Search

Background Cyclophosphamide (CYC) has known cytotoxic effects on ovarian reserve and has been linked to premature ovarian failure (POF) in systemic lupus erythematosus (SLE). The concurrent use of gonadotropin-releasing hormone agonists (GnRHas) is postulated to preserve ovarian function by reducing the number of follicles exposed to CYC, but there is paucity of data to establish its efficacy. We conducted a meta-analysis to summarize the effect of concurrent GnRHa use in persevering ovarian function and pregnancy. Methods English language databases of PubMed, Embase, and Cochrane were searched to include studies published between 2000 and 2021. Studies in females with rheumatic diseases receiving concurrent GnRHa and CYC therapy to evaluate ovarian preservation as defined by amenorrhea, follicle stimulating hormone (FSH), anti-mullerian hormone (AMH), or estradiol levels or successful pregnancy were included. We used a fixed effect, exact, Mantel-Haenszel approach to estimate the overall odds ratio (OR) and associated 95% confidence intervals (95% CIs). Results Seven studies with 218 female patients were included. The ovarian function was preserved in 125/132 (94.6%) of women who received GnRHa concurrently with CYC compared to 50/86 (58%) of women who did not receive GnRHa (OR = 10.3, CI = 4.83–36.29). The OR for pregnancy with GnRHa use = 2.94 (CI = 1.04–9.89). Conclusion Our results based on limited published studies suggest that concurrent GnRHa use preserves ovarian function and increase odds of pregnancy. It can be considered for premenopausal SLE females receiving CYC. Long-term follow-up studies are needed to establish the efficacy and safety of GnRHa use for ovarian preservation.

Cancer immunotherapy has significantly improved patient survival. Yet, half of patients do not respond to immunotherapy. Gut microbiomes have been linked to clinical responsiveness of melanoma patients on immunotherapies; however, different taxa have been associated with response status with implicated taxa inconsistent between studies. We used a tumor-agnostic approach to find common gut microbiome features of response among immunotherapy patients with different advanced stage cancers. A combined meta-analysis of 16S rRNA gene sequencing data from our mixed tumor cohort and three published immunotherapy gut microbiome datasets from different melanoma patient cohorts found certain gut bacterial taxa correlated with immunotherapy response status regardless of tumor type. Using multivariate

Children in the United States sleep less than the recommended amount and sleep deficiencies may be worse among disadvantaged children. Prior studies that compared sleep time in children of different race/ethnic groups mostly relied on questionnaires or were limited to small sample sizes. Our study takes advantage of the Adolescent Brain Cognitive Development study to compare total sleep time using a week of actigraphy data among American children (n = 4,207, 9 to 13 y old) of different racial/ethnic and income groups. We also assessed the effects of neighborhood deprivation, experience of discrimination, parent’s age at child’s birth, body mass index (BMI), and time the child fell asleep on sleep times. Daily total sleep time for the sample was 7.45 h and race/ethnicity, income, sex, age, BMI, were all significant predictors of total sleep time. Black children slept less than White children (∼34 min; Cohen’s d = 0.95), children from lower income families slept less than those from higher incomes (∼16 min; Cohen’s d = 0.44), boys slept less than girls (∼7 min; Cohen’s d = 0.18), and older children slept less than younger ones (∼32 min; Cohen’s d = 0.91); mostly due to later sleep times. Children with higher BMI also had shorter sleep times. Neither area deprivation index, experience of discrimination, or parent’s age at child’s birth significantly contributed to sleep time. Our findings indicate that children in the United States sleep significantly less than the recommended amount for healthy development and identifies significant racial and income disparities. Interventions to improve sleep hygiene in children will help improve health and ameliorate racial disparities in health outcomes.

