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Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD)., Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment., Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed., Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks., Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL., Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] β = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] β = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] β = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] β = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] β = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] β = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] β = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo., Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification., Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.

Importance: Obesity is a disease with a large socioeconomic burden. Endoscopic sleeve gastroplasty (ESG) is a minimally invasive endoscopic bariatric procedure with wide global adoption. More recently, new weight-loss medications, such as glucagon-like peptide-1 receptor agonists (eg, semaglutide), have attracted increased attention due to their efficacy. However, their cost-effectiveness over an extended period compared with ESG is a critical gap that needs to be better explored for informed health care decision-making., Objective: To assess the cost-effectiveness of semaglutide compared with ESG over 5 years for individuals with class II obesity., Design, Setting, and Participants: This economic evaluation study, conducted from September 1, 2022, to May 31, 2023, used a Markov cohort model to compare ESG and semaglutide, with a no-treatment baseline strategy. The study comprised adult patients in the US health care system with class II obesity (body mass index [BMI] of 35-39.9). The base case was a 45-year-old patient with class II obesity (BMI of 37). Patients undergoing ESG were subjected to risks of perioperative mortality and adverse events with resultant costs and decrement in quality of life., Interventions: Strategies included treatment with semaglutide and ESG., Main Outcomes and Measures: Costs (2022 US dollars), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) with a willingness-to-pay threshold of $100 000/QALY. A 5-year time horizon with a cycle length of 1 month with a 3% discount rate was used. Probabilities, costs, and quality-of-life estimates of the model were derived from published literature. One-way, 2-way, and probabilistic sensitivity analyses were also performed., Results: The model found that ESG was more cost-effective than semaglutide over a 5-year time horizon, with an ICER of -$595 532/QALY. Endoscopic sleeve gastroplasty added 0.06 QALYs and reduced total cost by $33 583 relative to semaglutide. The results remained robust on 1-way and probabilistic sensitivity analyses. Endoscopic sleeve gastroplasty sustained greater weight loss over 5 years vs semaglutide (BMI of 31.7 vs 33.0). To achieve nondominance, the annual price of semaglutide, currently $13 618, would need to be $3591., Conclusions and Relevance: This study suggests that ESG is cost saving compared with semaglutide in the treatment of class II obesity. On price threshold analyses, a 3-fold decrease in the price of semaglutide is needed to achieve nondominance.

Importance: In 2021, more than 80 000 US residents died from an opioid overdose. Public health intervention initiatives, such as the Helping to End Addiction Long-term (HEALing) Communities Study (HCS), are being launched with the goal of reducing opioid-related overdose deaths (OODs)., Objective: To estimate the change in the projected number of OODs under different scenarios of the duration of sustainment of interventions, compared with the status quo., Design, Setting, and Participants: This decision analytical model simulated the opioid epidemic in the 4 states participating in the HCS (ie, Kentucky, Massachusetts, New York, and Ohio) from 2020 to 2026. Participants were a simulated population transitioning from opioid misuse to opioid use disorder (OUD), overdose, treatment, and relapse. The model was calibrated using 2015 to 2020 data from the National Survey on Drug Use and Health, the US Centers for Disease Control and Prevention, and other sources for each state. The model accounts for reduced initiation of medications for OUD (MOUDs) and increased OODs during the COVID-19 pandemic., Exposure: Increasing MOUD initiation by 2- or 5-fold, improving MOUD retention to the rates achieved in clinical trial settings, increasing naloxone distribution efforts, and furthering safe opioid prescribing. An initial 2-year duration of interventions was simulated, with potential sustainment for up to 3 additional years., Main Outcomes and Measures: Projected reduction in number of OODs under different combinations and durations of sustainment of interventions., Results: Compared with the status quo, the estimated annual reduction in OODs at the end of the second year of interventions was 13% to 17% in Kentucky, 17% to 27% in Massachusetts, 15% to 22% in New York, and 15% to 22% in Ohio. Sustaining all interventions for an additional 3 years was estimated to reduce the annual number of OODs at the end of the fifth year by 18% to 27% in Kentucky, 28% to 46% in Massachusetts, 22% to 34% in New York, and 25% to 41% in Ohio. The longer the interventions were sustained, the better the outcomes; however, these positive gains would be washed out if interventions were not sustained., Conclusions and Relevance: In this decision analytical model study of the opioid epidemic in 4 US states, sustained implementation of interventions, including increased delivery of MOUDs and naloxone supply, was found to be needed to reduce OODs and prevent deaths from increasing again.

