower. We then evaluated the cost-effectiveness of HPV vaccination versus no vaccination (case 1) and combined modality therapy (CMT) versus chemotherapy alone for treatment of adult ESHL (case 2) using published simulation models. For each case study, we compared incremental cost-effectiveness ratios considering health sector impacts only (the "base-case" scenario) with incremental cost-effectiveness ratios incorporating broader value elements. RESULTS: For vaccination of US girls against HPV before sexual debut versus no vaccination, the base-case result was $38 334 per disability-adjusted life-year averted. Including each broader value element made cost-effectiveness progressively more favorable, with HPV vaccination becoming cost-saving (ie, reducing costs and averting more disability-adjusted life-years) when the analysis incorporated productivity costs. For CMT versus chemotherapy alone in patients with ESHL, the base-case result indicated that CMT was cost-saving. Including all elements made this treatment's net monetary benefits (the sum of its averted resource costs and the net value of its health impacts) less favorable, even as the contribution from CMT's near-term health benefits grew. CONCLUSIONS: Including broader value elements can substantially influence cost-effectiveness ratios, although the direction and the magnitude of their impact can differ across interventions and disease context.

Adaptation and validation of the patient assessment of chronic illness care in United States community pharmacies.

BACKGROUND: Roles for United States (US)-based community pharmacists in caring for persons with chronic conditions have greatly expanded. The Patient Assessment of Chronic Illness Care (PACIC) was developed to assess patients' perspectives of care received. However, successful application of this instrument in community pharmacies is uncertain. The objective of this study was to adapt the PACIC for use in community pharmacies (CP-PACIC), assess validity of the CP-PACIC and examine CP-PACIC scale score differences relative to patient characteristics. METHODS: This cross-sectional study surveyed chronically ill adults in Indiana, US who receive care from pharmacists in community pharmacies. The modified CP-PACIC scale consisted of 20-items, which were rated on a 5-point Likert scale from 0 (none of the time) to 4 (always). The total possible score ranged from 0 - 80. An exploratory factor analysis (EFA) was conducted to assess performance and dimensionality. CP-PACIC validity, including face validity, construct validity (via exploratory factor analysis) and internal consistency were assessed. Relationships between patient characteristics and scale scores were evaluated using appropriate statistical tests. RESULTS: Five hundred forty-six respondents' data were analyzed. EFA revealed a 2-factor solution (termed advanced pharmacy chronic illness care (AP) and traditional pharmacy chronic illness care (TP) subscales) accounting for 64.7% of variance; all 20 items were retained. The total 20-item CP-PACIC scale had a Cronbach's alpha (internal consistency) of 0.96; with a 12-item AP subscale Cronbach's alpha of 0.97 and 8-item TP subscale Cronbach's alpha of 0.89. Median total score was 12.0 [interquartile range = 27.3]. Median CP-PACIC sores varied across many respondent demographics (i.e., survey administration type, age, sex, education, health condition, number of pharmacy services received, community pharmacy type) such as whether respondents participated in one or more pharmacy service or not (29 vs. 10; p < .001). CONCLUSIONS: Unlike the original 5-subscale (patient activation, delivery system design, goal setting, problem solving, and follow-up/coordination) PACIC, analysis demonstrated a 2-factor (AP, TP) solution for the CP-PACIC scale with good internal consistency. As there are no standardized evaluation tools that exist, community pharmacies could find great value in using this CP-PACIC tool to benchmark performance and inform quality improvement strategies for patient care delivery.

An Evidence Review of Low-Value Care Recommendations: Inconsistency and Lack of Economic Evidence Considered.

