Estimating Transition Probabilities for Modeling Major Depression in Adolescents by Sex and Race or Ethnicity Combinations in the USA.

OBJECTIVE: About one-fifth of US adolescents experienced major depressive symptoms, but few studies have examined longitudinal trends of adolescents developing depression or recovering by demographic factors. We estimated new transition probability inputs, and then used them in a simulation model to project the epidemiologic burden and trajectory of depression of diverse adolescents by sex and race or ethnicity combinations. METHODS: Transition probabilities were first derived using parametric survival analysis of data from the National Longitudinal Study of Adolescent to Adult Health and then calibrated to cross-sectional data from the National Survey on Drug Use and Health. We developed a cohort state-transition model to simulate age-specific depression outcomes of US adolescents. A hypothetical adolescent cohort was modeled from 12-22 years with annual transitions. Model outcomes included proportions of youth experiencing depression, recovery, or depression-free cases and were reported for a US adolescent population by sex, race or ethnicity, and sex and race or ethnicity combinations. RESULTS: At 22 years of age, approximately 16% of adolescents had depression, 12% were in recovery, and 72% had never developed depression. Depression prevalence peaked around 16-17 years-old. Adolescents of multiracial or other race or ethnicity, White, American Indian or Alaska Native, and Hispanic, Latino, or Spanish descent were more likely to experience depression than other racial or ethnic groups. Depression trajectories generated by the model matched well with historical observational studies by sex and race or ethnicity, except for individuals from American Indian or Alaska Native and multiracial or other race or ethnicity backgrounds. CONCLUSIONS: This study validated new transition probabilities for future use in decision models evaluating adolescent depression policies or interventions. Different sets of transition parameters by demographic factors (sex and race or ethnicity combinations) were generated to support future health equity research, including distributional cost-effectiveness analysis. Further data disaggregated with respect to race, ethnicity, religion, income, geography, gender identity, sexual orientation, and disability would be helpful to project accurate estimates for historically minoritized communities.

Delivering COVID-19 vaccine trials at speed: the implementation of a phase IV UK multi-centre randomised controlled trial to determine safety and immunogenicity of COVID-19 vaccines co-administered with seasonal influenza vaccines (ComFluCOV).

BACKGROUND: In February 2021, the UK Department of Health and Social Care sought evidence on the safety and immunogenicity of COVID-19 and influenza vaccine co-administration to inform the 2021/2022 influenza vaccine policy. Co-administration could support vaccine uptake and reduce healthcare appointments. ComFluCOV was a randomised controlled trial designed to provide this evidence. This report outlines the methods used to deliver the trial in 6 months to answer an urgent public health question as part of the COVID-19 pandemic response. METHODS: ComFluCOV was commissioned by the Department of Health and Social Care and was managed by the Bristol Trials Centre, a UK-registered clinical trials unit. It was classed as an Urgent Public Health trial which facilitated fast-track regulatory approvals. Trial materials and databases were developed using in-house templates and those used in other COVID-19 vaccine trials. Participants were recruited by advertising, and via a trial website. Electronic trial systems enabled daily review of participant data. Weekly virtual meetings were held with stakeholders and trial sites. RESULTS: ComFluCOV was delivered within 6 months from inception to reporting, and trial milestones to inform the Department of Health and Social Care policy were met. Set-up was achieved within 1 month. Regulators provided expedited reviews, with feedback ahead of submission. Recruitment took place at 12 sites. Over 380 site staff were trained. Overall, 679 participants were recruited in two months. The final report to the Department of Health and Social Care was submitted in September 2021, following a preliminary safety report in May 2021. Trial results have been published. CONCLUSION: The rapid delivery of ComFluCOV was resource intensive. It was made possible in part due to a unique set of circumstances created by the pandemic situation including measures put in place to support urgent public health research and public support for COVID-19 vaccine research. Elements of the trial could be adopted to increase efficiency in 'non-pandemic' situations including working with a clinical trials unit to enable immediate mobilisation of a team of experienced researchers, greater sharing of resources between clinical trials units, use of electronic trial systems and virtual meetings. TRIAL REGISTRATION: ISRCTN14391248, submitted on 17/03/2021. Registered on 30/03/2021.

Working under short timescales to deliver a national trial: a case study of the ComFluCOV trial from a statistician's perspective.