Importance: Quantitative assessment of disease progression in patients with nonalcoholic fatty liver disease (NAFLD) has not been systematically examined using competing liver-related and non-liver-related mortality., Objective: To estimate long-term outcomes in NAFLD, accounting for competing liver-related and non-liver-related mortality associated with the different fibrosis stages of NAFLD using a simulated patient population., Design, Setting, and Participants: This decision analytical modeling study used individual-level state-transition simulation analysis and was conducted from September 1, 2017, to September 1, 2021. A publicly available interactive tool, dubbed NAFLD Simulator, was developed that simulates the natural history of NAFLD by age and fibrosis stage at the time of (hypothetical) diagnosis defined by liver biopsy. Model health states were defined by fibrosis states F0 to F4, decompensated cirrhosis, hepatocellular carcinoma (HCC), and liver transplant. Simulated patients could experience nonalcoholic steatohepatitis resolution, and their fibrosis stage could progress or regress. Transition probabilities between states were estimated from the literature as well as calibration, and the model reproduced the outcomes of a large observational study., Exposure: Simulated natural history of NAFLD., Main Outcomes and Measures: Main outcomes were life expectancy; all cause, liver-related, and non-liver-related mortality; and cumulative incidence of decompensated cirrhosis and/or HCC., Results: The model included 1 000 000 simulated patients with a mean (range) age of 49 (18-75) years at baseline, including 66% women. The life expectancy of patients aged 49 years was 25.3 (95% CI, 20.1-29.8) years for those with F0, 25.1 (95% CI, 20.1-29.4) years for those with F1, 23.6 (95% CI, 18.3-28.2) years for those with F2, 21.1 (95% CI, 15.6-26.3) years for those with F3, and 13.8 (95% CI, 10.3-17.6) years for those with F4 at the time of diagnosis. The estimated 10-year liver-related mortality was 0.1% (95% uncertainty interval [UI], <0.1%-0.2%) in F0, 0.2% (95% UI, 0.1%-0.4%) in F1, 1.0% (95% UI, 0.6%-1.7%) in F2, 4.0% (95% UI, 2.5%-5.9%) in F3, and 29.3% (95% UI, 21.8%-35.9%) in F4. The corresponding 10-year non-liver-related mortality was 1.8% (95% UI, 0.6%-5.0%) in F0, 2.4% (95% UI, 0.8%-6.3%) in F1, 5.2% (95% UI, 2.0%-11.9%) in F2, 9.7% (95% UI, 4.3%-18.1%) in F3, and 15.6% (95% UI, 10.1%-21.7%) in F4. Among patients aged 65 years, estimated 10-year non-liver-related mortality was higher than liver-related mortality in all fibrosis stages (eg, F2: 16.7% vs 0.8%; F3: 28.8% vs 3.0%; F4: 40.8% vs 21.9%)., Conclusions and Relevance: This decision analytic model study simulated stage-specific long-term outcomes, including liver- and non-liver-related mortality in patients with NAFLD. Depending on age and fibrosis stage, non-liver-related mortality was higher than liver-related mortality in patients with NAFLD. By translating surrogate markers into clinical outcomes, the NAFLD Simulator could be used as an educational tool among patients and clinicians to increase awareness of the health consequences of NAFLD.