BACKGROUND: Low-value care, typically defined as health services that provide little or no benefit, has potential to cause harm, incur unnecessary costs, and waste limited resources. Although evidence-based guidelines identifying low-value care have increased, the guidelines differ in the type of evidence they cite to support recommendations against its routine use. OBJECTIVE: We examined the evidentiary rationale underlying recommendations against low-value interventions. DESIGN: We identified 1167 "low-value care" recommendations across five US organizations: the US Preventive Services Task Force (USPSTF), the "Choosing Wisely" Initiative, American College of Physicians (ACP), American College of Cardiology/American Heart Association (ACC/AHA), and American Society of Clinical Oncology (ASCO). For each recommendation, we classified the reported evidentiary rationale into five groups: (1) low economic value; (2) no net clinical benefit; (3) little or no absolute clinical benefit; (4) insufficient evidence; (5) no reason mentioned. We further investigated whether any cited or otherwise available cost-effectiveness evidence was consistent with conventional low economic value benchmarks (e.g., exceeding $100,000 per quality-adjusted life-year). RESULTS: Of the identified low-value care recommendations, Choosing Wisely contributed the most (N=582, 50%), followed by ACC/AHA (N=250, 21%). The services deemed "low value" differed substantially across organizations. "No net clinical benefit" (N=428, 37%) and "little or no clinical benefit" (N=296, 25%) were the most commonly reported reasons for classifying an intervention as low value. Consideration of economic value was less frequently reported (N=171, 15%). When relevant cost-effectiveness studies were available, their results were mostly consistent with low-value care recommendations. CONCLUSIONS: Our study found that evidentiary rationales for low-value care vary substantially, with most recommendations relying on clinical evidence. Broadening the evidence base to incorporate cost-effectiveness evidence can help refine the definition of "low-value" care to reflect whether an intervention's costs are worth the benefits. Developing a consensus grading structure on the strength and evidentiary rationale may help improve de-implementation efforts for low-value care.

Do Centers for Medicare and Medicaid Services Quality Measures Reflect Cost-Effectiveness Evidence?

OBJECTIVES: Despite its importance of quality measures used by the Centers for Medicare and Medicaid Services, the underlying cost-effectiveness evidence has not been examined. This study aimed to analyze cost-effectiveness evidence associated with the Centers for Medicare and Medicaid Services quality measures. METHODS: After classifying 23 quality measures with the Donabedian's structure-process-outcome quality of care model, we identified cost-effectiveness analyses (CEAs) relevant to these measures from the Tufts Medical Center CEA Registry based on the PICOTS (population, intervention, comparator, outcome, time horizon, and setting) framework. We then summarized available incremental cost-effectiveness ratios (ICERs) to determine the cost-effectiveness of the quality measures. RESULTS: The 23 quality measures were categorized into 14 process, 7 outcome, and 2 structure measures. Cost-effectiveness evidence was only available for 8 of 14 process measures. Two measures (Tobacco Screening and Hemoglobin bA1c Control) were cost-saving and quality-adjusted life-years (QALYs) improving, and 5 (Depression Screening, Influenza Immunization, Colon Cancer Screening, Breast Cancer Screening, and Statin Therapy) were highly cost-effective (median ICER ≤ $50 000/QALY). The remaining measure (Fall Screening) had a median ICER of $120 000/QALY. No CEAs were available for 15 measures: 10 defined by subjective patient ratings and 5 employed outcome measures without specifying an intervention or process. CONCLUSIONS: When relevant CEAs were available, cost-effectiveness evidence was consistent with quality measures (measures were cost-effective). Nevertheless, most quality measures were based on subjective ratings or outcome measures, posing a challenge in identifying supporting economic evidence. Refining and aligning quality measures with cost-effectiveness evidence can help further improve healthcare efficiency by demonstrating that they are good indicators of both quality and cost-effectiveness of care.

Characterization of Bodily Pain and Use of Both Prescription and Non-Prescription Opioids in Tenants of Precarious Housing.

BACKGROUND: opioid use, which includes both prescribed and non-prescribed drugs, is relatively common amongst marginalized populations. Past research has shown that among those who use non-prescribed or diverted opioids recreationally, many were first exposed to the drug as prescribed pain medication. Objective: to better understand the relationship between pain and opioid use in tenants of precarious housing. Methods: in the present study, 440 individuals from a cohort living in homeless or precariously housed conditions in a neighborhood with high rates of poverty and drug use were interviewed for their bodily pain and opioid use. We examined the relationship between bodily pain levels, assessed using the Maudsley Addiction Profile questionnaire, and prescribed, non-prescribed and combined self-reported opioid use in the prior 28 days assessed using the Timeline Followback and Doctor-Prescribed Medication Timeline Followback questionnaires. Results: Analysis of the results indicated that sex (female), age (younger) and early exposure to opioids (≤ age 18) predicted current opioid use, but there was no association between current bodily pain levels and opioid use. Conclusions: these unexpected findings indicate the complex nature of the relationship between pain and opioid use in this population.

