Development of Predictive Models to Inform a Novel Risk Categorization Framework for Antibiotic Resistance in E. coli-Causing Uncomplicated Urinary Tract Infection.

BACKGROUND: In clinical practice, challenges in identifying patients with uncomplicated urinary tract infections (uUTIs) at risk of antibiotic non-susceptibility may lead to inappropriate prescribing and contribute to antibiotic resistance. We developed predictive models to quantify risk of non-susceptibility to four commonly prescribed antibiotic classes for uUTI, identify predictors of non-susceptibility to each class, and construct a corresponding risk categorization framework for non-susceptibility. METHODS: Eligible females aged ≥12 years with E. coli-caused uUTI were identified from Optum's de-identified Electronic Health Record dataset (10/1/2015‒2/29/2020). Four predictive models were developed to predict non-susceptibility to each antibiotic class and a risk categorization framework was developed to classify patients' isolates as low, moderate, and high risk of non-susceptibility to each antibiotic class. RESULTS: Predictive models were developed among 87487 patients. Key predictors of having a non-susceptible isolate to ≥3 antibiotic classes included number of previous UTI episodes, prior ß-lactam non-susceptibility, prior fluoroquinolone treatment, census bureau region, and race. The risk categorization framework classified 8.1%, 14.4%, 17.4%, and 6.3% of patients as having isolates at high risk of non-susceptibility to nitrofurantoin, trimethoprim-sulfamethoxazole, ß-lactams, and fluoroquinolones, respectively. Across classes, the proportion of patients categorized as having high-risk isolates was 3-12 folds higher among patients with non-susceptible isolates versus susceptible isolates. CONCLUSIONS: Our predictive models highlight factors that increase risk of non-susceptibility to antibiotics for uUTIs, while the risk categorization framework contextualizes risk of non-susceptibility to these treatments. Our findings provide valuable insight to clinicians treating uUTIs and may help inform empiric prescribing in this population.

Gastrointestinal manifestations in pediatric and adult patients with Rett syndrome: an analysis of US claims and physician survey data.

Aim: Patients with Rett syndrome (RTT) experience gastrointestinal (GI) manifestations. This study aimed to describe the prevalence of GI manifestations and the associated medical costs in patients with RTT in the USA. Patients & Methods: The study combined an insurance claims database analysis with a survey of 100 physicians experienced in RTT management. Results: GI manifestations affected 43.0% of 5940 patients, with increased prevalence in pediatric patients (45.6%) relative to adult patients (40.2%). Annualized mean medical cost of managing GI manifestations was $4473. Only 5.9-8.2% of neurologists and pediatricians ranked GI symptom management among the five most important treatment goals. Conclusion: Patients with RTT experience a high burden of GI manifestations, which translate to considerable medical costs. Importantly, the prevalence of GI manifestations was likely underestimated in this study, as only those symptoms which resulted in a healthcare encounter were captured.

Epidemiology and patient journey of Rett syndrome in the United States: a real-world evidence study.

BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder that almost exclusively affects females and is associated with high clinical burden. However, literature characterizing the real-world journey of patients with RTT is limited. This study provided an overview of the epidemiology, patient characteristics, clinical manifestations, healthcare resource utilization (HRU), costs, and treatment patterns of patients with RTT in the US. METHODS: IQVIA™ Medical Claims Data and Longitudinal Prescription Data (11/01/2016-10/31/2019) were used to identify female patients with RTT, with the first observed diagnosis defined as the index date. Annual incidence and prevalence of RTT were assessed over the entire study period; clinical manifestations, all-cause and RTT-related HRU and costs, and treatment patterns were evaluated during the observation period-from the index date to end of clinical activity or end of data availability, whichever occurred first. Results were further stratified into pediatric (< 18 years) and adult (≥ 18 years) subgroups. RESULTS: In 2019, prevalence and incidence of RTT was 0.32 and 0.23 per 10,000 enrollees, respectively. Among 5,940 female patients (pediatric: 3,078; adult: 2,862) with mean observation period of 2.04 years, the most prevalent clinical manifestations were neurological disorders (72.8%), gastrointestinal/nutritional disorders (41.9%), and orthopedic disorders (34.6%). The incidence rate of all-cause HRU was 44.43 visits per-patient-per-year and RTT-related HRU comprised 47% of all-cause HRU. Mean all-cause healthcare costs were $40,326 per-patient-per-year, with medical costs driven by home/hospice care visits, therapeutic services, outpatient visits, and inpatient visits. RTT-related healthcare costs comprised 45% of all-cause healthcare costs. The most prevalent supportive therapy and pharmacologic agent were feeding assistance (37.9%) and antiepileptic drugs (54.8%), respectively. Trends were similar by subgroup; although, rates of HRU were generally higher among pediatric patients relative to adult patients (all-cause: 52.43 and 35.86, respectively), which translated into higher mean healthcare costs (all-cause: $45,718 and $34,548, respectively). CONCLUSIONS: Patients with RTT have substantial disease burden, including prevalent clinical manifestations, high rates of HRU and annual healthcare costs, and reliance on pharmacologic and supportive therapies. These findings underscore the unmet need for effective therapies to target the multifactorial manifestations of RTT.

