Impact and cost-effectiveness of the 6-month BPaLM regimen for rifampicin-resistant tuberculosis in Moldova: A mathematical modeling analysis.

BACKGROUND: Emerging evidence suggests that shortened, simplified treatment regimens for rifampicin-resistant tuberculosis (RR-TB) can achieve comparable end-of-treatment (EOT) outcomes to longer regimens. We compared a 6-month regimen containing bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) to a standard of care strategy using a 9- or 18-month regimen depending on whether fluoroquinolone resistance (FQ-R) was detected on drug susceptibility testing (DST). METHODS AND FINDINGS: The primary objective was to determine whether 6 months of BPaLM is a cost-effective treatment strategy for RR-TB. We used genomic and demographic data to parameterize a mathematical model estimating long-term health outcomes measured in quality-adjusted life years (QALYs) and lifetime costs in 2022 USD ($) for each treatment strategy for patients 15 years and older diagnosed with pulmonary RR-TB in Moldova, a country with a high burden of TB drug resistance. For each individual, we simulated the natural history of TB and associated treatment outcomes, as well as the process of acquiring resistance to each of 12 anti-TB drugs. Compared to the standard of care, 6 months of BPaLM was cost-effective. This strategy was estimated to reduce lifetime costs by $3,366 (95% UI: [1,465, 5,742] p < 0.001) per individual, with a nonsignificant change in QALYs (-0.06; 95% UI: [-0.49, 0.03] p = 0.790). For those stopping moxifloxacin under the BPaLM regimen, continuing with BPaL plus clofazimine (BPaLC) provided more QALYs at lower cost than continuing with BPaL alone. Strategies based on 6 months of BPaLM had at least a 93% chance of being cost-effective, so long as BPaLC was continued in the event of stopping moxifloxacin. BPaLM for 6 months also reduced the average time spent with TB resistant to amikacin, bedaquiline, clofazimine, cycloserine, moxifloxacin, and pyrazinamide, while it increased the average time spent with TB resistant to delamanid and pretomanid. Sensitivity analyses showed 6 months of BPaLM to be cost-effective across a broad range of values for the relative effectiveness of BPaLM, and the proportion of the cohort with FQ-R. Compared to the standard of care, 6 months of BPaLM would be expected to save Moldova's national TB program budget $7.1 million (95% UI: [1.3 million, 15.4 million] p = 0.002) over the 5-year period from implementation. Our analysis did not account for all possible interactions between specific drugs with regard to treatment outcomes, resistance acquisition, or the consequences of specific types of severe adverse events, nor did we model how the intervention may affect TB transmission dynamics. CONCLUSIONS: Compared to standard of care, longer regimens, the implementation of the 6-month BPaLM regimen could improve the cost-effectiveness of care for individuals diagnosed with RR-TB, particularly in settings with a high burden of drug-resistant TB. Further research may be warranted to explore the impact and cost-effectiveness of shorter RR-TB regimens across settings with varied drug-resistant TB burdens and national income levels.

The Impact of Rapid Drug Susceptibility Tests on Gonorrhea Burden and the Life Span of Antibiotic Treatments: A Modeling Study Among Men Who Have Sex With Men in the United States.

Rapid point-of-care tests that diagnose gonococcal infections and identify susceptibility to antibiotics enable individualized treatment. This could improve patient outcomes and slow the emergence and spread of antibiotic resistance. However, little is known about the long-term impact of such diagnostics on the burden of gonorrhea and the effective life span of antibiotics. We used a mathematical model of gonorrhea transmission among men who have sex with men in the United States to project the annual rate of reported gonorrhea cases and the effective life span of ceftriaxone, the recommended antibiotic for first-line treatment of gonorrhea, as well as 2 previously recommended antibiotics, ciprofloxacin and tetracycline, when a rapid drug susceptibility test that estimates susceptibility to ciprofloxacin and tetracycline is available. The use of a rapid drug susceptibility test with ≥50% sensitivity and ≥95% specificity, defined in terms of correct ascertainment of drug susceptibility and nonsusceptibility status, could increase the combined effective life span of ciprofloxacin, tetracycline, and ceftriaxone by at least 2 years over 25 years of simulation. If test specificity is imperfect, however, the increase in the effective life span of antibiotics is accompanied by an increase in the rate of reported gonorrhea cases even under perfect sensitivity.

Cost-Effectiveness of CT, CTA, MRI, and Specialized MRI for Evaluation of Patients Presenting to the Emergency Department With Dizziness.