Importance: Undiagnosed atrial fibrillation (AF) is an important cause of stroke. Screening for AF using wrist-worn wearable devices may prevent strokes, but their cost-effectiveness is unknown., Objective: To evaluate the cost-effectiveness of contemporary AF screening strategies, particularly wrist-worn wearable devices., Design Setting and Participants: This economic evaluation used a microsimulation decision-analytic model and was conducted from September 8, 2020, to May 23, 2022, comprising 30 million simulated individuals with an age, sex, and comorbidity profile matching the US population aged 65 years or older., Interventions: Eight AF screening strategies, with 6 using wrist-worn wearable devices (watch or band photoplethysmography, with or without watch or band electrocardiography) and 2 using traditional modalities (ie, pulse palpation and 12-lead electrocardiogram) vs no screening., Main Outcomes and Measures: The primary outcome was the incremental cost-effectiveness ratio, defined as US dollars per quality-adjusted life-year (QALY). Secondary measures included rates of stroke and major bleeding., Results: In the base case analysis of this model, the mean (SD) age was 72.5 (7.5) years, and 50% of the individuals were women. All 6 screening strategies using wrist-worn wearable devices were estimated to be more effective than no screening (range of QALYs gained vs no screening, 226-957 per 100 000 individuals) and were associated with greater relative benefit than screening using traditional modalities (range of QALYs gained vs no screening, -116 to 93 per 100 000 individuals). Compared with no screening, screening using wrist-worn wearable devices was associated with a reduction in stroke incidence by 20 to 23 per 100 000 person-years but an increase in major bleeding by 20 to 44 per 100 000 person-years. The overall preferred strategy was wearable photoplethysmography, followed conditionally by wearable electrocardiography with patch monitor confirmation, which had an incremental cost-effectiveness ratio of $57 894 per QALY, meeting the acceptability threshold of $100 000 per QALY. The cost-effectiveness of screening was consistent across multiple scenarios, including strata of sex, screening at earlier ages (eg, ≥50 years), and with variation in the association of anticoagulation with risk of stroke in the setting of screening-detected AF., Conclusions and Relevance: This economic evaluation of AF screening using a microsimulation decision-analytic model suggests that screening using wearable devices is cost-effective compared with either no screening or AF screening using traditional methods., Competing Interests: Conflict of Interest Disclosures: Dr Singer reported receiving grants from Bristol Myers Squibb and personal fees from Bristol Myers Squibb, Fitbit Inc, Medtronic, Pfizer, and UpToDate outside the submitted work. Dr Atlas reported receiving grants from Bristol Myers Squibb/Pfizer Alliance and the American Heart Association and personal fees from Bristol Myers Squibb, Pfizer, and FitBit Inc outside the submitted work. Dr Ellinor reported receiving grants from IBM and Bayer AG during the conduct of the study and personal fees from Novartis, MyoKardia, and Bayer AG outside the submitted work. Dr McManus reported receiving grants from Bristol Myers Squibb, Pfizer, and Boehringer Ingelheim; personal fees from Bristol Myers Squibb, Pfizer, the Heart Rhythm Society, Avania Consulting, and Fitbit Inc; and nonfinancial support from Apple outside the submitted work. Dr Lubitz reported receiving grants from Bristol Myers Squibb/Pfizer, Fitbit Inc, IBM, Boehringer Ingelheim, Medtronic, Premier, the National Institutes of Health (NIH), and the American Heart Association and personal fees from Invitae, Blackstone Life Sciences, and Bristol Myers Squibb/Pfizer outside the submitted work. Dr Chhatwal reported receiving personal fees from Bayer, Flatiron, and Value Analytics Labs and holding stock in Apple and Alphabet outside the submitted work. No other disclosures were reported., (Copyright 2022 Chen W et al. JAMA Health Forum.)

Importance: A key question for policy makers and the public is what to expect from the COVID-19 pandemic going forward as states lift nonpharmacologic interventions (NPIs), such as indoor mask mandates, to prevent COVID-19 transmission., Objective: To project COVID-19 deaths between March 1, 2022, and December 31, 2022, in each of the 50 US states, District of Columbia, and Puerto Rico assuming different dates of lifting of mask mandates and NPIs., Design Setting and Participants: This simulation modeling study used the COVID-19 Policy Simulator compartmental model to project COVID-19 deaths from March 1, 2022, to December 31, 2022, using simulated populations in the 50 US states, District of Columbia, and Puerto Rico. Projected current epidemiologic trends for each state until December 31, 2022, assuming the current pace of vaccination is maintained into the future and modeling different dates of lifting NPIs., Exposures: Date of lifting statewide NPI mandates as March 1, April 1, May 1, June 1, or July 1, 2022., Main Outcomes and Measures: Projected COVID-19 incident deaths from March to December 2022., Results: With the high transmissibility of current circulating SARS-CoV-2 variants, the simulated lifting of NPIs in March 2022 was associated with resurgences of COVID-19 deaths in nearly every state. In comparison, delaying by even 1 month to lift NPIs in April 2022 was estimated to mitigate the amplitude of the surge. For most states, however, no amount of delay was estimated to be sufficient to prevent a surge in deaths completely. The primary factor associated with recurrent epidemics in the simulation was the assumed high effective reproduction number of unmitigated viral transmission. With a lower level of transmissibility similar to those of the ancestral strains, the model estimated that most states could remove NPIs in March 2022 and likely not see recurrent surges., Conclusions and Relevance: This simulation study estimated that the SARS-CoV-2 virus would likely continue to take a major toll in the US, even as cases continued to decrease. Because of the high transmissibility of the recent Delta and Omicron variants, premature lifting of NPIs could pose a substantial threat of rebounding surges in morbidity and mortality. At the same time, continued delay in lifting NPIs may not prevent future surges., Competing Interests: Conflict of Interest Disclosures: Dr Linas reported receiving grants from the National Institute on Drug Abuse, the US Centers for Disease Control and Prevention, and the National Science Foundation during the conduct of the study. Mr Dalgic reported that Value Analytics Labs provided consulting services for Janssen Pharmaceuticals outside the submitted work. Dr Ayer reported being a managing partner at Value Analytics Labs, a health care analytics firm, outside the submitted work. Dr Chhatwal reported receiving grants from the National Science Foundation and Rockefeller Foundation during the conduct of the study; and receiving personal fees from Value Analytics Labs outside the submitted work. No other disclosures were reported., (Copyright 2022 Linas BP et al. JAMA Health Forum.)