Profiling Disease and Economic Burden in CRSwNP Using Machine Learning.

Purpose: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with high healthcare resource utilization (HRU) and economic cost; however, heterogeneity of clinical burden among patients with differing clinical characteristics has not been fully elucidated. Here, an unsupervised machine learning approach supported by clinical validation identified distinct clusters of patients with CRSwNP and compared healthcare burden. Patients and Methods: This retrospective analysis identified adult patients with ≥2 claims for CRSwNP and date of first diagnosis (index date) between January 2015 and June 2019 from a healthcare database. Patients were required to have enrollment in the database 6-months pre- and 12-months post-index. Patients were assigned to clusters using latent class analysis. All-cause and nasal polyp (NP)-related HRU and costs were compared between clusters. Results: Among 12,807 patients, 5 clusters were identified: cluster 1: no surgery/low comorbidity/low medication use (n = 4076); cluster 2: no surgery/low comorbidity/high medication use (n = 2201); cluster 3: no surgery/high comorbidity/high medication use (n = 2093); cluster 4: surgery/low comorbidity/moderate medication use (n = 3168); cluster 5: surgery/high comorbidity/high medication use (n = 1269). All-cause HRU was similar across clusters. NP-related HRU was highest in the surgical clusters (clusters 4 and 5). All-cause costs were similar in clusters 1-3 ($15,833-$17,461) and highest in clusters 4 ($31,083) and 5 ($31,103), driven by outpatient costs. Total NP-related costs were also highest for clusters 4 and 5 ($14,193 and $16,100, respectively). Conclusion: Substantial heterogeneity exists in clinical and economic burden among patients with CRSwNP. Machine learning offers a novel approach to better understand the diverse, complex burden of illness in CRSwNP.

Impact of choice of inhalers for asthma care on global carbon footprint and societal costs: a long-term economic evaluation.

BACKGROUND: While effective asthma control medications reduce the burden of asthma, a significant subgroup of these treatments, namely metered-dose inhalers (MDIs), produce substantial greenhouse gas (GHG) emissions, thus contributing to climate change. This study quantified the global climate impact (i.e. carbon dioxide equivalent [CO2e] emissions) and costs of long-term status quo asthma inhaler use versus alternative scenarios substituting MDIs with propellant-free dry powder inhalers (DPIs). METHODS: Three scenarios were evaluated across 10-year (2020-2030) and 50-year (2020-2070) time horizons: A (status quo inhaler use), B and C (2% and 5% year-over-year substitution of MDIs with DPIs, respectively). Global inhaler volumes and costs at baseline were sourced from IQVIA, then projected using UN and WHO trends in per capita GDP, urbanization, and asthma population growth. Inhaler spending was assumed to fall by 90% following generic entry in 2030. The carbon footprint per inhaler and health damage factors for disability-adjusted life years (DALYs) were derived from literature. The US government's central and high-impact estimates for the social cost of carbon (SCC) were used to calculate emissions costs. RESULTS: Over 50 years, scenario A resulted in 826 million tonnes of CO2e emissions globally, with an associated SCC between 21% and 65% of the projected global spending on asthma inhalers. In comparison, CO2e emissions were reduced by 38% and 58% in Scenarios B and C, respectively, and DALYs improved by 33 and 51%. Depending on SCC estimates, Scenarios B and C increased global costs by 7.3% and 16.5%, respectively (central SCC), or decreased costs by 4.2% and 2.6% (high-impact SCC) versus Scenario A. Over 10 years, Scenario A resulted in 97 million tonnes of CO2e emissions globally, with an associated SCC between 4.4% and 12.2% of projected spending. In comparison, Scenarios B and C were associated with 12% and 24% reductions in CO2e emissions and improvements in DALYs by 11.5% and 22.7%, respectively. CONCLUSIONS: Global efforts by environmental and health-policy decision-makers to substitute currently available MDIs with DPIs for asthma control would result in substantial reductions in GHG emissions with manageable costs, or potential cost savings, depending on the SCC. Policies that decrease use of MDIs warrant global attention.