BACKGROUND: In early 2021, the Department of Health and Social Care in the UK called for research on the safety and immunogenicity of concomitant administration of COVID-19 and influenza vaccines. Co-administration of these vaccines would facilitate uptake and reduce the number of healthcare visits required. The ComFluCOV trial was designed to deliver the necessary evidence in time to inform the autumn (September-November) 2021 vaccination policy. This paper presents the statistical methodology applied to help successfully deliver the trial results in 6 months. METHODS: ComFluCOV was a parallel-group multicentre randomised controlled trial managed by the Bristol Trials Centre. Two study statisticians, supported by a senior statistician, worked together on all statistical tasks. Tools were developed to aid the pre-screening process. Automated data monitoring reports of clinic data and electronic diaries were produced daily and reviewed by the trial team and feedback provided to sites. Analyses were performed independently in parallel, and derivations and results of all outcomes were compared. RESULTS: Set-up was achieved in less than a month, and 679 participants were recruited over 8 weeks. A total of 537 [at least] daily reports outlining recruitment, protocol adherence, and data quality, and 695 daily reports of participant electronic diaries identifying any missed diary entries and adverse events were produced over a period of 16 weeks. A preliminary primary outcome analysis of validated data was reported to the Department of Health and Social Care in May 2021. The database was locked 6 weeks after the final participant follow-up and final analyses completed 3 weeks later. A pre-print publication was submitted within 14 days of the results being made available. The results were reported 6 months after first discussions about the trial. CONCLUSION: The statistical methodologies implemented in ComFluCOV helped to deliver the study in the timescale set. Working in a new clinical area to tight timescales was challenging. Having two statisticians working together on the study provided a quality assurance process that enabled analyses to be completed efficiently and ensured data were interpreted correctly. Processes developed could be applied to other studies to maximise quality, reduce the risk of errors, and overall provide enhanced validation methods. TRIAL REGISTRATION: ISRCTN14391248, registered on 30 March 2021.

Intermittent supplementation with fisetin improves arterial function in old mice by decreasing cellular senescence.

Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related arterial dysfunction, in part, by promoting oxidative stress and inflammation, which reduce the bioavailability of the vasodilatory molecule nitric oxide (NO). In the present study, we assessed the efficacy of fisetin, a natural compound, as a senolytic to reduce vascular cell senescence and SASP factors and improve arterial function in old mice. We found that fisetin decreased cellular senescence in human endothelial cell culture. In old mice, vascular cell senescence and SASP-related inflammation were lower 1 week after the final dose of oral intermittent (1 week on-2 weeks off-1 weeks on dosing) fisetin supplementation. Old fisetin-supplemented mice had higher endothelial function. Leveraging old p16-3MR mice, a transgenic model allowing genetic clearance of p16INK4A -positive senescent cells, we found that ex vivo removal of senescent cells from arteries isolated from vehicle- but not fisetin-treated mice increased endothelium-dependent dilation, demonstrating that fisetin improved endothelial function through senolysis. Enhanced endothelial function with fisetin was mediated by increased NO bioavailability and reduced cellular- and mitochondrial-related oxidative stress. Arterial stiffness was lower in fisetin-treated mice. Ex vivo genetic senolysis in aorta rings from p16-3MR mice did not further reduce mechanical wall stiffness in fisetin-treated mice, demonstrating lower arterial stiffness after fisetin was due to senolysis. Lower arterial stiffness with fisetin was accompanied by favorable arterial wall remodeling. The findings from this study identify fisetin as promising therapy for clinical translation to target excess cell senescence to treat age-related arterial dysfunction.

Protective effects of apigenin on the brain transcriptome with aging.

Brain aging is associated with reduced cognitive function that increases the risk for dementia. Apigenin is a bioactive plant compound that inhibits cellular aging processes and could protect against age-related cognitive dysfunction, but its mechanisms of action in the brain have not been comprehensively studied. We characterized brain transcriptome changes in young and old mice treated with apigenin in drinking water. We observed improved learning/memory in old treated mice, and our transcriptome analyses indicated that differentially expressed genes with aging and apigenin were primarily related to immune responses, inflammation, and cytokine regulation. Moreover, we found that genes/transcripts that were increased in old vs. young mice but downregulated with apigenin treatment in old animals were associated with immune activation/inflammation, whereas transcripts that were reduced with aging but increased with apigenin were related neuronal function and signaling. We also found that these transcriptome differences with aging and apigenin treatment were driven in part by glial cells. To follow up on these in vivo transcriptome findings, we studied aged astrocytes in vitro, and we found that apigenin reduced markers of inflammation and cellular senescence in these cells. Collectively, our data suggest that apigenin may protect against age-related cognitive dysfunction by suppressing neuro-inflammatory processes.

A mixed methods partner-focused cost and budget impact analysis to deploy implementation strategies for school-based prevention.