BACKGROUND. Underlying stroke is often misdiagnosed in patients presenting with dizziness. Although such patients are usually ineligible for acute stroke treatment, accurate diagnosis may still improve outcomes through selection of patients for secondary prevention measures. OBJECTIVE. The purpose of our study was to investigate the cost-effectiveness of differing neuroimaging approaches in the evaluation of patients presenting to the emergency department (ED) with dizziness who are not candidates for acute intervention. METHODS. A Markov decision-analytic model was constructed from a health care system perspective for the evaluation of a patient presenting to the ED with dizziness. Four diagnostic strategies were compared: noncontrast head CT, head and neck CTA, conventional brain MRI, and specialized brain MRI (including multiplanar high-resolution DWI). Differing long-term costs and outcomes related to stroke detection and secondary prevention measures were compared. Cost-effectiveness was calculated in terms of lifetime expenditures in 2022 U.S. dollars for each quality-adjusted life year (QALY); deterministic and probabilistic sensitivity analyses were performed. RESULTS. Specialized MRI resulted in the highest QALYs and was the most cost-effective strategy with US$13,477 greater cost and 0.48 greater QALYs compared with noncontrast head CT. Conventional MRI had the next-highest health benefit, although was dominated by extension with incremental cost of US$6757 and 0.25 QALY; CTA was also dominated by extension, with incremental cost of US$3952 for 0.13 QALY. Non-contrast CT alone had the lowest utility among the four imaging choices. In the deterministic sensitivity analyses, specialized MRI remained the most cost-effective strategy. Conventional MRI was more cost-effective than CTA across a wide range of model parameters, with incremental cost-effectiveness remaining less than US$30,000/QALY. Probabilistic sensitivity analysis yielded similar results as found in the base-case analysis, with specialized MRI being more cost-effective than conventional MRI, which in turn was more cost-effective than CTA. CONCLUSION. The use of MRI in patients presenting to the ED with dizziness improves stroke detection and selection for subsequent preventive measures. MRI-based evaluation leads to lower long-term costs and higher cumulative QALYs. CLINICAL IMPACT. MRI, incorporating specialized protocols when available, is the preferred approach for evaluation of patients presenting to the ED with dizziness, to establish a stroke diagnosis and to select patients for secondary prevention measures.

The Estimated Lifetime Quality-Adjusted Life-Years Lost Due to Chlamydia, Gonorrhea, and Trichomoniasis in the United States in 2018.

BACKGROUND: Comprehensive evaluation of the quality-adjusted life-years (QALYs) lost attributable to chlamydia, gonorrhea, andtrichomoniasis in the United States is lacking. METHODS: We adapted a previous probability-tree model to estimate the average number of lifetime QALYs lost due to genital chlamydia, gonorrhea, and trichomoniasis, per incident infection and at the population level, by sex and age group. We conducted multivariate sensitivity analyses to address uncertainty around key parameter values. RESULTS: The estimated total discounted lifetime QALYs lost for men and women, respectively, due to infections acquired in 2018, were 1541 (95% uncertainty interval [UI], 186-6358) and 111 872 (95% UI, 29 777-267 404) for chlamydia, 989 (95% UI, 127-3720) and 12 112 (95% UI, 2 410-33 895) for gonorrhea, and 386 (95% UI, 30-1851) and 4576 (95% UI, 13-30 355) for trichomoniasis. Total QALYs lost were highest among women aged 15-24 years with chlamydia. QALYs lost estimates were highly sensitive to disutilities (health losses) of infections and sequelae, and to duration of infections and chronic sequelae for chlamydia and gonorrhea in women. CONCLUSIONS: The 3 sexually transmitted infections cause substantial health losses in the United States, particularly gonorrhea and chlamydia among women. The estimates of lifetime QALYs lost per infection help to prioritize prevention policies and inform cost-effectiveness analyses of sexually transmitted infection interventions.

Estimation of the Lifetime Quality-Adjusted Life Years (QALYs) Lost Due to Syphilis Acquired in the United States in 2018.