Estimating the US pericarditis prevalence using national health encounter surveillance databases.

OBJECTIVE: To obtain a nationally representative annualized estimate of the prevalence of pericarditis (inflammation of the pericardium) in the United States (US) in order to better understand the potential burden on the health care system. METHODS: Three nationally representative datasets were used to estimate the annualized period prevalence and prevalence rate of pericarditis from 2007 to 2016: the National Ambulatory Medical Care Survey (NAMCS), the National Hospital Ambulatory Medical Care Survey (NHAMCS), and the Nationwide Inpatient Sample (NIS). Across all data sources, ICD-9/10 codes were used to identify healthcare encounters with ≥1 primary or secondary diagnosis related to pericarditis irrespective of duration or etiology. The prevalence of pericarditis in 2020 was extrapolated by multiplying the average annualized prevalence rate from 2007 to 2016 by the total US population as of March 2020. RESULTS: Data from NAMCS/NHAMCS (2007-2016) yielded an average annualized estimate of 125,209 patients with pericarditis, resulting in a pooled average annualized prevalence estimate of 40 patients with pericarditis per 100,000 persons. Data from NIS (2007-2016) yielded an average annualized estimate of 34,441 patients with pericarditis, resulting in a pooled average annualized prevalence estimate of 11 hospitalized patients with pericarditis per 100,000 persons. Extrapolation of these results based on the March 2020 population estimates from the US Census Bureau of 329,436,928 resulted in an estimated US prevalence of pericarditis to be approximately160,000. CONCLUSION: Despite certain methodologic limitations, our analysis of data from nationally representative sources support that pericarditis is a rare disease affecting substantially fewer than 200,000 persons in the US.

Carbon footprint and associated costs of asthma exacerbation care among UK adults.

INTRODUCTION: Asthma exacerbations are a primary driver of costs and health impacts from asthma. Despite research suggesting that asthma care has a disproportionate carbon footprint, emissions costs are not considered when evaluating its societal burden. To advance the understanding of greenhouse gas (GHG) emissions associated with asthma, we estimated the carbon footprint and associated costs of asthma exacerbation care by severity level among UK adults. METHODS: Guidelines for asthma exacerbation treatment in UK adults were reviewed by severity level: mild, moderate, and severe/life-threatening. Components of care for each severity were evaluated for GHG emission potential and key drivers were identified. Carbon dioxide equivalent (CO2e) emissions of drivers were sourced from published literature and combined to estimate the carbon footprint per exacerbation, by severity level. Emissions were scaled up to the annual UK adult population based on the annual number of exacerbations at each severity. Costs associated with emissions were estimated using the UK government's 2020 nontraded price of carbon, at £71 per tonne CO2e (tCO2e). RESULTS: Overall, emissions drivers for exacerbations were medical services, including patient-travel, and quick-relief inhalers. The annual number of mild, moderate, and severe/life-threatening asthma exacerbations among UK adults were 118.9 M, 5.5 M, and 2.4 M. Associated annual carbon footprints were estimated to be 83,455 tCO2e, 192,709 tCO2e, and 448,037 tCO2e for mild, moderate, and severe/life-threatening exacerbations, respectively, with a total of 724,201 tCO2e. Total annual emissions costs from exacerbation care were £51.3 M; £5.9 M, £13.6 M, and £31.7 M for mild, moderate, and severe/life-threatening exacerbations, respectively. CONCLUSION: GHG emissions from asthma exacerbation management were the highest for severe/life-threatening events, followed by moderate exacerbations. Treatment to reduce the severity and occurrence of exacerbations, such as effective, long-term control therapy via lower-emission dry powder inhalers (DPIs), can help mitigate asthma care emissions. For mild exacerbations, the use of DPIs can eliminate associated emissions.