BACKGROUND: Obtaining information on implementation strategy costs and local budget impacts from multiple perspectives is essential to data-driven decision-making about resource allocation for successful evidence-based intervention delivery. This mixed methods study determines the costs and priorities of deploying Enhanced Replicating Effective Programs (REP) to implement the Michigan Model for Health™, a universal school-based prevention intervention, from key shareholder perspectives. METHODS: Our study included teachers in 8 high schools across 3 Michigan counties as part of a pilot cluster randomized trial. We used activity-based costing, mapping key Enhanced REP activities across implementation phases. We included multiple perspectives, including state agencies, regional education service agencies, lead organization, and implementers. We also conducted a budget impact analysis (BIA, assessing the potential financial impact of adopting Enhanced REP) and a scenario analysis to estimate replication and account for cost variability. We used an experimental embedded mixed methods approach, conducting semi-structured interviews and collecting field notes during the trial to expand and explain the cost data and the implications of costs across relevant perspectives. RESULTS: Based on trial results, we estimate costs for deploying Enhanced REP are $11,903/school, with an estimated range between $8263/school and $15,201/school. We estimate that adding four additional schools, consistent with the pilot, would cost $8659/school. Qualitative results indicated misalignment in school and teacher priorities in some cases. Implementation activities, including training and implementation facilitation with the health coordinator, were sometimes in addition to regular teaching responsibilities. The extent to which this occurred was partly due to leadership priorities (e.g., sticking to the district PD schedule) and organizational priorities (e.g., budget). CONCLUSIONS: Previous research findings indicate that, from a societal perspective, universal prevention is an excellent return on investment. However, notable misalignment in cost burden and priorities exists across shareholder groups. Our results indicate significant personal time costs by teachers when engaging in implementation strategy activities that impose an opportunity cost. Additional strategies are needed to improve the alignment of costs and benefits to enhance the success and sustainability of implementation. We focus on those perspectives informed by the analysis and discuss opportunities to expand a multi-level focus and create greater alignment across perspectives. TRIAL REGISTRATION: ClinicalTrials.gov NCT04752189. Registered on 12 February 2021.

Preferences and experiences of pediatricians on implementing national guidelines on universal routine screening of adolescents for major depressive disorder: A qualitative study.

BACKGROUND: To explore the preferences of pediatricians for key factors around the implementation of universal routine screening guidelines for major depressive disorder in adolescent patients in a primary care setting. METHOD: Semi-structured qualitative interviews were conducted with U.S. pediatricians. Participants were recruited by convenience sampling and snowball sampling. Qualitive data were summarized using thematic analysis to identify themes relevant to preferences around implementing screening strategies for adolescent patients. Recruitment ended upon reaching thematic saturation when no new themes were revealed. RESULTS: Of the 14 participants, 11 identified as female, 3 male, 10 white, and 4 Asian. Top themes among pediatrician participants were around the screening modality (14/14 participants), screening validity (14/14), time barriers (14/14), and confidentiality barriers (12/14). Less frequently mentioned themes by pediatricians were workplace coordination and logistics (7/14), alternative starting ages for screening (7/14), more frequent screenings than annual screenings (3/14), and additional clinical training regarding depression diagnosis and treatment (2/14). LIMITATIONS: Pool of interviewed participants was limited by diversity in terms of geography, race/ethnicity, or practice settings. CONCLUSIONS: To promote the uptake of universal routine screening of adolescent major depression, pediatricians expressed it was important to address key implementation factors regarding the screening modality, screening validity, time constraints, and confidential care concerns in a primary care delivery context. Findings could be used to inform the development of implementation strategies to facilitate depression screening in primary care. Future research is needed to quantitively assess decisions and tradeoffs that pediatricians make when implementing universal screening to support adolescent mental health.

Cellular Senescence Contributes to Large Elastic Artery Stiffening and Endothelial Dysfunction With Aging: Amelioration With Senolytic Treatment.

BACKGROUND: Here, we assessed the role of cellular senescence and the senescence associated secretory phenotype (SASP) in age-related aortic stiffening and endothelial dysfunction. METHODS: We studied young (6-8 mo) and old (27-29 mo) p16-3MR mice, which allows for genetic-based clearance of senescent cells with ganciclovir (GCV). We also treated old C57BL/6N mice with the senolytic ABT-263. RESULTS: In old mice, GCV reduced aortic stiffness assessed by aortic pulse wave velocity (PWV; 477±10 vs. 382±7 cm/s, P<0.05) to young levels (old-GCV vs. young-vehicle, P=0.35); ABT-263 also reduced aortic PWV in old mice (446±9 to 356±11 cm/s, P<0.05). Aortic adventitial collagen was reduced by GCV (P<0.05) and ABT-263 (P=0.12) in old mice. To show an effect of the circulating SASP, we demonstrated that plasma exposure from Old-vehicle p16-3MR mice, but not from Old-GCV mice, induced aortic stiffening assessed ex vivo (elastic modulus; P<0.05). Plasma proteomics implicated glycolysis in circulating SASP-mediated aortic stiffening. In old p16-3MR mice, GCV increased endothelial function assessed via peak carotid artery endothelium-dependent dilation (EDD; Old-GCV, 94±1% vs. Old-vehicle, 84±2%, P<0.05) to young levels (Old-GCV vs. young-vehicle, P=0.98), and EDD was higher in old C57BL/6N mice treated with ABT-263 vs. vehicle (96±1% vs. 82±3%, P<0.05). Improvements in endothelial function were mediated by increased nitric oxide (NO) bioavailability (P<0.05) and reduced oxidative stress (P<0.05). Circulating SASP factors related to NO signaling were associated with greater NO-mediated EDD following senescent cell clearance. CONCLUSIONS: Cellular senescence and the SASP contribute to vascular aging and senolytics hold promise for improving age-related vascular function.