Clozapine-Associated Obsessive-Compulsive Symptoms and Their Management: A Systematic Review and Analysis of 107 Reported Cases.

BACKGROUND: It is not uncommon to find obsessive-compulsive symptoms (OCS) in patients treated with clozapine. These symptoms are attributed to anti-serotonergic effects of clozapine. The objective of this study was to conduct a systematic review of reported cases of clozapine-associated OCS to better understand the nature and management of these symptoms. METHODS: MEDLINE, Embase, and PsycINFO databases were searched with no publication year or language restrictions. Studies reporting cases of clozapine-associated OCS, either de novo or exacerbation of preexisting OCS, were included. The final search date was July 11, 2019. RESULTS: Fifty-seven studies, involving 107 cases (75 de novo, 32 exacerbated OCS), were included. Clozapine triggered moderate-severe OCS at varying doses (100-900 mg/day) and treatment durations (median 6 months, interquartile range 2-24 months). Higher severity was significantly associated with preexisting OCS, poorer insight into OCS, and active psychosis at the time of OCS. Common strategies to treat clozapine-associated OCS included adding selective serotonin reuptake inhibitors, clomipramine, or aripiprazole, often accompanied by clozapine dose reduction. The rate of response to antidepressants was 49% (29/59), where younger age, shorter duration of underlying illness, shorter cloza-pine treatment duration, better insight into OCS, and presence of taboo thoughts were significantly associated with antidepressant response. Subsequent clozapine dose reduction was effective in many non-responders, where aripiprazole was simultaneously added in 50% (8/16). CONCLUSIONS: Clozapine can trigger severe OCS. Adding aripiprazole with/without clozapine dose reduction may be a good alternative to antidepressants for managing clozapine-associated OCS. Clinicians should be more vigilant about these adverse effects and administer appropriate treatments.

Measuring "Fearonomic Effects" in Valuing Therapies: An Application to COVID-19 in China.

OBJECTIVES: To develop a checklist that helps quantify the economic impact associated with fear of contagion and to illustrate how one might use the checklist by presenting a case study featuring China during the coronavirus disease 2019 (COVID-19) outbreak. METHODS: Based on "fearonomic effects," a qualitative framework that conceptualizes the direct and indirect economic effects caused by the fear of contagion, we created a checklist to facilitate empirical estimation. As a case study, we first identified relevant sectors affected by China's lockdown policies implemented just before the Lunar New Year (LNY) week. To quantify the immediate impact, we then estimated the projected spending levels in 2020 in the absence of COVID-19 and compared these projections with actual spending during the LNY week. Data sources used include Chinese and global websites. To characterize uncertainty, we reported upper and lower bound estimates and calculated midpoints for each range. RESULTS: The COVID-19 epidemic is estimated to cost China's economy $283 billion ($196-369 billion), that is, ¥2.0 trillion renminbi (¥1.4-¥2.6 trillion), during the LNY week. Reduced restaurant and movie theater business ($106 [$103-$109] billion, 37.5% [36.4%-38.5%]) and reduced public transportation utilization ($96 [$13-$179] billion dollars, 33.9% [4.6%-63.3%]) explain most of this loss, followed by travel restrictions and the resulting loss of hotel business and tourism ($80.36 billion, 28.4%). CONCLUSION: Our checklist can help quantify the immediate and near-term impact of COVID-19 on a country's economy. It can also help researchers and policy makers consider the broader economic and social consequences when valuing future vaccines and treatments.

Growth and capacity for cost-effectiveness analysis in Africa.