Importance: In 2020 and early 2021, the National Football League (NFL) and National Collegiate Athletic Association (NCAA) opted to host football games in stadiums across the country. The in-person attendance of games varied with time and from county to county. There is currently no evidence on whether limited in-person attendance of games is associated with COVID-19 case numbers on a county-level., Objective: To assess whether NFL and NCAA football games with limited in-person attendance were associated with increased COVID-19 cases in the counties they were held compared with a matched set of counties., Design, Setting, and Participants: In this time-series cross-sectional study, every county hosting NFL or NCAA games with in-person attendance (treated group) in 2020 and 2021 was matched with a county that that did not host a game on the corresponding day but had an identical game history for up to 14 days prior (control group). A standard matching method was used to further refine this matched set so that the treated and matched control counties had similar population size, nonpharmaceutical interventions in place, and COVID-19 trends. The association of hosting games with in-person attendance with COVID-19 cases was assessed using a difference-in-difference estimator. Data were analyzed from August 29 to December 28, 2020., Exposures: Hosting NFL or NCAA games., Main Outcomes and Measures: The main outcome was estimation of new COVID-19 cases per 100 000 residents at the county level reported up to 14 days after a game among counties with NFL and NCAA games with in-person attendance., Results: A total of 528 games with in-person attendance (101 NFL games [19.1%]; 427 NCAA games [80.9%]) were included. The matching algorithm returned 361 matching sets of counties. The median (interquartile range [IQR]) number of attendance for NFL games was 9949 (6000 to 13 797) people. The median number of attendance for NCAA games was not available, and attendance was recorded as a binary variable. The median (IQR) daily new COVID-19 cases in treatment group counties hosting games was 26.14 (10.77-50.25) cases per 100 000 residents on game day. The median (IQR) daily new COVID-19 cases in control group counties where no games were played was 24.11 (9.64-48.55) cases per 100 000 residents on game day. The treatment effect size ranged from -5.17 to 4.72, with a mean (SD) of 1.21 (2.67) cases per 100 000 residents, within the 14-day period in all counties hosting the games, and the daily treatment effect trend remained relatively steady during this period., Conclusions and Relevance: This cross-sectional study did not find a consistent increase in the daily COVID-19 cases per 100 000 residents in counties where NFL and NCAA games were held with limited in-person attendance. These findings suggest that NFL and NCAA football games hosted with limited in-person attendance were not associated with substantial risk for increased local COVID-19 cases.

Importance: In the US, hepatocellular carcinoma (HCC), primarily associated with hepatitis C virus (HCV) infection, is the fastest rising cause of cancer-related death. Wider use of highly effective direct-acting antiviral agents (DAAs) substantially reduces the burden of chronic HCV infection, but the subsequent impacts with HCV-associated HCC remain unknown., Objective: To assess projected changes in the incidence rate of and surveillance burden for HCC in the era of DAA treatment for HCV., Design, Setting, and Participants: This decision analytical model study was performed from January 2019 to February 2020, using an individual-level state-transition simulation model to simulate disease progression, screening, and different waves of antiviral treatments for HCV in the US from 2012 to 2040., Interventions: Current clinical management for chronic HCV infection., Main Outcomes and Measures: Model outcomes were projected temporal trends and age distribution of incident HCC cases and candidates for HCC surveillance among patients with viremia and patients with virologically cured HCV., Results: The simulation model projected that the annual incidence of HCC among patients with viremia and patients with virologically cured HCV will continue increasing to 24 000 (95% uncertainty interval [UI], 18 000-31 000) cases until 2021. In patients with virologically cured HCV, incident HCC cases are projected to increase from 1000 (95% UI, 500-2100) in 2012 to the peak of 7000 (95% UI, 5000-9600) in 2031 with a subsequent decrease to 6000 (95% UI, 4300-8300) by 2040. The proportion of incident HCC cases that occur in individuals with virologically cured HCV is estimated to increase from 5.3% in 2012 to 45.8% in 2040. The number of candidates for HCC surveillance in the population with virologically cured HCV is projected to increase from 106 000 (95% UI, 70 000-178 000) in 2012 to the peak of 649 000 (95% UI, 512 000-824 000) in 2030 and decrease to 539 000 (95% UI, 421 000-687 000) by 2040, while the proportion of all candidates for surveillance who are virologically cured is estimated to increase from 8.5% to 64.6% during the same period. The average age of HCC incidence and surveillance candidates is estimated to increase from 55 in 2012 to 72 and 71, respectively, by 2040., Conclusions and Relevance: The results of this study suggest that the burden of HCC will shift from patients with viremia to patients with virologically cured HCV, and to older populations. Appropriate management may be warranted for early detection of HCC in patients who may no longer be receiving specialty care for liver conditions.