Estimating the causal effect of prenatal lead exposure on prepulse inhibition deficits in children and adolescents.

During pregnancy, maternal lead from earlier exposures mobilizes and crosses placental barriers, placing the developing fetus at risk for lead exposure and neurodevelopmental deficits. Some neuronal circuits known to be affected in neurodevelopment disorders can be probed with simple physiological behavioral paradigms. One such neural biomarker is Pre-Pulse Inhibition (PPI), an indicator of adequate sensorimotor gating processing. In clinical studies, deficits in PPI have been associated with neurodevelopmental disorders in human subjects. To our knowledge, no studies have examined the use of PPI as a biomarker of toxicant effects on the brain in epidemiological studies. We aimed to estimate the causal effect of prenatal lead exposure, assessed by maternal cortical bone lead concentrations, on PPI in 279 children from Mexico City. in vivo maternal cortical bone lead measurements were taken at four weeks postpartum at the mid-tibia shaft using a K-Shell X-ray fluorescence instrument. PPI recording occurred in an isolated clinical setting and eye blink responses were measured using electromyography. We assessed if the conditions for causal inference held in our study and used the results of our assessment to estimate the causal effect of prenatal lead exposure on PPI using an ordinary least squares regression model, a marginal structural model, and the parametric g-formula. Results were consistent across the three modeling approaches. For the parametric g-formula, a one standard deviation (10.0 µg/g) increase in prenatal lead significantly reduced PPI by approximately 19.0 % (95 % CI: 5.4 %, 34.3 %). This decrease is similar in magnitude to clinical studies on schizophrenia, which have observed PPI impairments in patients with schizophrenia as compared to controls. Our results are consistent with findings from other studies establishing an association between lead exposure and neurodevelopmental disorders in children and suggest that PPI may be useful as an objective biomarker of toxicant effects on the brain.

Suicidal ideation and attempts in the United States of America among stimulant-treated, non-stimulant-treated, and untreated patients with a diagnosis of attention-deficit/hyperactivity disorder.

BACKGROUND: Studies of the association between attention-deficit/hyperactivity disorder (ADHD) drug therapy and suicidal ideation and attempts (SIA) have conflicting results. METHODS: Cohorts of patients with ADHD aged 6 years or older with at least one pharmacy claim for a central nervous system (CNS) stimulant or a non-stimulant, or with no claims for ADHD pharmacotherapy, were identified in the US IBM® MarketScan® Research Database from January 2008 to March 2018. Incidence density rates (IDRs) of SIA (i.e., claims for suicide and self-inflicted poisoning, suicide and self-inflicted injuries, or suicidal ideation) were calculated. Cohorts were compared (CNS stimulants vs non-stimulants; CNS stimulants vs no pharmacotherapy) using hazard ratios (HRs) estimated from Cox proportional hazards models. Inverse-probability-of-treatment weighting (IPTW) was used to control for confounding. RESULTS: The study included 797,189 patients (CNS stimulants, 622,536; non-stimulants, 54,615; no pharmacotherapy, 120,038). IDRs of SIA (per 1000 patient-years) were: CNS stimulants, 5.8; non-stimulants, 10.5; and no pharmacotherapy, 10.0. The overall SIA risk was significantly lower with CNS stimulants than with non-stimulants (IPTW-adjusted HR = 0.70, 95% confidence interval = 0.61-0.81, p < 0.001) and no pharmacotherapy (0.62, 0.57-0.67, p < 0.001). LIMITATIONS: SIA assessment was based on diagnostic codes; suicidal ideation may not have been reported; completed suicides were generally not captured; and treatment was not verified. CONCLUSIONS: In this population-based study of patients with ADHD, SIA risk was significantly lower in those receiving CNS stimulants relative to those receiving non-stimulants or no pharmacotherapy, suggesting that CNS stimulants may attenuate SIA risk.

Toenail Metal Exposures in Fishermen from Bodo City, Nigeria.

We conducted exposure assessment using toenails from 20 fishermen living in Bodo City, a community of the Niger delta region in Nigeria. This community has been affected by over 4000 oil spills and environmental disasters. Fishing is the primary source of food and income for individuals in this community. Previous research in Bodo City found elevated metal levels in fish. Toenails were used as a biomarker to investigate the feasibility for use in risk assessment studies in developing countries. The toenails collected had significantly higher manganese levels (median 5.8 µg/g) and lead levels (median 0.98 µg/g) than those reported in more developed countries, comparable levels to those from other low-middle incomes countries. These exposure levels are likely a direct result of exposures from the environmental disasters the community has experienced and would be related to increased risks for many diseases previously associated with heavy metal exposures.

