Inconsistencies in the days supply values reported in pharmacy claims databases for biologics with long maintenance intervals.

BACKGROUND: Days supply values reported in large administrative claims databases are commonly used to estimate drug exposure and quantify adherence and persistence with prescribed therapy. In recent claims database studies assessing treatment patterns for biologic therapies, a high frequency of 28-31-days supply values has been observed for therapies with label-recommended maintenance dosing intervals longer than 4 weeks. Such inconsistencies suggest potential inaccuracy of days supply data. OBJECTIVE: To confirm the existence and describe the extent of inconsistencies in the reported days supply values and the documented fill intervals among prescription claims from administrative claims databases for 2 different biologics with label-recommended maintenance dosing intervals longer than 4 weeks and 2 biologics with intervals less than or equal to 4 weeks. METHODS: Using data from 2 large US administrative claims databases (IBM MarketScan Commercial Claims and Encounters and the Optum Clinformatics Data Mart Socio-economic Status [SES]), the reported days supply values and associated intervals between consecutive fills for 2 biologics with maintenance dosing intervals longer than 4 weeks (guselkumab and ustekinumab) and 2 with intervals less than or equal to 4 weeks (adalimumab and ixekizumab) were described. For all fill pairs with reported days supply values of 28-31 days, the percentage with inconsistent fill intervals (defined as >45 days or >60 days) was calculated. RESULTS: Across all datasets, the proportions of fill pairs with inconsistent days supply values and fill intervals (ie, days supply values of 28-31 days but fill intervals of >45 days) were 41.8%-73.4% for guselkumab, 33.4%-59.4% for ustekinumab, 8.5%-9.5% for adalimumab, and 7.3%-11.4% for ixekizumab. The same trend was observed across these biologics when using more than 60 days to define an inconsistent fill interval. Unlike adalimumab and ixekizumab, a wide distribution of fill intervals was observed among guselkumab and ustekinumab fill pairs with 28-31 days supply values, with peaks evident at approximately 28-31 days as well as around the label-recommended maintenance dosing intervals for these therapies (56 or 84 days). CONCLUSIONS: This study demonstrated a large discrepancy between days supply values and fill intervals reported in administrative claims data for biologics with label-recommended maintenance dosing intervals longer than 4 weeks (ie, guselkumab and ustekinumab), potentially suggesting widespread underestimation of days supply values for these therapies. Such inconsistencies in the reported days supply values may lead to underestimation of treatment adherence and persistence for these biologics, which could be mitigated by systematic data imputation. DISCLOSURES: This study was funded by Janssen Scientific Affairs, LLC. Ms Xu and Drs Ferrante, Fitzgerald, Pericone, and Wu are employees of Janssen Scientific Affairs, LLC, and shareholders of Johnson & Johnson, of which Janssen Scientific Affairs, LLC, is a wholly owned subsidiary. Funding for programming support and medical writing and editorial assistance was provided by Janssen.

Real-World Patient Characteristics, Treatment Patterns, and Mutation Testing Patterns Among US Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations.

INTRODUCTION: Approximately 15% of patients with non-small cell lung cancer (NSCLC) harbor an epidermal growth factor receptor mutation (EGFRm). Mutation testing (including EGFRm) is recommended for patients with advanced NSCLC (aNSCLC) prior to initiating first-line therapy (L1) or after progression on targeted therapy. To elucidate current and future unmet needs, the present study characterized real-world EGFR testing patterns and treatment patterns in patients with aNSCLC. METHODS: This retrospective observational cohort study evaluated newly diagnosed adult patients with aNSCLC (stage IIIB or higher) from the Flatiron Health database. Eligible patients received at least L1 during 2015-2020 (testing cohorts) or 2011-2020 (treatment cohorts). Eligible patients for the treatment cohorts had an EGFR mutation. RESULTS: The testing cohort included 22,726 patients, 75.5% had at least one EGFR test and 15.2% of those tested were positive for EGFR mutation. From 2015 to 2020, the median time from sample collection to test results decreased substantially while the proportion of NGS EGFR tests and use of plasma samples increased. The treatment cohort included 3701 patients (95% common mutations [cEGFR], 5.0% exon 20 insertions [ex20ins]). Three or more lines of therapy (LOTs) were observed in approximately 30% of patients. For L1, most cEGFR patients received EGFR tyrosine kinase inhibitors (EGFR-TKI, 68.1%) or platinum-based chemotherapy (PBC, 24.8%); most ex20ins patients received PBC (66.1%) or EGFR-TKI (17.5%). The most common L2 was EGFR-TKI (54.1%) or PBC (22.8%) for cEGFR and immunotherapy (25.9%) or PBC (25.9%) for ex20ins. No predominant L3 was evident in either group. CONCLUSION: This real-world study, among the largest analyses of testing patterns for patients with aNSCLC, demonstrates a comprehensive view of treatment patterns for patients with EGFR mutations, including ex20ins. Despite recent improvement, increased use of EGFR testing, including advanced methods, is needed to optimize treatment pathways and outcomes. Additionally, the lack of a predominant therapy in later lines indicates a need for new therapies.