Cost-effectiveness of surgical treatment of thumb carpometacarpal joint arthritis: a value of information study.

BACKGROUND: Thumb carpometacarpal (CMC) joint arthritis is one of the most prevalent arthritic conditions commonly treated with trapeziectomy alone or trapeziectomy with ligament reconstruction and tendon interposition (LRTI). We evaluate the cost-effectiveness and value of perfect and sample information of trapeziectomy alone, LRTI, and non-operative treatment. METHODS: A societal perspective decision tree was modeled. To understand the value of future research in comparing quality-of-life after trapeziectomy, LRTI, and non-operative management we characterized uncertainty by fitting distributions to EQ-5D utility data published from the United Kingdom hand surgery registry. We used Monte Carlo simulation for the probabilistic sensitivity analysis and to evaluate the value of perfect and sample information. RESULTS: Both trapeziectomy alone and LRTI were cost-effective compared to non-operative management ($2,540 and $3,511/QALY respectively). Trapeziectomy alone (base case total cost $8,251, QALY 14.08) was dominant compared to LRTI (base case total cost $8,798, QALY 13.34). However, probabilistic sensitivity analysis suggested there is a 12.5% chance LRTI may be preferred at a willingness-to-pay of $50,000/QALY. Sensitivity analysis revealed postoperative utilities are the most influential factors in determining cost-effectiveness. The value of perfect information was approximately $1,503/person. A study evaluating the quality-of-life of 1,000 patients in each arm undergoing trapeziectomy alone or LRTI could provide an expected $1,117 of information value. With approximately 40,000 CMC arthroplasties performed each year in the U.S., the annual value is close to $45 million. CONCLUSIONS: Trapeziectomy without LRTI appears to be the most cost-effective procedure in treating late-stage CMC arthritis and should be considered as first-line surgical treatment. There is substantial societal value in conducting additional research to better understand the relative quality-of-life improvements gained from these two common hand surgeries.

Best-worst scaling preferences among patients with well-controlled epilepsy: Pilot results.

Epilepsy is a common, serious condition. Fortunately, seizure risk decreases with increasing seizure-free time on antiseizure medications (ASMs). Eventually, patients may consider whether to stop ASMs, which requires weighing treatment benefit versus burden. We developed a questionnaire to quantify patient preferences relevant to ASM decision-making. Respondents rated how concerning they would finding relevant items (e.g., seizure risks, side effects, cost) on a Visual Analogue Scale (VAS, 0-100) and then repeatedly chose the most and least concerning item from subsets (best-worst scaling, BWS). We pretested with neurologists, then recruited adults with epilepsy who were seizure-free at least one year. Primary outcomes were recruitment rate, and qualitative and Likert-based feedback. Secondary outcomes included VAS ratings and best-minus-worst scores. Thirty-one of 60 (52%) contacted patients completed the study. Most patients felt VAS questions were clear (28; 90%), easy to use (27; 87%), and assessed preferences well (25; 83%). Corresponding results for BWS questions were 27 (87%), 29 (97%), and 23 (77%). Physicians suggested adding a 'warmup' question showing a completed example and simplifying terminology. Patients suggested ways to clarify instructions. Cost, inconvenience of taking medication, and laboratory monitoring were the least concerning items. Cognitive side effects and a 50% seizure risk in the next year were the most concerning items. Twelve (39%) of patients made at least one 'inconsistent choice' for example ranking a higher seizure risk as lower concern compared with a lower seizure risk, though 'inconsistent choices' represented only 3% of all question blocks. Our recruitment rate was favorable, most patients agreed the survey was clear, and we describe areas for improvement. 'Inconsistent' responses may lead us to collapse seizure probability items into a single 'seizure' category. Evidence regarding how patients weigh benefits and harms may inform care and guideline development.

Gaps in Prenatal Hepatitis B Screening and Management of HBsAg Positive Pregnant Persons in the U.S., 2015-2020.