Mortality Among Professional American-Style Football Players and Professional American Baseball Players.

Importance: Studies of American-style football players have suggested lower overall mortality rates compared with general populations, but with possibly increased neurodegenerative mortality. However, comparisons with general populations can introduce bias. This study compared mortality between US National Football League (NFL) and US Major League Baseball (MLB) players, a more appropriate comparison group of professional athletes. Objective: To compare all-cause and cause-specific mortality between NFL and MLB players. Design, Setting, and Participants: In this retrospective cohort study, the setting was US mortality from January 1, 1979, through December 31, 2013. The dates of analysis were January 2016 to April 2019. Participants were 3419 NFL and 2708 MLB players with at least 5 playing seasons. Exposures: Participation in the NFL compared with the MLB. Main Outcomes and Measures: Vital status and causes of death from the National Death Index from 1979 through 2013 were obtained. Cox proportional hazards regression models using age as the timescale were used to calculate hazard ratios (HRs) and 95% CIs to examine all-cause and cause-specific mortality among NFL players compared with MLB players, adjusted for race and decade of birth. Results: By the end of follow-up, there were 517 deaths (mean [SD] age, 59.6 [13.2] years) in the NFL cohort and 431 deaths (mean [SD] age, 66.7 [12.3] years) in the MLB cohort. Cardiovascular and neurodegenerative conditions, respectively, were noted as underlying or contributing causes in 498 and 39 deaths in the NFL and 225 and 16 deaths in the MLB. Compared with MLB players, NFL players had significantly elevated rates of all-cause (HR, 1.26; 95% CI, 1.10-1.44), cardiovascular disease (HR, 2.40; 95% CI, 2.03-2.84), and neurodegenerative disease (HR, 2.99; 95% CI, 1.64-5.45) mortality. Comparing hypothetical populations of 1000 NFL and 1000 MLB players followed up to age 75 years, there would be an excess 21 all-cause deaths among NFL players, as well as 77 and 11 more deaths with underlying or contributing causes that included cardiovascular and neurodegenerative conditions, respectively. Conclusions and Relevance: This study found that NFL players had elevated all-cause, cardiovascular, and neurodegenerative mortality rates compared with MLB players, although the absolute number of excess neurodegenerative deaths was still small. Factors that vary across these sports (eg, body habitus and head trauma) as opposed to those common across sports (eg, physical activity) could underlie the differences.

Methodological Challenges When Studying Distance to Care as an Exposure in Health Research.

Distance to care is a common exposure and proposed instrumental variable in health research, but it is vulnerable to violations of fundamental identifiability conditions for causal inference. We used data collected from the Botswana Birth Outcomes Surveillance study between 2014 and 2016 to outline 4 challenges and potential biases when using distance to care as an exposure and as a proposed instrument: selection bias, unmeasured confounding, lack of sufficiently well-defined interventions, and measurement error. We describe how these issues can arise, and we propose sensitivity analyses for estimating the degree of bias.

Socio-demographic predictors of prepulse inhibition: A prospective study in children and adolescents from Mexico City.

Prepulse inhibition (PPI) is a sensorimotor gating mechanism that reduces interfering influences to the neural processing of incoming stimuli, and is associated with several neurodevelopmental disorders. To date, research on PPI and neurodevelopmental disorders has primarily been in cross-sectional, clinical settings. In this prospective, epidemiologic study, we used a data-driven prediction model to identify socio-demographic predictors of PPI in children and adolescents from Mexico City to inform future etiologic studies evaluating PPI. We conducted variable selection and validation using a modified version of the multiple imputation random lasso (MIRL) variable selection algorithm. MIRL identified six predictors of PPI at a stimulus onset asynchrony of 120 ms or 240 ms. Of those six predictors, maternal education, birthweight, and total breastfeeding months were highlighted as previously unstudied variables associated with enhanced PPI. Our findings highlight the potential value of PPI as an adjunct screening tool for identifying children at risk for neurodevelopmental disorders and underscore the relevance for validation research on this topic.