As economic evaluation becomes increasingly essential to support universal health coverage (UHC), we aim to understand the growth, characteristics, and quality of cost-effectiveness analyses (CEA) conducted for Africa and to assess institutional capacity and relationship patterns among authors. We searched the Tufts Medical Center CEA Registries and four databases to identify CEAs for Africa. After extracting relevant information, we examined study characteristics, cost-effectiveness ratios, individual and institutional contribution to the literature, and network dyads at the author, institution, and country levels. The 358 identified CEAs for Africa primarily focused on sub-Saharan Africa (96%) and interventions for communicable diseases (77%). Of 2,121 intervention-specific ratios, 8% were deemed cost-saving, and most evaluated immunizations strategies. As 64% of studies included at least one African author, we observed widespread collaboration among international researchers and institutions. However, only 23% of first authors were affiliated with African institutions. The top producers of CEAs among African institutions are more adherent to methodological and reporting guidelines. Although economic evidence in Africa has grown substantially, the capacity for generating such evidence remains limited. Increasing the ability of regional institutions to produce high-quality evidence and facilitate knowledge transfer among African institutions has the potential to inform prioritization decisions for designing UHC.

Using QALYs versus DALYs to measure cost-effectiveness: How much does it matter?

OBJECTIVES: Quality-adjusted life-years (QALYs) and disability-adjusted life-years (DALYs) are commonly used in cost-effectiveness analysis (CEA) to measure health benefits. We sought to quantify and explain differences between QALY- and DALY-based cost-effectiveness ratios, and explore whether using one versus the other would materially affect conclusions about an intervention's cost-effectiveness. METHODS: We identified CEAs using both QALYs and DALYs from the Tufts Medical Center CEA Registry and Global Health CEA Registry, with a supplemental search to ensure comprehensive literature coverage. We calculated absolute and relative differences between the QALY- and DALY-based ratios, and compared ratios to common benchmarks (e.g., 1× gross domestic product per capita). We converted reported costs into US dollars. RESULTS: Among eleven published CEAs reporting both QALYs and DALYs, seven focused on pharmaceuticals and infectious disease, and five were conducted in high-income countries. Four studies concluded that the intervention was "dominant" (cost-saving). Among the QALY- and DALY-based ratios reported from the remaining seven studies, absolute differences ranged from approximately $2 to $15,000 per unit of benefit, and relative differences from 6-120 percent, but most differences were modest in comparison with the ratio value itself. The values assigned to utility and disability weights explained most observed differences. In comparison with cost-effectiveness thresholds, conclusions were consistent regardless of the ratio type in ten of eleven cases. CONCLUSIONS: Our results suggest that although QALY- and DALY-based ratios for the same intervention can differ, differences tend to be modest and do not materially affect comparisons to common cost-effectiveness thresholds.

Economic Value of Greater Access to Bariatric Procedures for Patients With Severe Obesity and Diabetes.

OBJECTIVE: Designing optimal insurance is important to ensure access to care for individuals that are most likely to benefit. We examined the potential impact of lowering patient cost-sharing for bariatric procedures. METHODS: After defining 10 subgroups by body mass index (BMI) and type 2 diabetes mellitus (T2DM), we analyzed the National Health and Nutrition Examination Survey datasets to estimate the prevalence of each subgroup. The MarketScan claims database provided utilization rates and costs of bariatric procedures. Using an existing cost-effectiveness model, we estimated the economic value of bariatric procedures under various cost-sharing levels (0%-25%) with 2 frameworks: (1) a traditional cost-effectiveness analysis and (2) a new approach that incorporates utilization effects across subgroups. RESULTS: The utilization rate was higher among individuals with T2DM than those without T2DM (90.4 vs. 59.1 cases per 100,000) for bariatric procedures, which were more cost-effective for those with T2DM and a higher BMI. After accounting for utilization effects, the economic value of bariatric surgery was $177 and $63 per individual from a lifetime and a 5-year time horizon, respectively. Under no patient cost-sharing for individuals with BMI≥40 and T2DM, utilization rates were expected to increase by 21 cases per 100,000, resulting in additional $2 realized value per patient and $7.07 million in returns at the US population level. CONCLUSIONS: Cost-sharing is a barrier to uptake of a clinical and cost-effective treatment for severe obesity. Reducing cost-sharing for patients with severe obesity and T2DM could potentially increase the utilization of bariatric procedures and result in greater economic value to payers.