Real-world evidence on adherence and completion of the two-dose recombinant zoster vaccine and associated factors in U.S. adults, 2017-2021.

INTRODUCTION: Poor compliance with adult vaccination recommendations contributes to substantial disease burden. Evidence on adherence, completion, and completion timeliness for the 2-dose recombinant herpes zoster vaccine (RZV) and factors associated with these outcomes is limited and not readily generalizable for the entire U.S. METHODS: This retrospective, observational study examined adherence, completion, and the impact of sociodemographic, clinical and geographical factors among U.S. adults ≥ 50 years receiving RZV (4/20/2017 to 3/31/2021), using a large, geographically representative administrative claims database. Continuous enrollment in a medical benefit plan for six months prior to and following the index date (first observed vaccine dose) was required. Adherence was defined as receipt of the 2nd dose within 2-6 months, per label recommendation. Completion (receipt of all doses) was assessed at 6, 12, 18, and 24 months. RESULTS: Among 726,352 adults included, the adherence rate was 71.8%. Among 208,311 adults with 24-month follow-up, the completion rate was 72.3% after 6 months and 86.2% after 24 months. Logistic regression showed low adherence/completion was associated with younger age, Black or Hispanic race/ethnicity, lower income, lower educational attainment, and possessing commercial rather than Medicare healthcare insurance. Recipients identified using pharmacy claims had much higher adherence (74.0%) than those identified using medical claims (48.0%). CONCLUSIONS: Adherence and completion rates for RZV are suboptimal, especially for adults aged 50-64, racial/ethnic minorities, individuals with lower socio-economic status and those without Medicare insurance. More research and public health efforts are needed to understand and address potential barriers to RZV uptake, adherence and completion.

Hepatitis vaccination adherence and completion rates and factors associated with low compliance: A claims-based analysis of U.S. adults.

Poor compliance with multi-dose vaccine schedules by adults for whom hepatitis (Hep) A and B vaccines are recommended contributes to major Hep A and B disease burdens among high-risk U.S. adults. Evidence on hepatitis vaccine series adherence, completion, timeliness of completion, and factors associated with these outcomes, is limited and not readily generalizable for U.S. adults. This retrospective, observational study examined adherence, completion, its timeliness, and the impact of sociodemographic and clinical factors on these outcomes among a large, geographically representative sample of U.S. adults. We analyzed the Optum Clinformatics SES administrative claims database (1/1/2010-6/30/2020) for recipients of 2-dose (HepA, HepB2) or 3-dose (HepB3, HepAB) hepatitis vaccines. Adherence was defined as receipt of booster doses within specified assessment periods, per label-recommended schedules. Completion (receipt of all doses) was assessed at 6, 12, 18, and 24 months.The study included 356,828 adults ≥19 years old who were continuously enrolled in a medical benefit plan for one (HepB2), six (HepB3; HepAB), or 18 months (HepA) prior to and following the index date (first observed vaccine dose). Adherence and 24-month completion rates were: HepA (27.0%, 28.4%), HepB2 (32.2%, 44.8%), HepB3 (14.3%, 37.3%), HepAB, (15.3%, 33.8%). Kaplan-Meier completion curves plateaued after about 6 months for HepB2 and about 12 months for HepA, HepB3, and HepAB vaccines. Logistic regression analyses showed risk for low adherence/completion was generally associated with male gender, younger age, Black or Hispanic race/ethnicity, lower educational or household income attainment, and more comorbidities. Adherence and completion rates for all hepatitis vaccine series are low, especially for males, younger adults, those with lower socio-economic status and more comorbidities. To our knowledge, this is the largest claims-based analysis of adherence and completion rates for U.S. adults initiating all currently available HepA and HepB vaccines. Findings may inform hepatitis vaccination programming.

Real-World Assessment of Weight Change in African American Females and Hispanics with HIV-1 After Initiating Integrase Strand-Transfer Inhibitors or Protease Inhibitors.