BACKGROUND: The purpose of this study was to estimate the health impact of syphilis in the United States in terms of the number of quality-adjusted life years (QALYs) lost attributable to infections in 2018. METHODS: We developed a Markov model that simulates the natural history and management of syphilis. The model was parameterized by sex and sexual orientation (women who have sex with men, men who have sex with women [MSW], and men who have sex with men [MSM]), and by age at primary infection. We developed a separate decision tree model to quantify health losses due to congenital syphilis. We estimated the average lifetime number of QALYs lost per infection, and the total expected lifetime number of QALYs lost due to syphilis acquired in 2018. RESULTS: We estimated the average number of discounted lifetime QALYs lost per infection as 0.09 (95% uncertainty interval [UI] .03-.19). The total expected number of QALYs lost due to syphilis acquired in 2018 was 13 349 (5071-31 360). Although per-case loss was the lowest among MSM (0.06), MSM accounted for 47.7% of the overall burden. For each case of congenital syphilis, we estimated 1.79 (1.43-2.16) and 0.06 (.01-.14) QALYs lost in the child and the mother, respectively. We projected 2332 (1871-28 250) and 79 (17-177) QALYs lost for children and mothers, respectively, due to congenital syphilis in 2018. CONCLUSIONS: Syphilis causes substantial health losses in adults and children. Quantifying these health losses in terms of QALYs can inform cost-effectiveness analyses and can facilitate comparisons of the burden of syphilis to that of other diseases.

Evaluating spatially adaptive guidelines for the treatment of gonorrhea to reduce the incidence of gonococcal infection and increase the effective lifespan of antibiotics.

In the absence of point-of-care gonorrhea diagnostics that report antibiotic susceptibility, gonorrhea treatment is empiric and determined by standardized guidelines. These guidelines are informed by estimates of resistance prevalence from national surveillance systems. We examined whether guidelines informed by local, rather than national, surveillance data could reduce the incidence of gonorrhea and increase the effective lifespan of antibiotics used in treatment guidelines. We used a transmission dynamic model of gonorrhea among men who have sex with men (MSM) in 16 U.S. metropolitan areas to determine whether spatially adaptive treatment guidelines based on local estimates of resistance prevalence can extend the effective lifespan of hypothetical antibiotics. The rate of gonorrhea cases in these metropolitan areas was 5,548 cases per 100,000 MSM in 2017. Under the current strategy of updating the treatment guideline when the prevalence of resistance exceeds 5%, we showed that spatially adaptive guidelines could reduce the annual rate of gonorrhea cases by 200 cases (95% uncertainty interval: 169, 232) per 100,000 MSM population while extending the use of a first-line antibiotic by 0.75 (0.55, 0.95) years. One potential strategy to reduce the incidence of gonorrhea while extending the effective lifespan of antibiotics is to inform treatment guidelines based on local, rather than national, resistance prevalence.

Cost-Effectiveness and Long-Term Savings of the Bright Bodies Intervention for Childhood Obesity.

OBJECTIVES: To estimate the cost and cost-effectiveness of Bright Bodies, a high-intensity, family-based intervention that has been demonstrated to improve body mass index (BMI) among children with obesity in a randomized controlled trial. METHODS: We developed a microsimulation model to project 10-year BMI trajectories of 8 to 16-year-old children with obesity, using data from the National Longitudinal Surveys and Centers for Disease Control and Prevention growth charts, and we validated the model using data from the Bright Bodies trial and a follow-up study. We used the trial data to estimate the average reduction in BMI per person-year over 10 years and the incremental costs of Bright Bodies, compared with the traditional clinical weight management (control), from a health system's perspective in 2020 US dollars. Using results from studies of Medical Expenditure Panel Survey data, we projected the long-term obesity-related medical expenditure. RESULTS: In the primary analysis, assuming depreciating effects postintervention, Bright Bodies is expected to reduce a participant's BMI by 1.67 kg/m2 (95% uncertainty interval 1.43-1.94) per year over 10 years as compared with control. The incremental intervention cost of Bright Bodies was $360 ($292-$421) per person compared with the clinical control. Nevertheless, savings in obesity-related healthcare expenditure offset these costs and the expected cost-savings of Bright Bodies is $1126 ($689-$1693) per person over 10-years. The projected time to achieve cost-savings compared with clinical control was 3.58 (2.63-5.17) years. CONCLUSIONS: Although resource-intensive, our findings suggest that Bright Bodies is cost-saving compared to the clinical control by averting future obesity-related healthcare costs among children with obesity.

CT With CTA Versus MRI in Patients Presenting to the Emergency Department With Dizziness: Analysis Using Propensity Score Matching.