BACKGROUND: The Advisory Committee for Immunization Practices (ACIP) recommends testing all pregnant women for hepatitis B surface antigen (HBsAg) and testing HBsAg-positive pregnant women for hepatitis B virus deoxyribonucleic acid (HBV DNA). HBsAg-positive pregnant persons are recommended by the American Association for the Study of Liver Diseases to receive regular monitoring, including alanine transaminase (ALT) and HBV DNA and antiviral therapy for active hepatitis and to prevent perinatal HBV transmission if HBV DNA level is >200,000 IU/mL. METHODS: Using Optum Clinformatics Data Mart Database claims data, pregnant women who received HBsAg testing and HBsAg-positive pregnant persons who received HBV DNA and alt testing and antiviral therapy during pregnancy and after delivery during January 1, 2015-December 31, 2020 were analyzed. RESULTS: Among 506,794 pregnancies, 14.6% did not receive HBsAg testing. Pregnant women more likely to receive testing for HBsAg (p<0.01) were persons aged ≥20 years, were Asian, had >1 child, or received education beyond high school. Among the 0.28% (1,437) pregnant women who tested positive for hepatitis B surface antigen, 46% were Asian. The proportion of HBsAg-positive pregnant women who received HBV DNA testing during pregnancy and in the 12 months after delivery was 44.3% and 28.6%, respectively; the proportion that received hepatitis B e antigen was 31.6% and 12.7%, respectively; the proportion that received ALT testing was 67.4% and 47%, respectively; and the proportion that received HBV antiviral therapy was 7% and 6.2%, respectively. CONCLUSIONS: This study suggests that as many as half a million (∼14%) pregnant persons who gave birth each year were not tested for HBsAg to prevent perinatal transmission. More than 50% of HBsAg-positive persons did not receive the recommended HBV-directed monitoring tests during pregnancy and after delivery.

Gaps and Disparities in Chronic Hepatitis B Monitoring and Treatment in the United States, 2016-2019.

BACKGROUND: Chronic hepatitis B (CHB) carries an increased risk of death from cirrhosis and hepatocellular carcinoma (HCC). The American Association for the Study of Liver Diseases recommends patients with CHB receive monitoring of disease activity, including ALT, hepatitis B virus (HBV) DNA, hepatitis B e-antigen (HBeAg), and liver imaging for patients who experience an increased risk for HCC. HBV antiviral therapy is recommended for patients with active hepatitis and cirrhosis. METHODS: Monitoring and treatment of adults with new CHB diagnoses were analyzed using Optum Clinformatics Data Mart Database claims data from January 1, 2016, to December 31, 2019. RESULTS: Among 5978 patients with new CHB diagnosis, only 56% with cirrhosis and 50% without cirrhosis had claims for≥1 ALT and either HBV DNA or HBeAg test, and among patients recommended for HCC surveillance, 82% with cirrhosis and 57% without cirrhosis had claims for≥1 liver imaging within 12 months of diagnosis. Although antiviral treatment is recommended for patients with cirrhosis, only 29% of patients with cirrhosis had≥1 claim for HBV antiviral therapy within 12 months of CHB diagnosis. Multivariable analysis showed patients who were male, Asian, privately insured, or had cirrhosis were more likely (P<0.05) to receive ALT and either HBV DNA or HBeAg tests and HBV antiviral therapy within 12 months of diagnosis. CONCLUSION: Many patients diagnosed with CHB are not receiving the clinical assessment and treatment recommended. A comprehensive initiative is needed to address the patient, provider, and system-related barriers to improve the clinical management of CHB.

The burden of Chronic Pelvic Pain (CPP): Costs and quality of life of women and men with CPP treated in outpatient referral centers.

INTRODUCTION: Chronic Pelvic Pain (CPP) is a complex, multifaceted condition that affects both women and men. There is limited literature on the cost utilization the healthcare system and CPP patients incur. The purpose of this analysis is to characterize the overall healthcare utilization, cost burden, and quality-of-life restrictions experienced by CPP patients using data from an outpatient pelvic rehabilitation practice. METHODS: Healthcare utilization data was gathered by systematically reviewing and analyzing data from new patient visit progress notes stored in the clinic's electronic health records (EHR). We obtained in-network costs by using the FAIR Health Consumer online database. Overall costs were then calculated as the utilization times the per-unit costs from the FAIR database. Additionally, data on patients' visual analogue scale (VAS), absenteeism, presenteeism emergency room visits, usage of common pain medications, use of diagnostics, and participation in common treatment modalities was gathered. RESULTS: Data from 607 patients was used. The overall cost burden per patient for all surgeries combined was $15,750 for in-network services. The cost burden for diagnostics was $5,264.22 and treatments was $8,937 per patient for in-network treatments. CONCLUSION: Chronic Pelvic Pain was found to have a large cost burden of $29,951 for in-network services which includes treatments, diagnostics, and surgeries. This analysis sets the stage for future investigations involving data on costs of medications that patients have tried prior to presenting to us and costs associated with work hours lost.

Cost-effectiveness of Aflibercept Monotherapy vs Bevacizumab First Followed by Aflibercept If Needed for Diabetic Macular Edema.