Background: Studies have shown an increase in weight among people living with HIV (PLWH) who initiated integrase strand transfer inhibitors (INSTI). However, weight gain with INSTI-based regimens vs other regimens in females or racial/ethnic minorities is poorly understood. Objective: This study assessed differences in weight gain among treatment-naïve, female, African Americans and Hispanics after initiating INSTI-based vs protease inhibitor (PI)-based regimens. Methods: This retrospective, observational cohort study included data from the Optum® deidentified Electronic Health Record Database. Female African Americans or Hispanics initiating INSTI- or PI-based regimens between January 1, 2015, and December 31, 2018 (first prescription was index date), with ≥12-month baseline and follow-up periods, ≥1 weight measure during each period, and no prior antiretroviral (ARV) use were included. Inverse probability of treatment weighting was used to reduce selection bias and improve cohort comparability. Multivariable models were used to compare absolute weight/body mass index (BMI) changes and proportion of patients with weight/BMI increases from pre- to post-index (last measure between the 4th and 12th months post-index). Results: Weighted cohorts included 3407 African American females (INSTI, 1704; PI, 1703) and 3711 Hispanics (INSTI, 1865; PI, 1846) PLWH. Mean time to follow-up weight measure was ~9.5 months. Among female African Americans, INSTI initiators had a 1.5 kg greater mean weight gain (2.1 kg vs 0.6 kg; P = 0.033), and a higher proportion with ≥5% weight gain (32% vs 29%; odds ratio [OR]=1.2; 95% CI [1.0-1.4]) than PI initiators. Among Hispanics, INSTI and PI initiators had similar mean increases in weight (2.1 and 1.8 kg, respectively), but INSTI initiators had a higher proportion with ≥5% weight gain (31% vs 27%; OR=1.2; 95% CI [1.1-1.4]). Female African American INSTI initiators were more likely to shift from normal or overweight to a worse BMI classification. Hispanic INSTI initiators were less likely to shift from normal BMI to overweight but more likely to shift from normal or overweight to obese. Conclusion: In a real-world setting, INSTI-based regimens were associated with greater weight gain for treatment-naïve female African Americans, compared with PI-based regimens. Differences between regimens were less consistent for Hispanics. These results may inform ARV choice for PLWH who are at risk for ARV-related weight gain.

Trends in US emergency department visits and subsequent hospital admission among patients with inflammatory bowel disease presenting with abdominal pain: a real-world study from a national emergency department sample database.

Background/Objective: This study evaluated emergency department (ED) visit trends, subsequent inpatient admissions for patients with inflammatory bowel disease (IBD) diagnosis and IBD-related abdominal pain (AP), and hospital-level variation in inpatient admission rates in the USA (US). Methods: This population-based, cross-sectional study included data from Nationwide Emergency Department Sample (NEDS, 2006─2013) database. Patients ≥18 years of age with primary ED diagnosis of IBD/IBD-related AP were included. Variables included demographics, insurance information, household income, Quan-Charlson comorbidity score, ED discharge disposition, and length of hospital stay (2006, 2010, and 2013). Variation between hospitals using risk-adjusted admission ratio was estimated. Results: Annual ED visits for IBD/100,000 US population increased (30 in 2006 vs 42 in 2013, p = 0.09), subsequent admissions remained stable (20 in 2006 vs 23 in 2013, p = 0.52). ED visits for IBD-related AP increased by 71% (7 in 2006 vs 12 in 2013; p = 0.12), subsequent admissions were stable (0.50 in 2006 vs 0.58 in 2013; p = 0.88). Proportion of patients with subsequent hospitalization decreased (IBD: 65.7% to 55.7%; IBD-related AP: 6.9% to 4.9%). Variation in subsequent inpatient admissions was 1.42 (IBD) and 1.96 (IBD-related AP). Conclusions: An increase in annual ED visits was observed for patients with IBD and IBD-related AP; however, subsequent inpatient admission rate remained stable.

Association of depression symptom severity with short-term risk of an initial hospital encounter in adults with major depressive disorder.

BACKGROUND: Despite the availability of pharmacologic and nonpharmacologic treatment options, depression continues to be one of the leading causes of disability worldwide. This study evaluated whether depression symptom severity, as measured by PHQ-9 score, of patients diagnosed with MDD is associated with short-term risk of a hospital encounter (ER visit or inpatient stay). METHODS: Adults with ≥1 PHQ-9 assessment in an outpatient setting (index date) and ≥ 1 MDD diagnosis within 6 months prior were included from the de-identified Optum Electronic Health Record database (April 2016-June 2019). Patients were categorized by depression symptom severity based on PHQ-9 scores obtained by natural language processing. Crude rates, adjusted absolute risks, and adjusted relative risks of all-cause and MDD-related hospital encounters within 30 days following assessment of depression severity were determined. RESULTS: The study population consisted of 280,145 patients with MDD and ≥ 1 PHQ-9 assessment in an outpatient setting. Based on PHQ-9 scores, 26.9% of patients were categorized as having none/minimal depression symptom severity, 16.4% as mild, 24.7% as moderate, 19.6% as moderately severe, and 12.5% as severe. Among patients with none/minimal, mild, moderate, moderately severe, and severe depression, the adjusted absolute short-term risks of an initial all-cause hospital encounter were 4.1, 4.4, 4.8, 5.6, and 6.5%, respectively; MDD-related hospital encounter adjusted absolute risks were 0.8, 1.0, 1.3, 1.6, and 2.1%, respectively. Compared to patients with none/minimal depression symptom severity, the adjusted relative risks of an all-cause hospital encounter were 1.60 (95% CI 1.50-1.70) for those with severe, 1.36 (1.29-1.44) for those with moderately severe, 1.18 (1.12-1.25) for those with moderate, and 1.07 (1.00-1.13) for those with mild depression symptom severity. CONCLUSIONS: These study findings indicate that depression symptom severity is a key driver of short-term risk of hospital encounters, emphasizing the need for timely interventions that can ameliorate depression symptom severity.