Importance: The amyloid/tau/neurodegeneration (A/T/N) framework uses cerebrospinal fluid (CSF) levels of total tau (tTau) as a marker of neurodegeneration and CSF levels of phosphorylated tau 181 (pTau181) as a marker of tau tangles. However, it is unclear whether CSF levels of tTau and pTau181 have similar or different trajectories over the course of Alzheimer disease., Objectives: To examine the rates of change in CSF levels of tTau and pTau181 across the Alzheimer disease course and how the rates of change are associated with brain atrophy as measured by magnetic resonance imaging., Design, Setting, and Participants: This cohort study was set in tertiary research clinics. Each participant was a member of a pedigree with a known mutation for dominantly inherited Alzheimer disease. Participants were divided into 3 groups on the basis of the presence of a mutation and their Clinical Dementia Rating score. Data analysis was performed in June 2019., Main Outcomes and Measures: Rates of change of CSF tTau and pTau181 levels and their association with the rate of change of brain volume., Results: Data from 465 participants (283 mutation carriers and 182 noncarriers) were analyzed. The mean (SD) age of the cohort was 37.8 (11.3) years, and 262 (56.3%) were women. The mean (SD) follow-up duration was 2.7 (1.5) years. Two or more longitudinal CSF and magnetic resonance imaging assessments were available for 160 and 247 participants, respectively. Sixty-five percent of mutation carriers (183) did not have symptoms at baseline (Clinical Dementia Rating score, 0). For mutation carriers, the annual rates of change for CSF tTau and pTau181 became significantly different from 0 approximately 10 years before the estimated year of onset (mean [SE] rates of change, 5.5 [2.8] for tTau [P = .05] and 0.7 [0.3] for pTau 181 [P = .04]) and 15 years before onset (mean [SE] rates of change, 5.4 [3.9] for tTau [P = .17] and 1.1 [0.5] for pTau181 [P = .03]), respectively. The rate of change of pTau181 was positive and increased at the early stages of the disease, showing a positive rate of change starting at 15 estimated years before onset until 5 estimated years before onset (mean [SE], 0.4 [0.3]), followed by a positive but decreasing rate of change at year 0 (mean [SE], 0.1 [0.3]) and then negative rates of change at 5 years (mean [SE], -0.3 [0.4]) and 10 years (mean [SE], -0.6 [0.6]) after symptom onset. In individuals without symptoms (Clinical Dementia Rating score, 0), the rates of change of CSF tTau and pTau181 were negatively associated with brain atrophy (high rates of change in CSF measures were associated with low rates of change in brain volume in asymptomatic stages). After symptom onset (Clinical Dementia Rating score, >0), an increased rate of brain atrophy was not associated with rates of change of levels of both CSF tTau and pTau181., Conclusions and Relevance: These findings suggest that CSF tTau and pTau181 may have different associations with brain atrophy across the disease time course. These results have implications for understanding the dynamics of disease pathobiology and interpreting neuronal injury biomarker concentrations in response to Alzheimer disease progression and disease-modifying therapies.

Importance: Chronic hepatitis C virus (HCV) infection is a global health problem. The World Health Assembly recently pledged to eliminate HCV by 2030. However, in Pakistan, a country with one of the highest prevalence rates, the feasibility and cost of HCV elimination are not known., Objectives: To investigate whether and under what conditions HCV elimination is feasible in Pakistan and to estimate the cost of such elimination., Design, Setting, and Participants: This decision analytical model study used a microsimulation model of the HCV epidemic in Pakistan from 2015 to 2030. Using Pakistan-specific variables, the model simulated the landscape of HCV in Pakistan and evaluated the minimum required screening and treatment rates needed to eliminate HCV in Pakistan. The study used simulated individuals chronically infected with HCV from 2015 to 2030. The analysis was performed in 2018., Interventions: The status quo and 7 scenarios that can lead to HCV elimination in Pakistan by 2030, which were defined by different combinations of tests for screening, detection of viremia before treatment, and confirmation of treatment response., Main Outcomes and Measures: Temporal trends in HCV infection prevalence, mortality, and disability-adjusted life-years and total cost of HCV infection care under the status quo and scenarios that can eliminate HCV by 2030., Results: Under the status quo, from 2015 to 2030, 1.44 million people are projected to die of HCV infection; 48% of deaths would be among people younger than 50 years. To achieve HCV elimination in Pakistan, HCV testing would need to be scaled up to at least 25 million people to diagnose 900 000 persons and treatment to 700 000 people per year. Compared with the status quo, the elimination scenario would avert 323 000 liver-related deaths and 13.0 million HCV-associated disability-adjusted life-years from 2015 to 2030. The elimination scenario was associated with cost savings of $2.6 billion from 2018 to 2030 with use of a point-of-care test for population-wide antibody screening and detection of viremia and treatment response., Conclusions and Relevance: Substantial scale-up of HCV testing and treatment may be essential to eliminate HCV infection in Pakistan, and such a strategy may be associated with cost savings in the near future. Although HCV elimination in Pakistan may be ambitious, strategic planning and strong support from the government may aid in its elimination.