PURPOSE Automatic muscle segmentation is critical for advancing our understanding of human physiology, biomechanics, and musculoskeletal pathologies, as it allows for timely exploration of large multi-dimensional image sets. Segmentation models are rarely developed/validated for the pediatric model. As such, autosegmentation is not available to explore how muscle architectural changes during development and how disease/pathology affects the developing musculoskeletal system. Thus, we aimed to develop and validate an end-to-end, fully automated, deep learning model for accurate segmentation of the rectus femoris and vastus lateral, medialis, and intermedialis using a pediatric database. METHODS We developed a two-stage cascaded deep learning model in a coarse-to-fine manner. In the first stage, the U2 -Net roughly detects the muscle subcompartment region. Then, in the second stage, the shape-aware 3D semantic segmentation method SASSNet refines the cropped target regions to generate the more finer and accurate segmentation masks. We utilized multifeature image maps in both stages to stabilize performance and validated their use with an ablation study. The second-stage SASSNet was independently run and evaluated with three different cropped region resolutions: the original image resolution, and images downsampled 2× and 4× (high, mid, and low). The relationship between image resolution and segmentation accuracy was explored. In addition, the patella was included as a comparator to past work. We evaluated segmentation accuracy using leave-one-out testing on a database of 3D MR images (0.43 × 0.43 × 2 mm) from 40 pediatric participants (age 15.3 ± 1.9 years, 55.8 ± 11.8 kg, 164.2 ± 7.9 cm, 38F/2 M). RESULTS The mid-resolution second stage produced the best results for the vastus medialis, rectus femoris, and patella (Dice similarity coefficient = 95.0%, 95.1%, 93.7%), whereas the low-resolution second stage produced the best results for the vastus lateralis and vastus intermedialis (DSC = 94.5% and 93.7%). In comparing the low- to mid-resolution cases, the vasti intermedialis, vastus medialis, rectus femoris, and patella produced significant differences (p = 0.0015, p = 0.0101, p

To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. Data from a clinically diverse PA patient population ( https://clinicaltrials.gov/ct2/show/NCT02890342 ) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k-Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. Forty participants enrolled in the study; five underwent liver transplant. Analysis with k-means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1-13C-propionate oxidation, play roles in defining PA subtypes. Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA.

Research conducted during the COVID-19 Pandemic has identified two co-occurring public health concerns: loneliness and substance use. Findings from research conducted prior to the pandemic are inconclusive as to the links between loneliness and substance use. This study aimed to measure associations of loneliness with three different types of substance use during COVID-19: daily number of alcoholic drinks, cannabis use, and non-cannabis drug use.Data were obtained between October 2020 and May 2021 from 2,648 US adults (MThe unconditional means model indicated that 59.0% of the variance in the daily number of alcoholic drinks was due to within-person variability. GLMLM analyses revealed that, overall, people drank more on days when they felt a particularly high or particularly low degree of loneliness (positive quadratic effect). There was a negative and significant within-person association between daily loneliness and the likelihood of cannabis use. There was also a positive and significant within-person association between daily loneliness and the likelihood of non-cannabis drug use.Associations between loneliness and substance use vary with substance type and whether within- or between-person differences are assessed. These findings are relevant to the persistence of substance use disorders and thus of potential clinical importance. Individuals who do not experience severe loneliness at intake but who show daily increases in loneliness above baseline levels are at heightened risk of alcohol and non-cannabis drug use. Future research could profitably examine just-in-time adaptive interventions that assess fluctuations in loneliness to prevent the development or exacerbation of substance use disorders.

Growing evidence indicates fractal analysis (FA) has potential as a computational tool to assess tumor microvasculature in glioblastoma (GBM). As fractal parameters of microvasculature have shown to be reliable quantitative biomarkers in brain tumors, there has been similar success in measuring the architecture of tumor tissue using FA in other tumor types. However, evaluating fractal parameters of tissue structure in relation to the microvasculature has not yet been implemented in GBM. We aimed to assess the utility of this methodology in quantifying structural characteristics of GBM cytoarchitecture and vascularity by correlating fractal parameters with gene expression.Formalin-fixed paraffin-embedded specimens were retrospectively collected from 43 patients following resection of a newly diagnosed GBM; 4 normal brain specimens were obtained from epilepsy surgeries as controls. Tumor samples were processed using FA employing a software-based box-counting method algorithm and custom messenger RNA expression assays. Fractal parameters were then correlated with clinical features, outcomes, and a panel of 92 genes associated with vascularity and angiogenesis.Statistical analysis demonstrated that fractal-based indices were not adequate parameters for distinction of GBM cytoarchitecture compared with normal brain specimens. Correlation analysis of our gene expression findings suggested that hematoxylin and eosin-based FA may have adequate sensitivity to detect associations with vascular gene expression.The combination of neuropathological assessment and histology does not provide optimized data for FA in GBM. However, an association between FA and gene expression in GBM of genes pertaining to cytoarchitecture and angiogenesis warrants further investigation.