Treatment Persistence and Adherence Among Patients With Psoriatic Arthritis Who Initiated Targeted Immune Modulators in the US: A Retrospective Cohort Study.

INTRODUCTION: This study compared treatment persistence and adherence among psoriatic arthritis (PsA) patients in the US who initiated an interleukin-12/23 inhibitor (IL-12/23i) versus those who initiated tumor necrosis factor inhibitors (TNFis), targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), or interleukin-17 inhibitors (IL-17is). METHODS: Adults diagnosed with PsA with ≥ 1 claim for a targeted immune modulator were selected from the IBM MarketScan® Commercial and Medicare Supplemental databases (October 1, 2013-October 31, 2018). The date of the first claim was the index date. Patients had continuous health plan enrollment for ≥ 12 months pre-index and ≥ 12-month post-index period. Pairwise propensity score matching with nearest-neighbor technique was performed. Persistence duration, discontinuation rate, and the proportion of days covered (PDC) were evaluated in biologic/tsDMARD naïve patients who initiated TNFis, IL-17is, tsDMARDs, or IL-12/23i (reference group). RESULTS: There were 238 matched patient pairs for TNFi versus IL-12/23i, 238 pairs for tsDMARD versus IL-12/23i, and 189 pairs for IL-17is versus IL-12/23i. Duration of persistence was longer for the IL-12/23i cohort than for the TNFi (269 vs. 215 days, p < 0.001) or tsDMARD (269 vs. 213 days, p < 0.001) cohorts, but comparable between the IL-12/23i and IL-17i cohorts (267 vs. 246 days, p = 0.199). Fewer patients in the IL-12/23i cohort discontinued their index medication than in the TNFi (53.4% vs. 73.9%, p < 0.001) or tsDMARD (53.4% vs. 71.8%, p < 0.001) cohorts, but no significant difference was observed between the IL-12/23i and IL-17i cohorts (52.9% vs. 58.2%, p = 0.288). During the 12-month follow-up, adherence (i.e., PDC) was higher among those who initiated an IL-12/23i than among those who initiated TNFis (0.64 vs. 0.56, p = 0.004) or tsDMARDs (0.64 vs. 0.58, p = 0.027), but similar to those who initiated IL-17is (0.64 vs. 0.65, p = 0.589). CONCLUSION: In this real-world study of PsA therapies with differing mechanisms of action, the IL-12/23i demonstrated longer persistence and higher adherence than either TNFis or tsDMARDs, and comparability to IL-17is.

Treatment adherence and persistence of five commonly prescribed medications for moderate to severe psoriasis in a U.S. commercially insured population.

OBJECTIVE: To evaluate medication discontinuation, persistence, and adherence of moderate to severe psoriasis patients treated with adalimumab, apremilast, etanercept, secukinumab, and ustekinumab. METHODS: Adult patients diagnosed with psoriasis and ≥1 psoriasis pharmacy or medical claim of any of the five psoriasis medications (index date) and continuous insurance enrollment were included from the Optum Clinformatics database during the intake period (7/1/2014-9/30/2017). Medication discontinuation, persistence, medication possession ratio (MPR), and proportion of days covered (PDC) were evaluated during a 12-month post-index follow-up period, using three gap definitions. RESULTS: Among the study population (n = 8524), 34.4% initiated adalimumab, 25.7% apremilast, 9.0% etanercept, 7.1% secukinumab, and 23.7% ustekinumab. Mean age ranged from 48.7 to 52.2 years. For all three gap definitions, discontinuation was lowest and persistence greatest among ustekinumab treated patients (48.4% and 59.8%, respectively using the default definition). A greater proportion of ustekinumab patients had an MPR ≥80% (81.8%) than adalimumab (67.9%), apremilast (54.9%), etanercept (56.4%), and secukinumab (68.0%) patients. Also, 50.6% of ustekinumab patients had a PDC ≥80% versus 35.6%, 23.9%, 19.5%, and 41.7% of adalimumab, apremilast, etanercept, and secukinumab patients, respectively. CONCLUSIONS: Although heterogeneity across cohorts may explain some medication utilization differences, ustekinumab was associated with lower discontinuation and greater persistence and adherence.