Importance: The DRCR Retina Network Protocol AC showed no significant difference in visual acuity outcomes over 2 years between treatment with aflibercept monotherapy and bevacizumab first with switching to aflibercept for suboptimal response in treating diabetic macular edema (DME). Understanding the estimated cost and cost-effectiveness of these approaches is important. Objective: To evaluate the cost and cost-effectiveness of aflibercept monotherapy vs bevacizumab-first strategies for DME treatment. Design, Setting, and Participants: This economic evaluation was a preplanned secondary analysis of a US randomized clinical trial of participants aged 18 years or older with center-involved DME and best-corrected visual acuity of 20/50 to 20/320 enrolled from December 15, 2017, through November 25, 2019. Interventions: Aflibercept monotherapy or bevacizumab first, switching to aflibercept in eyes with protocol-defined suboptimal response. Main Outcomes and Measures: Between February and July 2022, the incremental cost-effectiveness ratio (ICER) in cost per quality-adjusted life-year (QALY) over 2 years was assessed. Efficacy and resource utilization data from the randomized clinical trial were used with health utility mapping from the literature and Medicare unit costs. Results: This study included 228 participants (median age, 62 [range, 34-91 years; 116 [51%] female and 112 [49%] male; 44 [19%] Black or African American, 60 [26%] Hispanic or Latino, and 117 [51%] White) with 1 study eye. The aflibercept monotherapy group included 116 participants, and the bevacizumab-first group included 112, of whom 62.5% were eventually switched to aflibercept. Over 2 years, the cost of aflibercept monotherapy was $26 504 (95% CI, $24 796-$28 212) vs $13 929 (95% CI, $11 984-$15 874) for the bevacizumab-first group, a difference of $12 575 (95% CI, $9987-$15 163). The aflibercept monotherapy group gained 0.015 (95% CI, -0.011 to 0.041) QALYs using the better-seeing eye and had an ICER of $837 077 per QALY gained compared with the bevacizumab-first group. Aflibercept could be cost-effective with an ICER of $100 000 per QALY if the price per dose were $305 or less or the price of bevacizumab was $1307 per dose or more. Conclusions and Relevance: Variability in individual needs will influence clinician and patient decisions about how to treat specific eyes with DME. While the bevacizumab-first group costs still averaged approximately $14 000 over 2 years, this approach, as used in this study, may confer substantial cost savings on a societal level without sacrificing visual acuity gains over 2 years compared with aflibercept monotherapy.

Cost-effectiveness of Staple Line Reinforcement in Laparoscopic Sleeve Gastrectomy.

OBJECTIVE: To perform a cost-effectiveness analysis of staple-line reinforcement in laparoscopic sleeve gastrectomy. SUMMARY OF BACKGROUND DATA: Exponential increases in surgical costs have underscored the critical need for evidence-based methods to determine the relative value of surgical devices. One such device is staple-line reinforcement, thought to decrease bleeding rates in laparoscopic sleeve gastrectomy. METHODS: Two intervention arms were modeled, staple-line reinforcement and standard nonreinforced stapling. Bleed and leak rates and 30-day treatment costs were obtained from national and state registries. Quality-adjusted life-year (QALY) values were drawn from previous literature. Device prices were drawn from institutional data. A final incremental cost-effectiveness ratio was calculated, and one-way and probabilistic sensitivity analyses were performed. RESULTS: A total of 346,530 patient records from 2012 to 2018 were included. Complication rates for the reinforced and standard cohorts were 0.05% for major bleed in both cohorts ( P = 0.8841); 0.45% compared with 0.59% for minor bleed ( P < 0.0001); and 0.24% compared with 0.26% for leak ( P = 0.4812). Median cost for a major bleed was $5552 ($3287, $16,817) and $2406 ($1861, $3484) for a minor bleed. Median leak cost was $9897 ($4589, $21,619) and median cost for patients who did not experience a bleed, leak, or other serious complication was $1908 ($1712, $2739). Mean incremental cost of reinforced stapling compared with standard was $819.60/surgery. Net QALY gain with reinforced stapling compared with standard was 0.00002. The resultant incremental cost-effectiveness ratio was $40,553,000/QALY. One-way and probabilistic sensitivity analyses failed to produce a value below $150,000/QALY. CONCLUSIONS: Compared with standard stapling, reinforced stapling reduces minor postoperative bleeding but not major bleeding or leaks and is not cost-effective if routinely used in laparoscopic sleeve gastrectomy.

Clinical event reductions in high-risk patients after renal denervation projected from the global SYMPLICITY registry.