DOCLINE®, the U.S. National Library of Medicine’s (NLM) interlibrary loan (ILL) request system, sought to better understand its role in providing information access during public health events (PHE...

PURPOSE: Automatic muscle segmentation is critical for advancing our understanding of human physiology, biomechanics, and musculoskeletal pathologies, as it allows for timely exploration of large multi-dimensional image sets. Segmentation models are rarely developed/validated for the pediatric model. As such, auto-segmentation is not available to explore how muscle architectural changes during development and how disease/pathology affects the developing musculoskeletal system. Thus, we aimed to develop and validate an end-to-end, fully automated, deep learning model for accurate segmentation of the rectus femoris and vastus lateral, medialis, and intermedialis using a pediatric database. METHODS: We developed a two-stage cascaded deep learning model in a coarse-to-fine manner. In the first stage, the U(2)-Net roughly detects the muscle sub-compartment region. Then, in the second stage, the Shape-aware 3D semantic segmentation method SASSNet refines the cropped target regions to generate the more finer and accurate segmentation masks. We utilized multi-feature image maps in both stages to stabilize performance and validated their use with an ablation study. The second stage SASSNet was independently run and evaluated with three different cropped region resolutions: the original image resolution, and images down-sampled 2x & 4x (high, mid, and low). The relationship between image resolution and segmentation accuracy was explored. In addition, the patella was included as a comparator to past work. We evaluated segmentation accuracy using leave-one-out testing on a database of 3D MR images (0.43×0.43×2mm) from 40 pediatric participants (age 15.3±1.9years, 55.8±11.8kg, 164.2±7.9cm, 38F/2M). RESULTS: The mid-resolution second stage produced the best results for the vastus medialis, rectus femoris, and patella (Dice Similarity Coefficient = 95.0%, 95.1%, 93.7%), whereas the low-resolution second stage produced the best results for the vastus lateralis and vastus intermedialis (DSC = 94.5% and 93.7%). In comparing the low- to mid-resolution cases, the vasti intermedialis, vastus medialis, rectus femoris, and patella produced significant differences (p=0.0015, p=0.0101, p

Fatigue is a persistent and debilitating symptom following radiation therapy for prostate cancer. However, it is not well-understood how radiation targeted to a small region of the body can lead to broad changes in behavior. In this study, we used targeted pelvic irradiation of healthy male mice to test whether inflammatory signaling mediates changes in voluntary physical activity levels. First, we tested the relationship between radiation dose, blood cell counts, and fatigue-like behavior measured as voluntary wheel-running activity. Next, we used oral minocycline treatments to reduce inflammation and found that minocycline reduces, but does not eliminate, the fatigue-like behavioral changes induced by radiation. We also used a strain of mice lacking the MyD88 adaptor protein and found that these mice also showed less fatigue-like behavior than the wild-type controls. Finally, using serum and brain tissue samples, we determined changes in inflammatory signaling induced by irradiation in wild-type, minocycline treated, and MyD88 knockout mice. We found that irradiation increased serum levels of IL-6, a change that was partially reversed in mice treated with minocycline or lacking MyD88. Overall, our results suggest that inflammation plays a causal role in radiation-induced fatigue and that IL-6 may be an important mediator., Highlights • Pelvic irradiation leads to fatigue-like behavior that is dose-dependent. • Radiation increases serum levels of many cytokines, including IL-6. • Minocycline treatment can reduce radiation-induced fatigue and serum IL-6. • MyD88 gene deletion can reduce radiation-induced fatigue and serum IL-6.