Real-World Comparative Effectiveness of Canagliflozin Versus Empagliflozin and Dapagliflozin in Patients with Type 2 Diabetes in the United States.

INTRODUCTION: While several sodium glucose co-transporter 2 (SGLT2) inhibitors are approved as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus (T2DM), there are no clinical trial data providing head-to-head comparisons of the efficacy and safety of these therapies. Real-world analyses can provide valuable evidence on the effectiveness of competing treatments. This study compared the real-world glycemic effectiveness of SGLT2 inhibitors in individuals with T2DM. METHODS: Patients who initiated canagliflozin 300 mg versus empagliflozin 25 mg or dapagliflozin 10 mg were identified from the Optum® De-identified Clinformatics® Extended Data Mart-Date of Death database and propensity score matched. Achievement of HbA1c < 8.0% (Healthcare Effectiveness Data and Information Set [HEDIS] target) and > 9.0% (HEDIS poor control) after 6 months of treatment was calculated. RESULTS: Post-baseline HbA1c was similar in the canagliflozin and empagliflozin cohorts (7.65% versus 7.57%), as was percent of patients with HbA1c < 8.0% or > 9.0%. Post-baseline HbA1c was lower with canagliflozin versus dapagliflozin (7.58% versus 7.74%; P = 0.0247). The canagliflozin cohort was more likely to achieve HbA1c < 8.0% than the dapagliflozin cohort (P = 0.0292); the likelihood of achieving HbA1c > 9.0% was similar. CONCLUSION: In patients with T2DM, HbA1c outcomes were similar with canagliflozin and empagliflozin. Patients on canagliflozin versus dapagliflozin were more likely to have a lower HbA1c and reach HbA1c < 8.0% after 6 months. These results may provide important information for clinicians as they decide the appropriate treatment for their patients with T2DM.

Real-World Assessment of Weight Change in People with HIV-1 After Initiating Integrase Strand Transfer Inhibitors or Protease Inhibitors.

BACKGROUND: Studies have shown an increase in weight among people living with human immunodeficiency virus (PLWH) who have also initiated integrase strand transfer inhibitors (INSTI). However, limited data are available regarding comparison of these changes with other antiretroviral regimens. OBJECTIVE: To assess differences in weight gain after initiating INSTI- versus protease inhibitor (PI)-based regimens among treatment-naïve PLWH overall, and among a subpopulation of females only. METHODS: This retrospective, observational cohort study included data from the Optum ® deidentified Electronic Health Record (EHR) database. Adult PLWH who initiated INSTI- or PI-based regimens between March 1, 2016 and June 30, 2018 (index date was the first INSTI or PI prescription in this period) with ≥12-month baseline and follow-up periods, ≥1 weight measure during each period, and no prior antiretroviral use were included. The last weight measure between 12 months pre- and 30 days post-index was defined as baseline weight; the last measure between the months 4 and 12 of follow-up was defined as post-weight. Weight change was reported as absolute change and proportion of patients with increased weight. Cohorts were balanced using propensity score (PS) matching. Multivariable models were used to compare outcomes of interest. RESULTS: After matching, 1588 patients were included (794 per cohort). At baseline, 46% were <50 years old, 26% were females, 12% had Type II diabetes and 30% had hypertension (mean baseline weight: INSTI: 83 kg (183 lb), PI: 82 kg (181 lb); P = 0.3). The mean time to follow-up weight measure was 9.3 months; INSTI initiators had a 1.3 kg (2.9 lb) greater mean weight gain (95% CI: 0.5-2.0), and a higher proportion with ≥5% weight gain (30.7% vs 26.1%; [OR=1.3, 95% CI: 1.0-1.6]) than PI initiators. Differences in weight gain between regimens were larger among females; female INSTI initiators had a 2.5 kg (5.3 lb) greater mean weight gain (95% CI: 0.7-4.2) and a higher proportion with ≥5% weight gain (37.5% vs 26.4%; OR=1.7; 95% CI [1.1-2.6]) than PI initiators. CONCLUSION: In a real-world setting, compared to PI-based regimens, INSTI-based regimens are associated with greater weight gain for treatment-naïve PLWH. This study may inform HIV treatment choice for health care providers.

Real-world 2-year treatment patterns among patients with psoriatic arthritis treated with injectable biologic therapies.