BACKGROUND. CT with CTA is widely used to exclude stroke in patients with dizziness, although MRI has higher sensitivity. OBJECTIVE. The purpose of this article was to compare patients presenting to the emergency department (ED) with dizziness who undergo CT with CTA alone versus those who undergo MRI in terms of stroke-related management and outcomes. METHODS. This retrospective study included 1917 patients (mean age, 59.5 years; 776 men, 1141 women) presenting to the ED with dizziness from January 1, 2018, to December 31, 2021. A first propensity score matching analysis incorporated demographic characteristics, medical history, findings from the review of systems, physical examination findings, and symptoms to construct matched groups of patients discharged from the ED after undergoing head CT with head and neck CTA alone and patients who underwent brain MRI (with or without CT and CTA). Outcomes were compared. A second analysis compared matched patients discharged after CT with CTA alone and patients who underwent specialized abbreviated MRI using multiplanar high-resolution DWI for increased sensitivity for posterior circulation stroke. Sensitivity analyses were performed involving MRI examinations performed as the first or only neuroimaging examination and involving alternative matching and imputation techniques. RESULTS. In the first analysis (406 patients per group), patients who underwent MRI, compared with patients who underwent CT with CTA alone, showed greater frequency of critical neuroimaging results (10.1% vs 4.7%, p = .005), change in secondary stroke prevention medication (9.6% vs 3.2%, p = .001), and subsequent echocardiography evaluation (6.4% vs 1.0%, p < .001). In the second analysis (100 patients per group), patients who underwent specialized abbreviated MRI, compared with patients who underwent CT with CTA alone, showed greater frequency of critical neuroimaging results (10.0% vs 2.0%, p = .04), change in secondary stroke prevention medication (14.0% vs 1.0%, p = .001), and subsequent echocardiography evaluation (12.0% vs 2.0%, p = .01) and lower frequency of 90-day ED readmissions (12.0% vs 28.0%, p = .008). Sensitivity analyses showed qualitatively similar findings. CONCLUSION. A proportion of patients discharged after CT with CTA alone may have benefitted from alternative or additional evaluation by MRI (including MRI using a specialized abbreviated protocol). CLINICAL IMPACT. Use of MRI may motivate clinically impactful management changes in patients presenting with dizziness.

Cost-effectiveness analysis of typhoid conjugate vaccines in an outbreak setting: a modeling study.

BACKGROUND: Several prolonged typhoid fever epidemics have been reported since 2010 throughout eastern and southern Africa, including Malawi, caused by multidrug-resistant Salmonella Typhi. The World Health Organization recommends the use of typhoid conjugate vaccines (TCVs) in outbreak settings; however, current data are limited on how and when TCVs might be introduced in response to outbreaks. METHODOLOGY: We developed a stochastic model of typhoid transmission fitted to data from Queen Elizabeth Central Hospital in Blantyre, Malawi from January 1996 to February 2015. We used the model to evaluate the cost-effectiveness of vaccination strategies over a 10-year time horizon in three scenarios: (1) when an outbreak is likely to occur; (2) when an outbreak is unlikely to occur within the next ten years; and (3) when an outbreak has already occurred and is unlikely to occur again. We considered three vaccination strategies compared to the status quo of no vaccination: (a) preventative routine vaccination at 9 months of age; (b) preventative routine vaccination plus a catch-up campaign to 15 years of age; and (c) reactive vaccination with a catch-up campaign to age 15 (for Scenario 1). We also explored variations in outbreak definitions, delays in implementation of reactive vaccination, and the timing of preventive vaccination relative to the outbreak. RESULTS: Assuming an outbreak occurs within 10 years, we estimated that the various vaccination strategies would prevent a median of 15-60% of disability-adjusted life-years (DALYs). Reactive vaccination was the preferred strategy for WTP values of $0-300 per DALY averted. For WTP values > $300, introduction of preventative routine TCV immunization with a catch-up campaign was the preferred strategy. Routine vaccination with a catch-up campaign was cost-effective for WTP values above $890 per DALY averted if no outbreak occurs and > $140 per DALY averted if implemented after the outbreak has already occurred. CONCLUSIONS: Countries for which the spread of antimicrobial resistance is likely to lead to outbreaks of typhoid fever should consider TCV introduction. Reactive vaccination can be a cost-effective strategy, but only if delays in vaccine deployment are minimal; otherwise, introduction of preventive routine immunization with a catch-up campaign is the preferred strategy.

Generating simple classification rules to predict local surges in COVID-19 hospitalizations.