AIMS: Renal denervation has been shown to lower blood pressure in sham-controlled trials and represents a device-based treatment option for hypertension. We sought to project clinical event reductions after radiofrequency renal denervation using a novel modelling approach. METHODS AND RESULTS: The Global SYMPLICITY Registry is a global, prospective all-comer registry to evaluate safety and efficacy after renal denervation. For this analysis, change in office systolic blood pressure from baseline was calculated from reported follow-up in the Global SYMPLICITY Registry. Relative risks for death and other cardiovascular events as well as numbers needed to treat for event avoidance were obtained for the respective blood pressure reductions based on previously reported meta-regression analyses for the full cohort and high-risk subgroups including type 2 diabetes, chronic kidney disease, resistant hypertension, and high basal cardiovascular risk. Average baseline office systolic blood pressure and reduction estimates for the full cohort (N = 2651) were 166±25 and -14.8 ± 0.4 mmHg, respectively. Mean reductions in blood pressure ranged from -11.0--21.8 mmHg for the studied high-risk subgroups. Projected relative risks ranged from 0.57 for stroke in the resistant hypertension cohort to 0.92 for death in the diabetes cohort. Significant absolute reductions in major adverse cardiovascular events over 3 years compared with the projected control (8.6 ± 0.7% observed vs. 11.7 ± 0.9% for projected control; P < 0.01) were primarily due to reduced stroke incidence. The robustness of findings was confirmed in sensitivity and scenario analyses. CONCLUSION: Model-based projections suggest radiofrequency renal denervation for patients with uncontrolled hypertension adds considerable clinical benefit across a spectrum of different cohort characteristics.

Impact of the national hepatitis B immunization program in China: a modeling study.

BACKGROUND: Elimination of hepatitis B virus (HBV) is a striking challenge for countries with high or moderate disease burden. Therefore, using China as a practical case to share experiences for similar countries may accelerate the achievement of the WHO 2030 target of 90% reduction in HBV-related incidence. We aim to evaluate the impact of national HBV immunization strategies in China; and the feasibility to achieve WHO 2030 targets under different scenarios. METHODS: We constructed an expanded Susceptible-Exposed-Infectious-Recovered (SEIR) model and decision tree-Markov model to estimate the epidemic of HBV in China, assess the feasibility of 2030 Elimination Goals through the projections and conduct the economic analysis. Least square method was used to calibrate the expanded SEIR model by yearly data of laboratory-confirmed HBV cases from 1990 to 2018. Two models were separately used to evaluate the impact and cost-effectiveness of HBV vaccine by comparing prevalence of chronic HBV infections, quality-adjusted life-years (QALYs), incremental cost effectiveness ratio and benefit-cost ratio (BCR) under various intervention options, providing a basis for exploring new containment strategies. RESULTS: Between 1990 and 2020, the number of chronic HBV infections decreased by 33.9%. The current status quo would lead to 55.73 million infections (3.95% prevalence) in 2030, compared to 90.63 million (6.42% prevalence) of the "Without the NIP" scenario (NIP: National Immunization Program), 114.78 million (8.13% prevalence) without any interventions. The prevention of mother to child transmission (PMTCT) strategy showed a net benefit as 12,283.50 dollars per person, with BCR as 12.66, which is higher than that of universal vaccination at 9.49. Compared with no screening and no vaccination, the PMTCT strategy could save 7726.03 dollars for each QALY increase. CONCLUSIONS: Our findings proved the HBV vaccination has demonstrated a substantial positive impact on controlling the epidemic of HBV in terms of effectiveness and economy after about 30 years of implementation of the national hepatitis B immunization program which also provided containment experience for high or medium burden countries. As for China, the next step should focus on exploring strategies to improve diagnosis and treatment coverage to reduce the burden of HBV-related deaths and ultimately eliminate HBV.

Initiation of 3,3-dimethyl-1-butanol at midlife prevents endothelial dysfunction and attenuates in vivo aortic stiffening with ageing in mice.