Objectives: To assess long-term (2-year) biologic treatment patterns of psoriatic arthritis (PsA) patients who initiated adalimumab, certolizumab pegol, etanercept, golimumab, or ustekinumab.Methods: Adult patients with ≥1 pharmacy or medical claim for injectable PsA biologics (index date) were identified from the Optum's Clinformatics Data Mart (1 January 2013-31 December 2016). Adherence, persistence, post-discontinuation treatment patterns, and addition of adjunctive medications were evaluated by index biologic.Results: Of 996 patients included (mean [SD] age: 51.5 [12.6] years; female: 49.4%), the most common index biologics initiated were adalimumab (47.9%) and etanercept (34.5%). The mean [SD] proportion of days covered was 0.48 [0.32] for the index biologics. During the 24-month follow-up period, 19.7% of patients persisted on their index biologic; ustekinumab had the highest persistence rate (27.2%), followed by adalimumab (22.0%), golimumab (18.4%), certolizumab pegol (15.6%), and etanercept (15.4%). Of the 800 patients (80.3%) who discontinued their index biologic therapy, 35.0% restarted, 40.1% switched to another biologic, and 31.8% did neither during the follow-up period. The most common biologics patients switched to were adalimumab (31.2%) and ustekinumab (18.7%). Among patients who persisted with their index biologic for ≥90 days (n = 753), ≥1 adjunctive medication was added for 50.1% of patients. The most common adjunctive medications included corticosteroids (28.0% of patients), opioids (17.0%), nonsteroidal anti-inflammatory drugs (NSAIDs) (13.8%), and conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) (7.3%).Conclusions: In this real-world study of use of biologic PsA therapies, 24-month persistence was low (19.7%), and treatment was frequently supplemented with adjunctive medications.

Emergency Department Visits and Subsequent Hospital Admission Trends for Patients with Chest Pain and a History of Coronary Artery Disease.

INTRODUCTION: Hospitalization is the largest component of health care spending in the United States. Most hospitalized patients first visit the emergency department (ED), where hospitalization decisions are made. Optimal utilization of hospital resources is critical for all stakeholders. METHODS: We performed a population-based, cross-sectional study evaluating ED visits and subsequent inpatient admissions for patients with coronary artery disease (CAD) and chest pain (CP) suggestive of CAD from 2006 to 2013 using the Nationwide Emergency Department Sample database weighted for national estimates. We analyzed trends using a generalized linear regression model with a Poisson distribution and Wald test. RESULTS: From 2006 to 2013, there was a 15% decrease in ED visits for CAD (p < 0.01), while ED visit rates for CP increased 31% (p < 0.01). Subsequent inpatient admission rates decreased 18% for CAD (p < 0.01) and 33% for CP (p < 0.01). Trends were not modified by patient and hospital strata. CONCLUSION: ED visits and subsequent inpatient admissions resulting from CAD decreased from 2006 to 2013. Patients with CP had a substantially higher number of ED visits, with a significant decline in inpatient admissions.

Total cost of care for castration-resistant prostate cancer in a commercially insured population and a medicare supplemental insured population.

Background: The total cost of healthcare for patients with castration-resistant prostate cancer (CRPC) is an important component for assessing value of treatment options. The need for real-world evidence has increased with the introduction of oral targeted therapies for metastatic and nonmetastatic disease. In this study, we examined patient healthcare costs during periods of nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC).Methods: This retrospective cohort study captured data from claims in the Truven Health MarketScan Commercial and Medicare Supplemental (Medigap) databases (1/1/2012-12/31/2016). Male patients (≥18 years) with ≥1 prostate cancer diagnosis, a subsequent metastatic diagnosis, and prescription claim for an mCRPC-indicated therapy (index date) were included. Patients were considered to have nmCRPC during the 12-month period prior to mCRPC if they had ≥1 claim for androgen deprivation therapy. Unadjusted all-cause healthcare resource utilization (HRU) and associated costs in 2016 USD per patient per year (PPPY) were determined for nmCRPC and mCRPC periods.Results: Patients included from the Commercial database (N = 449) had an average age of 59.4 ± 4.5 (standard deviation) years and a mean Quan Charlson Comorbidity Index (QCI) score of 2.8 ± 1.6. Among patients included from the Medigap database (N = 1,173), the mean age was 78.6 ± 7.2 years and mean QCI score was 3.3 ± 2.0. Across all healthcare resource types, HRU was approximately 1.5-2.5 times greater after a diagnosis of metastasis for both study populations. For commercially insured patients, total all-cause healthcare costs increased 6.2-fold from the nmCRPC to mCRPC periods ($29,192 to $182,156 PPPY). Likewise, among Medigap patients, total all-cause healthcare costs increased 5.1-fold from the nmCRPC to mCRPC periods ($27,549 to $139,847).Conclusions: In this study, the cost of care during 2012-2016 was substantially higher for mCRPC than nmCRPC, underscoring the value of interventions that may delay progression to metastases in high-risk individuals.