Aims This pilot study aimed to identify associations of loneliness and daily alcohol consumption among US adults during the Coronavirus Disease-2019 pandemic. Method Participants completed daily assessments for 30 days. Results Results suggest people who feel lonelier on average drink more alcohol, however, people who feel lonelier than usual drink less. Conclusion Findings highlight the need to disaggregate within- and between-person components of alcohol use.

Cancer-related fatigue is an extremely common and debilitating psychiatric symptom that affects up to 80% of cancer patients. Despite its negative impact on the patient’s quality of life, there is no well-established biomarker or mechanisms associated with this debilitating condition. The functional brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism (SNP) has been associated with a variety of psychiatric illnesses. We hypothesized that Val66Met may influence the risk for developing cancer-related fatigue. BDNF Val66Met was analyzed by polymerase chain reaction in 180 patients with confirmed cancer diagnoses. Fatigue was measured using the Functional Assessment of Cancer Therapy-Fatigue (FACIT-Fatigue) questionnaire. Depression was measured using the Hamilton Depression Scale (HAM-D). Data were transformed when necessary and regression models were constructed to access the association between genotype and symptom severity. Participants carrying the Met allele reported significantly less fatigue compared to the Val/Val genotype group. The presence of the Met allele did not influence depression levels. The results suggest that the BDNF Val66Met polymorphism confers protective advantage against cancer-related fatigue; whereas having the Val/Val genotype may be a genetic risk factor. Findings from this study not only provide clues to the neural basis of cancer-related fatigue, but also allow for symptom severity prediction and patient education with the goal to improve symptom management.

Much of the burden associated with schizophrenia is attributed to its early onset and chronic nature. Treatment with once monthly paliperidone palmitate (PP1M) is associated with lower healthcare utilization and better adherence as compared to oral atypical antipsychotics (OAAs). This study aimed to evaluate real-world effectiveness of PP1M and OAA therapies among US-based adult Medicaid patients with schizophrenia, overall and among young adults aged 18-35 years.Adult patients with a diagnosis of schizophrenia and at least two claims for PP1M or OAA between January 1, 2010 and December 31, 2014 were selected from the IBM Watson Health MarketScan Medicaid Database. Treatment patterns and healthcare resource utilization and costs were compared between PP1M and OAA treatment groups following inverse probability of treatment (IPT) weighting to adjust for potential differences. Utilization and cost outcomes were estimated using OLS and weighted Poisson regression models.After IPT weighting, the young adult PP1M and OAA cohorts were comprised of 3,095 and 3,155 patients, respectively. PP1M patients had a higher duration of continuous treatment exposure (168.2 vs 132.5 days, p = .004) and better adherence on the index medication (proportion of days covered ≥80%: 19.0% vs 17.1%, p .049). Young adults treated with PP1M were 37% less likely to have an all-cause inpatient admission (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.53-0.74) and 33% less likely to have an ER visit (OR = 0.67, 95% CI = 0.55-0.81) compared to OAA young adult patients, but 27% more likely to have an all-cause outpatient office visit (OR = 1.27, 95% CI = 1.02-1.56). PP1M patients incurred significantly lower medical costs as compared to OAA patients.Medicaid patients with schizophrenia treated with PP1M have higher medication adherence and have fewer hospitalizations as compared to patients treated with OAAs. PP1M may lead to reduced healthcare utilization and improved clinical outcomes.