Low rates of vaccination, emergence of novel variants of SARS-CoV-2, and increasing transmission relating to seasonal changes and relaxation of mitigation measures leave many US communities at risk for surges of COVID-19 that might strain hospital capacity, as in previous waves. The trajectories of COVID-19 hospitalizations differ across communities depending on their age distributions, vaccination coverage, cumulative incidence, and adoption of risk mitigating behaviors. Yet, existing predictive models of COVID-19 hospitalizations are almost exclusively focused on national- and state-level predictions. This leaves local policymakers in urgent need of tools that can provide early warnings about the possibility that COVID-19 hospitalizations may rise to levels that exceed local capacity. In this work, we develop a framework to generate simple classification rules to predict whether COVID-19 hospitalization will exceed the local hospitalization capacity within a 4- or 8-week period if no additional mitigating strategies are implemented during this time. This framework uses a simulation model of SARS-CoV-2 transmission and COVID-19 hospitalizations in the US to train classification decision trees that are robust to changes in the data-generating process and future uncertainties. These generated classification rules use real-time data related to hospital occupancy and new hospitalizations associated with COVID-19, and when available, genomic surveillance of SARS-CoV-2. We show that these classification rules present reasonable accuracy, sensitivity, and specificity (all ≥ 80%) in predicting local surges in hospitalizations under numerous simulated scenarios, which capture substantial uncertainties over the future trajectories of COVID-19. Our proposed classification rules are simple, visual, and straightforward to use in practice by local decision makers without the need to perform numerical computations.

Head and Neck CTA Utilization: Analysis of Ordering Frequency and Nonroutine Results Communication, With Focus on the 50 Most Common Emergency Department Clinical Presentations.

BACKGROUND. Utilization of head and neck CTA in the emergency department (ED) has grown disproportionately to other neuroimaging examinations. OBJECTIVE. The purpose of this article was to characterize utilization of head and neck CTA in the ED, comparing utilization and frequency of nonroutine results communication among patients' chief concerns. METHODS. All adult ED visits for a single health care system from January 2014 to December 2017 were retrospectively reviewed. Variables recorded included chief concerns, whether head and neck CTA was performed, and, if so, whether the report documented nonroutine results communication. The 50 chief concerns resulting in the highest number of head and neck CTA examinations were identified. Frequencies of head and neck CTA ordering and of nonroutine results communication were calculated. A subset of reports documenting nonroutine communication were manually reviewed. RESULTS. Head and neck CTA was ordered in 2.5% (17,903) of 708,145 ED visits in 236,476 patients (mean age, 49.8 ± 20.5 [SD] years; 110,952 men, 125,521 women, 3 unknown sex). Head and neck CTA was ordered for 833 distinct chief concerns. Nonroutine results communication was documented for 17.6% (3155/17,903) of examinations. Among the 50 chief concerns associated with the highest number of examinations, frequency of ordering head and neck CTA ranged from less than 0.5% (five concerns) to 55.2% (stroke code), and frequency of nonroutine communication ranged from 5.6% (transient ischemic attack) to 67.5% (unresponsive). Chief concerns not among the 50 most common accounted for 50.0% (8956/17,903) of examinations; these exhibited a collective frequency of nonroutine communication of 4.8% (429/8956). Manual review of 11.1% (350/3155) of reports with a nonroutine communication indicated an acute finding related to the indication in 51.1%, nonemergent but potentially explanatory finding in 14.0%, incidental finding in 28.0%, and communication of negative results in 6.9%. CONCLUSION. Head and neck CTA is ordered in 2.5% of ED visits for a wide range of chief concerns. Frequencies of ordering and of nonroutine results communication are highly variable among chief concerns. Acute indication-related findings account for half of nonroutine radiologist communications. CLINICAL IMPACT. Insight into patterns regarding head and neck CTA ordering and nonroutine results may help optimize patient selection and radiologist communications in the ED setting.

Scenarios to improve CT head utilization in the emergency department delineated by critical results reporting.