Real-world comparison of hospitalization costs for heart failure in type 2 diabetes mellitus patients with established cardiovascular disease treated with canagliflozin versus other antihyperglycemic agents.

Aims: This real-world study compared hospitalization for heart failure (HHF) costs and all-cause healthcare costs in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease treated with the sodium glucose co-transporter 2 inhibitor (SGLT2i) canagliflozin and non-SGLT2i antihyperglycemic agents (AHAs).Materials and methods: Propensity score-matched cohorts from a retrospective observational study (OBSERVE-4D) using the Truven MarketScan Commercial Claims and Encounters and Optum Clinformatics databases were analyzed. HHF and all-cause healthcare costs per-patient-per-month (PPPM) were compared for patients initiated on canagliflozin and non-SGLT2i AHAs in the on-treatment analysis.Results: Baseline characteristics were well balanced between matched cohorts that included new users of canagliflozin or non-SGLT2i AHAs in the Truven (13,954 and 45,101, respectively) and Optum (11,490 and 53,360, respectively) databases. The mean (95% CI) PPPM cost of HHF was lower for canagliflozin than for non-SGLT2i AHAs in analyses of both the Truven ($21.31 [$21.25, $21.37]) and Optum ($30.43 [$30.41, $30.45]) databases. The mean (95% CI) PPPM all-cause healthcare cost was also lower for canagliflozin than for non-SGLT2i AHAs in analyses of both the Truven ($321 [$280, $361]) and Optum ($449 [$402, $495]) databases.Limitations: This study is subject to the limitations inherent to observational research including potential for coding errors and biases and unobserved confounding. Because all patients were in commercially administered health plans, these findings cannot be easily generalized to uninsured or Medicaid populations. Patient costs were evaluated up to and including their first HHF event. Post-discharge costs such as the costs of subsequent rehospitalizations were not included in this analysis.Conclusions: For patients with T2DM and established cardiovascular disease in this real-world study, treatment with canagliflozin was associated with lower HHF costs and all-cause healthcare costs compared with treatment with non-SGLT2i AHAs.

Legionella eukaryotic-like type IV substrates interfere with organelle trafficking.

Legionella pneumophila, the causative agent of Legionnaires' disease, evades phago-lysosome fusion in mammalian and protozoan hosts to create a suitable niche for intracellular replication. To modulate vesicle trafficking pathways, L. pneumophila translocates effector proteins into eukaryotic cells through a Type IVB macro-molecular transport system called the Icm-Dot system. In this study, we employed a fluorescence-based translocation assay to show that 33 previously identified Legionella eukaryotic-like genes (leg) encode substrates of the Icm-Dot secretion system. To assess which of these proteins may contribute to the disruption of vesicle trafficking, we expressed each gene in yeast and looked for phenotypes related to vacuolar protein sorting. We found that LegC3-GFP and LegC7/YlfA-GFP caused the mis-secretion of CPY-Invertase, a fusion protein normally restricted to the yeast vacuole. We also found that LegC7/YlfA-GFP and its paralog LegC2/YlfB-GFP formed large structures around the yeast vacuole while LegC3-GFP localized to the plasma membrane and a fragmented vacuole. In mammalian cells, LegC2/YlfB-GFP and LegC7/YlfA-GFP were found within large structures that co-localized with anti-KDEL antibodies but excluded the lysosomal marker LAMP-1, similar to what is observed in Legionella-containing vacuoles. LegC3-GFP, in contrast, was observed as smaller structures which had no obvious co-localization with KDEL or LAMP-1. Finally, LegC3-GFP caused the accumulation of many endosome-like structures containing undigested material when expressed in the protozoan host Dictyostelium discoideum. Our results demonstrate that multiple Leg proteins are Icm/Dot-dependent substrates and that LegC3, LegC7/YlfA, and LegC2/YlfB may contribute to the intracellular trafficking of L. pneumophila by interfering with highly conserved pathways that modulate vesicle maturation.

Evidence for acquisition of Legionella type IV secretion substrates via interdomain horizontal gene transfer.

Intracellular pathogens exploit host cell functions to create a replication niche inside eukaryotic cells. The causative agent of Legionnaires' disease, the gamma-proteobacterium Legionella pneumophila, resides and replicates within a modified vacuole of protozoan and mammalian cells. L. pneumophila translocates effector proteins into host cells through the Icm-Dot complex, a specialized type IVB secretion system that is required for intracellular growth. To find out if some effector proteins may have been acquired through interdomain horizontal gene transfer (HGT), we performed a bioinformatic screen that searched for eukaryotic motifs in all open reading frames of the L. pneumophila Philadelphia-1 genome. We found 44 uncharacterized genes with many distinct eukaryotic motifs. Most of these genes contain G+C biases compared to other L. pneumophila genes, supporting the theory that they were acquired through HGT. Furthermore, we found that several of them are expressed and up-regulated in stationary phase in an RpoS-dependent manner. In addition, at least seven of these gene products are translocated into host cells via the Icm-Dot complex, confirming their role in the intracellular environment. Reminiscent of the case with most Icm-Dot substrates, most of the strains containing mutations in these genes grew comparably to the parent strain intracellularly. Our findings suggest that in L. pneumophila, interdomain HGT may have been a major mechanism for the acquisition of determinants of infection.