Association of Antidepressant Use With Drug-Related Extrapyramidal Symptoms: A Pharmacoepidemiological Study.

BACKGROUND: Antidepressants are one of the most prescribed classes of medications. A number of case reports have linked these drugs to extrapyramidal symptoms (EPSs), but no large epidemiologic study to date has examined this association. We sought to quantify the association of EPSs with different antidepressants by undertaking a large pharmacoepidemiologic study. METHODS: A nested case-control study was conducted using a large health claims database in the United States from June 2006 to December 2015. Subjects with a diagnosis of primary Parkinson disease and those who received prescriptions of levodopa, ropinirole, pramipexole, domperidone, metoclopramide, entacapone, benztropine, selegiline, rasagiline, diphenhydramine, trihexyphenidyl, typical and atypical antipsychotics, and tricyclic antidepressants were excluded. Cases were followed to the first billing code for an extrapyramidal event or last date of enrollment in the cohort. For each case, 10 control subjects were matched by follow-up time, calendar time, and age through density-based sampling. Rate ratios were computed using conditional logistic regression adjusting for other covariates. RESULTS: We identified 3,838 subjects with EPSs compared with 38,380 age-matched control subjects. Rate ratios with respect to EPSs were as follows: duloxetine, 5.68 (95% confidence interval [CI], 4.29-7.53); mirtazapine, 3.78 (95% CI, 1.71-8.32); citalopram, 3.47 (95% CI, 2.68-4.50); escitalopram, 3.23 (95% CI, 2.44-4.26); paroxetine, 3.07 (95% CI, 2.15-4.40); sertraline, 2.57 (95% CI, 2.02-3.28); venlafaxine, 2.37 (95% CI, 1.71-3.29); bupropion, 2.31 (95% CI, 1.67-3.21); and fluoxetine, 2.03 (95% CI, 1.48-2.78). CONCLUSIONS: This observational study demonstrates a harmful association between the incidence of Parkinson disease or associated EPSs and use of the antidepressants duloxetine, mirtazapine, citalopram, escitalopram, paroxetine, sertraline, venlafaxine, bupropion, and fluoxetine.

Use and Misuse of Cost-Effectiveness Analysis Thresholds in Low- and Middle-Income Countries: Trends in Cost-per-DALY Studies.

OBJECTIVES: To determine what thresholds are most often cited in the cost-effectiveness literature for low- and middle-income countries (LMICs), given various recommendations proposed and used in the literature to date, and thereafter to assess whether studies appropriately justified their use of threshold values. METHODS: We reviewed the contents of the Tufts Medical Center Global Health Cost-Effectiveness Analysis Registry, a repository of all English language cost-per-disability-adjusted life-year averted studies indexed in PubMed. Our review included all catalogued cost-per-disability-adjusted life-year studies published from 2000 through 2015. We restricted attention to studies that investigated interventions in LMICs. RESULTS: Our analysis identified 381 studies (80%) focused on LMICs. Of these studies, 250 (66%) cited the World Health Organization's 1 to 3 times gross domestic product per capita threshold. A full-text review of 60 (24%) of these articles (randomly selected) revealed that none justified use of this threshold in the particular country or countries studied beyond citing (generic) guideline documents. CONCLUSIONS: Cost-effectiveness analysis can help inform health care spending, but its value depends on incorporating assumptions that are valid for the applicable setting. Rather than rely on commonly used, generic economic thresholds, we encourage authors to use context-specific thresholds that reflect local preferences.

New Onset Focal Stabbing Headache Associated With Peripheral Vertigo: A Case Report.

We present a novel case of a focal stabbing headache sharing features of primary stabbing headache that started and resolved with the onset and resolution of a course of self-limiting peripheral vertigo. The association of onset and improvement of the stabbing headaches support the trigeminal and vestibular reciprocal relationships. Vestibular input may be the driving force and a potential target for treatment.