PURPOSE: Increasing use of advanced imaging in the emergency department (ED) has resulted in higher cost without better outcomes. Our goal was to evaluate the yield of CT head exams by scenario to guide efforts at improving patient selection. METHODS: We performed a retrospective study at an academic medical center over 4 years (1/1/2014-12/31/2017). The chief complaint, imaging order, and exam result text were obtained for all adult ED encounters. For the 50 most common chief complaints leading to CT head exams, the ratio of exams to total encounters and ratio of critical results to imaging studies were calculated. Significant difference in "yield" was assessed via binomial test. RESULTS: Over 708,145 adult ED encounters, 58,783 CT head exams were ordered, with an overall critical result yield of 8.0%. The three most common chief complaints had higher yield (p < 0.05): altered mental status (9.8%), fall (9.7%), and new headache (10.1%). Lower yield (p < 0.05) was found for 19 chief complaints: dizziness (6.2%), falls in patients > 65 years old (7.1%), syncope (5.3%), seizure with known epilepsy (4.8%), chest pain (3.7%), head injury (4.9%), headache re-evaluation (7.0%), alcohol intoxication (2.5%), fatigue (6.5%), headache-recurrent or in the setting of known migraines (5.2%), hypertension (4.4%), lethargy (5.8%), loss of consciousness (5.3%), migraine (3.2%), psychiatric evaluation (2.9%), near syncope (4.6%), drug problem (3.1%), symptomatically decreased blood sugar (3.2%), and suicidal (1.7%). CONCLUSION: Our study provides a priority list of low yield scenarios of CT head use for improvement of patient selection.

Best Buy in Public Health or Luxury Expense?: The Cost-effectiveness of a Pediatric Operating Room in Uganda From the Societal Perspective.

OBJECTIVE: To determine the cost-effectiveness of building and maintaining a dedicated pediatric operating room (OR) in Uganda from the societal perspective. BACKGROUND: Despite the heavy burden of pediatric surgical disease in low-income countries, definitive treatment is limited as surgical infrastructure is inadequate to meet the need, leading to preventable morbidity and mortality in children. METHODS: In this economic model, we used a decision tree template to compare the intervention of a dedicated pediatric OR in Uganda for a year versus the absence of a pediatric OR. Costs were included from the government, charity, and patient perspectives. OR and ward case-log informed epidemiological and patient outcomes data, and measured cost per disability adjusted life year averted and cost per life saved. The incremental cost-effectiveness ratio (ICER) was calculated between the intervention and counterfactual scenario. Costs are reported in 2015 US$ and inflated by 5.5%. FINDINGS: In Uganda, the implementation of a dedicated pediatric OR has an ICER of $37.25 per disability adjusted life year averted or $3321 per life saved, compared with no existing operating room. The ICER is well below multiple cost-effectiveness thresholds including one times the country's gross domestic product per capita ($694). The ICER remained robust under 1-way and probabilistic sensitivity analyses. CONCLUSION: Our model ICER suggests that the construction and maintenance of a dedicated pediatric operating room in sub-Saharan Africa is very-cost effective if hospital space and personnel pre-exist to staff the facility. This supports infrastructure implementation for surgery in sub-Saharan Africa as a worthwhile investment.

Tracking and predicting U.S. influenza activity with a real-time surveillance network.

Each year in the United States, influenza causes illness in 9.2 to 35.6 million individuals and is responsible for 12,000 to 56,000 deaths. The U.S. Centers for Disease Control and Prevention (CDC) tracks influenza activity through a national surveillance network. These data are only available after a delay of 1 to 2 weeks, and thus influenza epidemiologists and transmission modelers have explored the use of other data sources to produce more timely estimates and predictions of influenza activity. We evaluated whether data collected from a national commercial network of influenza diagnostic machines could produce valid estimates of the current burden and help to predict influenza trends in the United States. Quidel Corporation provided us with de-identified influenza test results transmitted in real-time from a national network of influenza test machines called the Influenza Test System (ITS). We used this ITS dataset to estimate and predict influenza-like illness (ILI) activity in the United States over the 2015-2016 and 2016-2017 influenza seasons. First, we developed linear logistic models on national and regional geographic scales that accurately estimated two CDC influenza metrics: the proportion of influenza test results that are positive and the proportion of physician visits that are ILI-related. We then used our estimated ILI-related proportion of physician visits in transmission models to produce improved predictions of influenza trends in the United States at both the regional and national scale. These findings suggest that ITS can be leveraged to improve "nowcasts" and short-term forecasts of U.S. influenza activity.

Adaptive guidelines for the treatment of gonorrhea to increase the effective life span of antibiotics among men who have sex with men in the United States: A mathematical modeling study.