Factors contributing to hydrogen peroxide resistance in Streptococcus pneumoniae include pyruvate oxidase (SpxB) and avoidance of the toxic effects of the fenton reaction.

Aerobic growth of Streptococcus pneumoniae results in production of amounts of hydrogen peroxide (H(2)O(2)) that may exceed 1 mM in the surrounding media. H(2)O(2) production by S. pneumoniae has been shown to kill or inhibit the growth of other respiratory tract flora, as well as to have cytotoxic effects on host cells and tissue. The mechanisms allowing S. pneumoniae, a catalase-deficient species, to survive endogenously generated concentrations of H(2)O(2) that are sufficient to kill other bacterial species is unknown. In the present study, pyruvate oxidase (SpxB), the enzyme responsible for endogenous H(2)O(2) production, was required for survival during exposure to high levels (20 mM) of exogenously added H(2)O(2). Pretreatment with H(2)O(2) did not increase H(2)O(2) resistance in the mutant, suggesting that SpxB activity itself is required, rather than an H(2)O(2)-inducible pathway. SpxB mutants synthesized 85% less acetyl-phosphate, a potential source of ATP. During H(2)O(2) exposure, ATP levels decreased more rapidly in spxB mutants than in wild-type cells, suggesting that the increased killing of spxB mutants was due to more rapid ATP depletion. Together, these data support the hypothesis that S. pneumoniae SpxB contributes to an H(2)O(2)-resistant energy source that maintains viability during oxidative stress. Thus, SpxB is required for resistance to the toxic by-product of its own activity. Although H(2)O(2)-dependent hydroxyl radical production and the intracellular concentration of free iron were similar to that of Escherichia coli, killing by H(2)O(2) was unaffected by iron chelators, suggesting that S. pneumoniae has a novel mechanism to avoid the toxic effects of the Fenton reaction.

Multiple mechanisms for choline transport and utilization in Haemophilus influenzae.

Haemophilus influenzae obtains choline from either its growth medium or host cell membrane lipids and expresses it on its lipopolysaccharide (LPS) in the form of phosphorylcholine (ChoP), which contributes to its pathogenesis by mimicry of host cell molecules. Two genes (licB and betT) revealed by whole genomic analysis as encoding potential choline transporters were tested for their role in LPS-ChoP synthesis. The betT gene in H. influenzae is similar to betT in Escherichia coli, which functions in choline transport for the generation of betaine in osmoprotection. The licB gene has homology to bacterial permeases including betT and is encoded in the lic1 locus, which is essential for the expression of LPS-ChoP. In the presence of high concentrations of choline, neither licB nor betT were necessary for expression of LPS-ChoP raising the possibility that other unidentified choline uptake mechanisms may exist in this species. However, under choline limiting conditions, including growth in human nasal airway surface fluid, the licB, but not betT, gene was required for choline transport and synthesis of LPS-ChoP suggesting that LicB functions as a high affinity choline permease. The betT, but not licB, gene was shown to function in osmoprotection in H. influenzae, similar to the role of betT in E. coli. Further analysis demonstrated growth condition dependent differences in the regulation of transcription of the licB and betT genes. We conclude that H. influenzae may have multiple mechanisms for choline uptake and distinct pathways for choline utilization in LPS-ChoP biosynthesis and osmoregulation.

Short-sequence tandem and nontandem DNA repeats and endogenous hydrogen peroxide production contribute to genetic instability of Streptococcus pneumoniae.

Loss-of-function mutations in the following seven pneumococcal genes were detected and analyzed: pspA, spxB, xba, licD2, lytA, nanA, and atpC. Factors associated with these mutations included (i) frameshifts caused by reversible gain and loss of single bases within homopolymeric repeats as short as 6 bases, (ii) deletions caused by recombinational events between nontandem direct repeats as short as 8 bases, and (iii) substitutions of guanine residues caused at an increased frequency by the high levels of hydrogen peroxide (>2 mM) typically generated by this species under aerobic growth conditions. The latter accounted for a frequency as high as 2.8 x 10(-6) for spontaneous mutation to resistance to optochin and was 10- to 200-fold lower in the absence of detectable levels of H2O2. Some of these mutations appear to have been selected for in vivo during pneumococcal infection, perhaps as a consequence of immune pressure or oxidative stress.