Vascular dysfunction: develops progressively with ageing; increases the risk of cardiovascular diseases (CVD); and is characterized by endothelial dysfunction and arterial stiffening, which are primarily mediated by superoxide-driven oxidative stress and consequently reduced nitric oxide (NO) bioavailability and arterial structural changes. Interventions initiated before vascular dysfunction manifests may have more promise for reducing CVD risk than interventions targeting established dysfunction. Gut microbiome-derived trimethylamine N-oxide (TMAO) induces vascular dysfunction, is associated with higher CV risk, and can be suppressed by 3,3-dimethyl-1-butanol (DMB). We investigated whether DMB supplementation could prevent age-related vascular dysfunction in C57BL/6N mice when initiated prior to development of dysfunction. Mice received drinking water with 1% DMB or normal drinking water (control) from midlife (18 months) until being studied at 21, 24 or 27 months of age, and were compared to young adult (5 month) mice. Endothelial function [carotid artery endothelium-dependent dilatation (EDD) to acetylcholine; pressure myography] progressively declined with age in control mice, which was fully prevented by DMB via higher NO-mediated EDD and lower superoxide-related suppression of EDD (normalization of EDD with the superoxide dismutase mimetic TEMPOL). In vivo aortic stiffness (pulse wave velocity) increased progressively with age in controls, but DMB attenuated stiffening by ∼ 70%, probably due to preservation of endothelial function, as DMB did not affect aortic intrinsic mechanical (structural) stiffness (stress-strain testing) nor adventitial abundance of the arterial structural protein collagen. Our findings indicate that long-term DMB supplementation prevents/attenuates age-related vascular dysfunction, and therefore has potential for translation to humans for reducing CV risk with ageing. KEY POINTS: Vascular dysfunction, characterized by endothelial dysfunction and arterial stiffening, develops progressively with ageing and increases the risk of cardiovascular diseases (CVD). Interventions aimed at preventing the development of CV risk factors have more potential for preventing CVD relative to those aimed at reversing established dysfunction. The gut microbiome-derived metabolite trimethylamine N-oxide (TMAO) induces vascular dysfunction, is associated with higher CV risk and can be suppressed by supplementation with 3,3-dimethyl-1-butanol (DMB). In mice, DMB prevented the development of endothelial dysfunction and delayed and attenuated in vivo arterial stiffening with ageing when supplementation was initiated in midlife, prior to the development of dysfunction. DMB supplementation or other TMAO-suppressing interventions have potential for translation to humans for reducing CV risk with ageing.

Estimation of Potential Deaths Averted From Hypothetical US Income Support Policies.

Importance: Income has a negative, nonlinear association with all-cause mortality. Income support policies may prevent deaths among low-income populations by raising their incomes. Objective: To estimate the deaths that could be averted among working-age adults age 18 to 64 years with hypothetical income support policies in the US. Design Setting and Population: An open, multicohort life-table model was developed that simulated working-age adults age 18 to 64 years in the US over 5 to 40 years. Publicly available household income data and previous estimates of the income-mortality association were used to generate mortality rates by income group. Deterministic sensitivity analyses were conducted to evaluate the effect of parameter uncertainty and various model assumptions on the findings. Interventions: In addition to a no-intervention scenario, 4 hypothetical income support policies were modeled: universal basic income, modified LIFT Act, poverty alleviation, and negative income tax. Main Outcome and Measures: The main outcome was the number of deaths averted, which was calculated by subtracting the number of deaths experienced in the no-intervention scenario from the number of deaths experienced with the various income support policies. Results: Base-case assumptions used average mortality rates by age, sex, and income group, a 20-year time horizon, and a 3-year lag time. Universal basic income worth $12 000 per year per individual was estimated to avert the most deaths among working-age adults (42 000-104 000 per year), followed by a negative income tax that guaranteed an income of 133% of the federal poverty level (19 000-67 000 per year). A modified LIFT Act that provided $6000 to individuals with annual household incomes less than $100 000 was estimated to avert 17 000 to 52 000 deaths per year. A targeted approach that alleviated poverty was estimated to prevent 12 000 to 32 000 deaths among the lowest-income, working-age adult population. Results were most sensitive to several inputs and assumptions, primarily the income-based mortality rates, analytic time horizon, and assumed time lag between when a policy was implemented and when individuals experienced the mortality benefit of having higher incomes. Conclusions and Relevance: In this modeling study, 4 hypothetical income support policies were estimated to avert thousands of deaths among working-age US adults every year. Additional research is needed to understand the true association of income gains with mortality. Discussions about the costs and benefits of income support policies should include potential gains in health.

Costs and health impact of delayed implementation of a national hepatitis B treatment program in China.

Background: Hepatitis B virus (HBV) infection is a leading public health problem in China. COVID-19 pandemic has interrupted the delivery of health care interventions worldwide, including HBV infection control. Methods: In this study, we used a Markov model to quantify the costs and population health impact of HBV treatment in China for the following scenarios: 1) current practice with only 17% of treatment eligible HBV infected adults receiving antiviral treatment; 2) reaching the World Health Organization (WHO) treatment target of 80% by 2030 with a steady increase in treatment rate beginning in 2022; and 3) the effect of a 1-5-year delay in meeting the 2030 WHO treatment target. A one-way as well as a probabilistic sensitivity analysis were conducted. Results: Without increasing antiviral treatment for treatment eligible HBV infected adults, the life-time health care costs for the estimated 89.2 million adults living with HBV in China is US$1305 billion and 10.8 million (12%) will die from HBV-related liver disease. Increasing treatment to achieve the WHO 80% target by 2030 would save US$472 billion and prevent 3.3 million HBV-related deaths. We estimated that a 1-year delay beyond 2030 in reaching the WHO 80% treatment target would likely lead to US$55 billion increase in future health care costs, and an additional 334 000 future deaths from HBV-related liver disease or cancer. Conclusions: Reaching the WHO 2030 with minimal delays would have an immense health and economic benefit. Implementing a national treatment program for HBV in China should be a key priority for policymakers.