Importance: Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals., Objective: To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET)., Design, Setting and Participants: This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET., Main Outcomes and Measures: A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined., Results: The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = -0.11 [0.05]; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = -0.15 [0.09]; 95% CI, -0.32 to 0.01; P = .07)., Conclusions and Relevance: Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

Importance: Deaths due to opioid overdose have tripled in the last decade. Efforts to curb this trend have focused on restricting the prescription opioid supply; however, the near-term effects of such efforts are unknown., Objective: To project effects of interventions to lower prescription opioid misuse on opioid overdose deaths from 2016 to 2025., Design, Setting, and Participants: This system dynamics (mathematical) model of the US opioid epidemic projected outcomes of simulated individuals who engage in nonmedical prescription or illicit opioid use from 2016 to 2025. The analysis was performed in 2018 by retrospectively calibrating the model from 2002 to 2015 data from the National Survey on Drug Use and Health and the Centers for Disease Control and Prevention., Interventions: Comparison of interventions that would lower the incidence of prescription opioid misuse from 2016 to 2025 based on historical trends (a 7.5% reduction per year) and 50% faster than historical trends (an 11.3% reduction per year), vs a circumstance in which the incidence of misuse remained constant after 2015., Main Outcomes and Measures: Opioid overdose deaths from prescription and illicit opioids from 2016 to 2025 under each intervention., Results: Under the status quo, the annual number of opioid overdose deaths is projected to increase from 33 100 in 2015 to 81 700 (95% uncertainty interval [UI], 63 600-101 700) in 2025 (a 147% increase from 2015). From 2016 to 2025, 700 400 (95% UI, 590 200-817 100) individuals in the United States are projected to die from opioid overdose, with 80% of the deaths attributable to illicit opioids. The number of individuals using illicit opioids is projected to increase by 61%-from 0.93 million (95% UI, 0.83-1.03 million) in 2015 to 1.50 million (95% UI, 0.98-2.22 million) by 2025. Across all interventions tested, further lowering the incidence of prescription opioid misuse from 2015 levels is projected to decrease overdose deaths by only 3.0% to 5.3%., Conclusions and Relevance: This study's findings suggest that interventions targeting prescription opioid misuse such as prescription monitoring programs may have a modest effect, at best, on the number of opioid overdose deaths in the near future. Additional policy interventions are urgently needed to change the course of the epidemic.

Importance: Obesity is the most common risk factor for nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease that can lead to cirrhosis and hepatocellular carcinoma. Weight loss can be an effective treatment for obesity and may slow the progression of advanced liver disease., Objective: To assess the cost-effectiveness of bariatric surgery in patients with NASH and compensated cirrhosis., Design, Setting, and Participants: This economic evaluation study used a Markov-based state-transition model to simulate the benefits and risks of laparoscopic sleeve gastrectomy (SG), laparoscopic Roux-en-Y gastric bypass (GB), and intensive lifestyle intervention (ILI) compared with usual care in patients with NASH and compensated cirrhosis and varying baseline weight (overweight, mild obesity, moderate obesity, and severe obesity). Patients faced varied risks of perioperative mortality and complications depending on the type of surgery they underwent. Data were collected on March 22, 2017., Main Outcomes and Measures: Life-years, quality-adjusted life-years (QALYs), costs (in 2017 $US), and incremental cost-effectiveness ratios (ICERs) were calculated., Results: Demographic characteristics of the patient population were based on a previously published prospective study (n = 161). Patients in the model were 41.0% female, and the base case age was 54 years. Compared with usual care, SG was associated with an increase in QALYs of 0.263 to 1.180 (bounds of ranges represent overweight to severe obesity); GB, 0.263 to 1.207; and ILI, 0.004 to 0.216. Sleeve gastrectomy was also associated with an increase in life-years of 0.693 to 1.930; GB, 0.694 to 1.947; and ILI, 0.012 to 0.114. With usual care, expected life-years in overweight, mild obesity, moderate obesity, and severe obesity were 12.939, 11.949, 10.976, and 10.095, respectively. With usual care, QALY in overweight was 6.418; mild obesity, 5.790; moderate obesity, 5.186; and severe obesity, 4.577. Sleeve gastrectomy was the most cost-effective option for patients across all weight classes assessed: ICER for SG in patients with overweight was $66 119 per QALY; mild obesity, $18 716 per QALY; moderate obesity, $10 274 per QALY; and severe obesity, $6563 per QALY. A threshold analysis on the procedure cost of GB found that for GB to be cost-effective, the cost of the surgery must be decreased from its baseline value of $28 734 by $4889 for mild obesity, by $3189 for moderate obesity, and by $2289 for severe obesity. In overweight patients, GB involved fewer QALYs than SG, and thus decreasing the cost of surgery would not result in cost-effectiveness., Conclusions and Relevance: Bariatric surgery could be highly cost-effective in patients with NASH compensated cirrhosis and obesity or overweight. The findings from this analysis suggest that it can inform clinical trials evaluating the effect of bariatric procedures in patients with NASH cirrhosis, including those with a lower body mass index.