To compare healthcare utilization and costs between patients with type 2 diabetes (T2D) treated with exenatide (Bydureon) once weekly (EQW) and patients treated with insulin glargine (IG).Using the MarketScan Commercial and Medicare Supplemental databases, we conducted a retrospective cohort study of adult US patients with claim with a diagnosis of T2D, initiating EQW or IG from February 1, 2012 to June 30, 2014 (first claim = index date). All-cause and diabetes-related utilization and costs were measured during the 12 months after the index date. EQW patients were matched 1:1 to IG patients, using propensity scores. Logistic and ordinary least-squares regression models were fit to model differences between the matched cohorts.There were 7749 EQW patients matched to 7749 IG patients. EQW patients had significantly (P .05) lower odds of all-cause inpatient (IP) admissions (odds ratio = 0.737 [95% confidence interval, 0.661, 0.822]), diabetes-related IP admissions (0.720 [95% confidence interval, 0.635, 0.815]) and diabetes-related IP admissions or emergency room visits (0.778 [95% confidence interval, 0.713, 0.847]). EQW patients had significantly (P .05) lower all-cause (cost difference = -113 USD [95% confidence interval, -120 USD, -106 USD]) and diabetes-related (-806 USD [95% confidence interval, -871 USD, -746 USD]) medical costs, and had significantly (P .05) higher all-cause total costs (ie, medical plus pharmacy) (3228 USD [95% confidence interval, 3110 USD, 3367 USD]), diabetes-related total costs (1951 USD [95% confidence interval, 1873 USD, 2036 USD]), all-cause pharmacy costs (2792 USD [95% confidence interval, 2700 USD, 2928 USD]) and diabetes-related pharmacy costs (1923 USD [95% confidence interval, 1890 USD, 1957 USD]) than those of IG patients.Among adults with T2D, EQW initiators had lower odds of IP admission and lower medical costs in the 12 months after initiation than IG initiators. Higher total costs in EQW patients were driven by greater pharmacy costs.

Aims To compare adherence (proportion of days covered [PDC]), persistence, and treatment patterns among patients with type 2 diabetes mellitus (T2DM) newly initiating glucagon-like peptide-1 receptor agonists (GLP-1RAs). More specifically, the main objectives were to compare dulaglutide vs exenatide once weekly and dulaglutide vs liraglutide. Methods Patients with T2DM newly initiating dulaglutide, albiglutide, exenatide once weekly, exenatide twice daily and liraglutide between November 2014 and April 2015 were hierarchically selected from Truven Health's MarketScan Research Databases. Propensity score matching was used to account for selection bias. Adherence to and persistence with the index GLP-1RA, and switching and augmentation patterns were assessed during the 6-month post-index period. Results Mean adherence for the matched cohorts was significantly higher for dulaglutide than for exenatide once weekly (0.72 vs 0.61; P

To assess the economic impact of urinary tract infections (UTIs) and genital mycotic infections (GMIs) among patients with type 2 diabetes mellitus (T2DM) initiated on canagliflozin.Administrative claims data from April 2013 through June 2014 MarketScanRates of UTI claims 90 days post-index were similar in patients receiving canagliflozin for T2DM (n = 31,257) and matched controls (2.7% vs 2.8%, p = .677). More canagliflozin than control patients had GMI claims (1.2% vs 0.6%, p .001) and antifungal utilization (5.3% vs 2.6%, p .001). Mean post-index costs to treat UTIs were lower but not significantly different for canagliflozin patients vs matched controls ($27.61 vs $37.33, p = .150). GMI treatment costs were higher for the canagliflozin cohort ($3.68 vs $2.44, p = .041). Combined costs to treat either UTI and/or GMI averaged $31.29 per patient for the canagliflozin cohort v $39.77 for controls (p = .211). Rates and costs of UTIs and GMIs were higher for females than males, but the canagliflozin vs control trends observed for the overall sample were similar for both sexes. There were no significant cost differences between the canagliflozin and control cohorts among patients aged 18-64. Among patients aged 65 and above, GMI treatment costs were not significantly different, but costs to treat UTIs and either UTI and/or GMI were significantly lower for canagliflozin patients vs controls.In a real-world setting, the costs to payers of treating UTIs and GMIs are generally similar for patients with T2DM initiated on canagliflozin vs other AHAs.