BACKGROUND: The rise of gonococcal antimicrobial resistance highlights the need for strategies that extend the clinically useful life span of antibiotics. Because there is limited evidence to support the current practice of switching empiric first-line antibiotic when resistance exceeds 5% in the population, our objective was to compare the impact of alternative strategies on the effective life spans of antibiotics and the overall burden of gonorrhea. METHODS AND FINDINGS: We developed and calibrated a mathematical model of gonorrhea transmission among men who have sex with men (MSM) in the United States. We calibrated the model to the estimated prevalence of gonorrhea, the rate of gonorrhea cases, and the proportion of cases presenting symptoms among MSM in the US. We used this model to project the effective life span of antibiotics and the number of gonorrhea cases expected under current and alternative surveillance strategies over a 50-year simulation period. We demonstrate that compared to the current practice, a strategy that uses quarterly (as opposed to yearly) surveillance estimates and incorporates both the estimated prevalence of resistance and the trend in the prevalence of resistance to determine treatment guidelines could extend the effective life span of antibiotics by 0.83 years. This is equivalent to successfully treating an additional 80.1 (95% uncertainty interval: [47.7, 111.9]) gonorrhea cases per 100,000 MSM population each year with the first-line antibiotics without worsening the burden of gonorrhea. If the annual number of isolates tested for drug susceptibility is doubled, this strategy could increase the effective life span of antibiotics by 0.94 years, which is equivalent to successfully treating an additional 91.1 (54.3, 127.3) gonorrhea cases per 100,000 MSM population each year without increasing the incidence of gonorrhea. Study limitations include that our conclusions might not be generalizable to other settings because our model describes the transmission of gonorrhea among the US MSM population, and, to better capture uncertainty in the characteristics of current and future antibiotics, we chose to model hypothetical drugs with characteristics similar to the antibiotics commonly used in gonorrhea treatment. CONCLUSIONS: Our results suggest that use of data from surveillance programs could be expanded to prolong the clinical effectiveness of antibiotics without increasing the burden of the disease. This highlights the importance of maintaining effective surveillance systems and the engagement of policy makers to turn surveillance findings into timely and effective decisions.

Predicting the Impact of Typhoid Conjugate Vaccines on Antimicrobial Resistance.

BACKGROUND: Empiric prescribing of antimicrobials in typhoid-endemic settings has increased selective pressure on the development of antimicrobial-resistant Salmonella enterica serovar Typhi. The introduction of typhoid conjugate vaccines (TCVs) in these settings may relieve this selective pressure, thereby reducing resistant infections and improving health outcomes. METHODS: A deterministic transmission dynamic model was developed to simulate the impact of TCVs on the number and proportion of antimicrobial-resistant typhoid infections and chronic carriers. One-way sensitivity analyses were performed to ascertain particularly impactful model parameters influencing the proportion of antimicrobial-resistant infections and the proportion of cases averted over 10 years. RESULTS: The model simulations suggested that increasing vaccination coverage would decrease the total number of antimicrobial-resistant typhoid infections but not affect the proportion of cases that were antimicrobial resistant. In the base-case scenario with 80% vaccination coverage, 35% of all typhoid infections were antimicrobial resistant, and 44% of the total cases were averted over 10 years by vaccination. Vaccination also decreased both the total number and proportion of chronic carriers of antimicrobial-resistant infections. The prevalence of chronic carriers, recovery rates from infection, and relative fitness of resistant strains were identified as crucially important parameters. CONCLUSIONS: Model predictions for the proportion of antimicrobial resistant infections and number of cases averted depended strongly on the relative fitness of the resistant strain(s), prevalence of chronic carriers, and rates of recovery without treatment. Further elucidation of these parameter values in real-world typhoid-endemic settings will improve model predictions and assist in targeting future vaccination campaigns and treatment strategies.

The cost-effectiveness of alternative vaccination strategies for polyvalent meningococcal vaccines in Burkina Faso: A transmission dynamic modeling study.