Importance: In the last 4 decades, survival among patients with human papillomavirus (HPV)-associated cancers has improved, while the incidence of these cancers has increased among younger cohorts. Among survivors of HPV-associated cancers, persistent HPV infection may remain a risk factor for preventable HPV-associated second primary cancers (HPV-SPCs)., Objectives: To investigate the risk of HPV-SPCs among survivors of HPV-associated index cancers and to test the hypothesis that the HPV-SPC risk among these persons has increased over the last 4 decades., Design, Setting, and Participants: A retrospective cohort study of 9 cancer registries of the Surveillance, Epidemiology, and End Results (SEER) database was conducted to identify patients with HPV-associated (cervical, vaginal, vulvar, oropharyngeal, anal, and penile) cancers diagnosed from January 1, 1973, through December 31, 2014. The dates of analysis were July 1, 2017, to January 31, 2018., Main Outcomes and Measures: The HPV-SPC risk was quantified by calculating standard incidence ratios (SIRs) and excess absolute risks (EARs) per 10 000 person-years at risk (PYR). The HPV-SPC risk by time was estimated using Poisson regression., Results: From 113 272 (73 085 female and 40 187 male) survivors of HPV-associated cancers, 1397 women and 1098 men developed HPV-SPCs. The SIRs for HPV-SPCs were 6.2 (95% CI, 5.9-6.6) among women and 15.8 (95% CI, 14.9-16.8) among men. The EARs were 18.2 per 10 000 PYR for women and 53.5 per 10 000 PYR for men. Among both women and men, those who had index oropharyngeal cancers had the highest HPV-SPC risk (SIR, 19.8 [95% CI, 18.4-21.4] and EAR, 80.6 per 10 000 PYR among women; SIR, 18.0 [95% CI, 16.9-19.1] and EAR, 61.5 per 10 000 PYR among men). Women who had index cervical cancers and men who had index anal cancers had the lowest HPV-SPC risk (SIR, 2.4 [95% CI, 2.2-2.7] and EAR, 4.5 per 10 000 PYR among women; SIR, 6.5 [95% CI, 4.7-8.8] and EAR, 18.5 per 10 000 PYR among men). Both women and men who had index HPV-associated cancers of any kind had a significantly higher risk of oropharyngeal HPV-SPCs. Over the last 4 decades, the risk of developing most types of HPV-SPCs after index cervical, vaginal, and vulvar cancers increased., Conclusions and Relevance: According to this study, the HPV-SPC risk among survivors of HPV-associated cancers is significant, implying that persistent HPV infection at multiple sites may be associated with HPV-SPCs. These findings have the potential to inform surveillance recommendations for survivors of HPV-associated cancers.

Importance: Abnormal accumulation of tau and amyloid-β (Aβ) proteins in the human brain are 2 pathologic hallmarks of Alzheimer disease (AD). Because pathologic processes begin decades before the onset of the clinical manifestations, the study of the cortical distribution of early-stage pathologic alterations is critical in understanding the underpinnings of the disease., Objectives: To identify the in vivo brain spatial distributions of tau and Aβ deposits in a sample of cognitively normal participants in the Harvard Aging Brain Study, determine spatial patterns of pathologic alterations, and provide means for improved individual in vivo staging., Design, Setting, and Participants: Eighty-eight individuals from the general community underwent flortaucipir 18 T807 (18F-T807) and carbon 11-labeled Pittsburgh Compound B (11C-PiB) positron emission tomographic (PET) imaging. A voxel-level hierarchical clustering approach was used to obtain the main clustering partitions corresponding to the cortical distribution maps of 18F-T807 and 11C-PiB. Hierarchical relationships between areas of distinctive pathologic deposits were then studied. Using cerebellar gray reference, 18F-T807 data were expressed as standardized uptake value ratio, and 11C-PiB were given as distribution volume ratio., Main Outcomes and Measures: Main in vivo and hierarchically organized tau and Aβ deposits in the elderly brain., Results: Of the 88 study participants, 39 (44%) were men, with a mean (SD) age of 76.2 (6.2) years. The tau and Aβ maps both displayed optimal cortical partitions at 4 clusters. The tau deposits were grouped in the temporal lobe, distributed in heteromodal areas, medial and visual regions, and primary somatomotor cortex; the Aβ deposits were clustered in the heteromodal areas and rather patchy in distributed regions involving the primary cortices, medial structures, and temporal areas. Moreover, tau deposits in the temporal lobe and distributed heteromodal areas were tightly nested., Conclusions and Relevance: Tau and Aβ deposits in the elderly brain generally display well-defined hierarchical cortical relationships as well as overlaps between the principal clusters of both pathologic alterations in the heteromodal association regions. These findings represent systematic, large-scale mechanisms of early AD pathology.

Importance: Severe obesity affects 4% to 6% of US youth and is increasing in prevalence. Bariatric surgery for the treatment of adolescents with severe obesity is becoming more common, but data on cost-effectiveness are limited., Objective: To assess the cost-effectiveness of bariatric surgery for adolescents with obesity using recently published results from the Teen-Longitudinal Assessment of Bariatric Surgery study., Design, Setting, and Patients: A state-transition model was constructed to compare 2 strategies: no surgery and bariatric surgery. In the no surgery strategy, patients remained at their initial body mass index (calculated as weight in kilograms divided by height in meters squared) over time. In the bariatric surgery strategy, patients were subjected to risks of perioperative mortality and complications as well as initial morbidity but also experienced longer-term quality-of-life improvements associated with weight loss. Cohort demographic information-of the 228 patients included, the mean (SD) age was 17 (1.6) years, the mean (range) body mass index was 53 (34-88), and 171 (75.0%) were female-surgery-related outcomes, and base case time horizon (3 years) were based on data from the Teen-Longitudinal Assessment of Bariatric Surgery study. One-way and probabilistic sensitivity analyses were performed., Main Outcomes and Measures: Quality-adjusted life-years (QALYs), total costs (in US dollars adjusted to 2015-year values using the Consumer Price Index), and incremental cost-effectiveness ratios (ICERs). A willingness-to-pay threshold of $100 000 per QALY was used to assess cost-effectiveness., Results: After 3 years, surgery led to a gain of 0.199 QALYs compared with no surgery at an incremental cost of $30 747, yielding an unfavorable ICER of $154 684 per QALY. When the clinical study results were extrapolated to 4 years, the ICER decreased to $114 078 per QALY and became cost-effective by 5 years with an ICER of $91 032 per QALY. Outcomes were robust in most 1-way and probabilistic sensitivity analyses., Conclusions and Relevance: Bariatric surgery incurs substantial initial cost and morbidity. We found that surgery could be a cost-effective treatment for adolescents with severe obesity if assessed over a time horizon of 5 years. Our study underscores the need for long-term clinical trials in adolescents with at least 5 years of follow-up data that capture financial and quality-of-life end points.

Importance: Autosomal dominant Alzheimer disease (ADAD) is caused by rare genetic mutations in 3 specific genes in contrast to late-onset Alzheimer disease (LOAD), which has a more polygenetic risk profile., Objective: To assess the similarities and differences in functional connectivity changes owing to ADAD and LOAD., Design, Setting, and Participants: We analyzed functional connectivity in multiple brain resting state networks (RSNs) in a cross-sectional cohort of participants with ADAD (n = 79) and LOAD (n = 444), using resting-state functional connectivity magnetic resonance imaging at multiple international academic sites., Main Outcomes and Measures: For both types of AD, we quantified and compared functional connectivity changes in RSNs as a function of dementia severity measured by the Clinical Dementia Rating Scale. In ADAD, we qualitatively investigated functional connectivity changes with respect to estimated years from onset of symptoms within 5 RSNs., Results: A decrease in functional connectivity with increasing Clinical Dementia Rating scores were similar for both LOAD and ADAD in multiple RSNs. Ordinal logistic regression models constructed in one type of Alzheimer disease accurately predicted clinical dementia rating scores in the other, further demonstrating the similarity of functional connectivity loss in each disease type. Among participants with ADAD, functional connectivity in multiple RSNs appeared qualitatively lower in asymptomatic mutation carriers near their anticipated age of symptom onset compared with asymptomatic mutation noncarriers., Conclusions and Relevance: Resting-state functional connectivity magnetic resonance imaging changes with progressing AD severity are similar between ADAD and LOAD. Resting-state functional connectivity magnetic resonance imaging may be a useful end point for LOAD and ADAD therapy trials. Moreover, the disease process of ADAD may be an effective model for the LOAD disease process.