BACKGROUND: The introduction of a conjugate vaccine for serogroup A Neisseria meningitidis has dramatically reduced disease in the African meningitis belt. In this context, important questions remain about the performance of different vaccine policies that target remaining serogroups. Here, we estimate the health impact and cost associated with several alternative vaccination policies in Burkina Faso. METHODS AND FINDINGS: We developed and calibrated a mathematical model of meningococcal transmission to project the disability-adjusted life years (DALYs) averted and costs associated with the current Base policy (serogroup A conjugate vaccination at 9 months, as part of the Expanded Program on Immunization [EPI], plus district-specific reactive vaccination campaigns using polyvalent meningococcal polysaccharide [PMP] vaccine in response to outbreaks) and three alternative policies: (1) Base Prime: novel polyvalent meningococcal conjugate (PMC) vaccine replaces the serogroup A conjugate in EPI and is also used in reactive campaigns; (2) Prevention 1: PMC used in EPI and in a nationwide catch-up campaign for 1-18-year-olds; and (3) Prevention 2: Prevention 1, except the nationwide campaign includes individuals up to 29 years old. Over a 30-year simulation period, Prevention 2 would avert 78% of the meningococcal cases (95% prediction interval: 63%-90%) expected under the Base policy if serogroup A is not replaced by remaining serogroups after elimination, and would avert 87% (77%-93%) of meningococcal cases if complete strain replacement occurs. Compared to the Base policy and at the PMC vaccine price of US$4 per dose, strategies that use PMC vaccine (i.e., Base Prime and Preventions 1 and 2) are expected to be cost saving if strain replacement occurs, and would cost US$51 (-US$236, US$490), US$188 (-US$97, US$626), and US$246 (-US$53, US$703) per DALY averted, respectively, if strain replacement does not occur. An important potential limitation of our study is the simplifying assumption that all circulating meningococcal serogroups can be aggregated into a single group; while this assumption is critical for model tractability, it would compromise the insights derived from our model if the effectiveness of the vaccine differs markedly between serogroups or if there are complex between-serogroup interactions that influence the frequency and magnitude of future meningitis epidemics. CONCLUSIONS: Our results suggest that a vaccination strategy that includes a catch-up nationwide immunization campaign in young adults with a PMC vaccine and the addition of this new vaccine into EPI is cost-effective and would avert a substantial portion of meningococcal cases expected under the current World Health Organization-recommended strategy of reactive vaccination. This analysis is limited to Burkina Faso and assumes that polyvalent vaccines offer equal protection against all meningococcal serogroups; further studies are needed to evaluate the robustness of this assumption and applicability for other countries in the meningitis belt.

Prospects for Tuberculosis Elimination in the United States: Results of a Transmission Dynamic Model.

We estimated long-term tuberculosis (TB) trends in the US population and assessed prospects for TB elimination. We used a detailed simulation model allowing for changes in TB transmission, immigration, and other TB risk determinants. Five hypothetical scenarios were evaluated from 2017 to 2100: 1) maintain current TB prevention and treatment activities (base case); 2) provision of latent TB infection testing and treatment for new legal immigrants; 3) increased uptake of latent TB infection screening and treatment among high-risk populations, including a 3-month isoniazid-rifapentine regimen; 4) improved TB case detection; and 5) improved TB treatment quality. Under the base case, we estimate that by 2050, TB incidence will decline to 14 cases per million, a 52% (95% posterior interval (PI): 35, 67) reduction from 2016, and 82% (95% posterior interval: 78, 86) of incident TB will be among persons born outside of the United States. Intensified TB control could reduce incidence by 77% (95% posterior interval: 66, 85) by 2050. We predict TB may be eliminated in US-born but not non-US-born persons by 2100. Results were sensitive to numbers of people entering the United States with latent or active TB, and were robust to alternative interpretations of epidemiologic evidence. TB elimination in the United States remains a distant goal; however, strengthening TB prevention and treatment could produce important health benefits.

A Likelihood Approach for Real-Time Calibration of Stochastic Compartmental Epidemic Models.

Stochastic transmission dynamic models are especially useful for studying the early emergence of novel pathogens given the importance of chance events when the number of infectious individuals is small. However, methods for parameter estimation and prediction for these types of stochastic models remain limited. In this manuscript, we describe a calibration and prediction framework for stochastic compartmental transmission models of epidemics. The proposed method, Multiple Shooting for Stochastic systems (MSS), applies a linear noise approximation to describe the size of the fluctuations, and uses each new surveillance observation to update the belief about the true epidemic state. Using simulated outbreaks of a novel viral pathogen, we evaluate the accuracy of MSS for real-time parameter estimation and prediction during epidemics. We assume that weekly counts for the number of new diagnosed cases are available and serve as an imperfect proxy of incidence. We show that MSS produces accurate estimates of key epidemic parameters (i.e. mean duration of infectiousness, R0, and Reff) and can provide an accurate estimate of the unobserved number of infectious individuals during the course of an epidemic. MSS also allows for accurate prediction of the number and timing of future hospitalizations and the overall attack rate. We compare the performance of MSS to three state-of-the-art benchmark methods: 1) a likelihood approximation with an assumption of independent Poisson observations; 2) a particle filtering method; and 3) an ensemble Kalman filter method. We find that MSS significantly outperforms each of these three benchmark methods in the majority of epidemic scenarios tested. In summary, MSS is a promising method that may improve on current approaches for calibration and prediction using stochastic models of epidemics.