To identify the prevalence of comorbidities in pregnant women and examine the incremental costs of these conditions on the care for mothers and their newborns.This was a retrospective comparative cohort study of women ages 15-49 years with a documented live-birth delivery using de-identified claims from the MarketScan Research Commercial Claims and Encounters database incurred between January 1, 2007, and December 31, 2011. Total health care costs from date of first pregnancy-related claim through 3 months postdelivery were reported; pregnancy-related comorbidities prior to the pregnancy diagnosis were identified and categorized in the 12 months prior to the pregnancy diagnosis, and costs associated with each condition were compiled. A subset of newborns was matched to their mothers using a unique family identifier and their costs were captured for the three months following birth. Comparisons of costs for both mothers and newborns were made using both unadjusted and multivariate analyses between mothers with and without each condition.A total of 322,141 women with live births were identified; 135,572 of these mothers were linked to their newborn(s). Prevalent conditions included back disorders (8.9%), mental disorders (6.5%), headache (5.5%), allergic rhinitis (5.5%), and osteoarthritis (4.8%). Diabetes (0.97%) and hypertension (1.9%) were associated with the highest adjusted incremental costs of care in both mothers ($6,211 [95% confidence interval 5,720-6,702] and $3,367 [95% CI 2,935-3,799] respectively) and newborns ($2,067 [95% CI 1,515-2618]; and $1,210 [95% CI 725-1,695] respectively). The two most common conditions, back disorders and mental disorders, were associated with unadjusted costs of $1,895/$978 (mothers/infants) and $2,097/$1,902 (mothers/infants) respectively.Preexisting conditions common in pregnant women may result in additional resource utilization and costs for both mothers and newborns.

OBJECTIVE To quantify the burden associated with overactive bladder (OAB) within a commercially-insured United States (US) population. METHODS Adults with OAB identified from the MarketScan databases (2008 to 2013) were propensity score matched 1:1 to non-OAB controls. Per-patient-per-month (PPPM) direct healthcare costs, and indirect costs attributable to workplace absence and short-term disability (STD), were estimated. RESULTS Adjusted PPPM healthcare costs were higher for OAB patients than matched controls for both direct costs ($3003 vs $1123; P

Gene Colice,1 David Price,2,3 Maria Gerhardsson de Verdier,4 Karma Rabon-Stith,5 Christopher Ambrose,5 Katherine Cappell,6 Debra E Irwin,7 Paul Juneau,7 Anna Vlahiotis7 In collaboration with Respiratory Effectiveness Group (REG) 1Global Medicines Development, AstraZeneca, Gaithersburg, MD, USA; 2Observational & Pragmatic Research Institute, Singapore; 3Centre of Academic Primary Care, University of Aberdeen, Aberdeen, UK; 4Global Medical Affairs, AstraZeneca, Mölndal, Sweden; 5Global Medical Affairs, AstraZeneca, Gaithersburg, MD, USA; 6Custom Data Analytics, Life Sciences, Truven Health Analytics, an IBM Watson Health Company, Ann Arbor, MI, USA; 7Outcomes Research, Life Sciences, Truven Health Analytics, an IBM Watson Health Company, Bethesda, MD, USA Rationale: DPP-4 may regulate immunological pathways implicated in asthma. Assessing whether DPP-4 inhibitor (DPP-4i) use might affect asthma control is clinically important because DPP-4i use in type 2 diabetes mellitus management (T2DM) is increasing. This study evaluated associations between DPP-4i use and asthma control.Methods: This was a retrospective, observational, matched cohort study using administrative claims in the MarketScan® Commercial Claims and Encounters (Commercial) and Medicare Supplemental and Coordination of Benefits (Medicare Supplemental) databases. Adult asthma patients initiating an oral DPP-4i or a non-DPP-4i between November 1, 2006 and March 31, 2014 were included. Patients were followed for asthma-related outcomes for 12 months after initiation of the antidiabetes medication. Outcomes included risk-domain asthma control (RDAC), defined as no asthma hospitalizations, no lower respiratory tract infections, and no oral corticosteroid (OCS) prescriptions; overall asthma control (RDAC criteria plus limited short-acting beta agonist use); treatment stability (RDAC criteria plus no increase of ≥50% in inhaled corticosteroid dose or addition of other asthma therapy); and severe asthma exacerbation rates (asthma-related hospitalizations, emergency room visits, or acute treatments with OCS). Comparisons were made between two matched cohorts (DPP-4i vs. non-DPP-4i initiators) using multivariable logistic regression and generalized linear modeling. Covariates included baseline demographic and clinical characteristics related to asthma and T2DM.Results: The adjusted odds of achieving RDAC (odds ratio [OR]: 1.05; 95% CI: 0.964 to 1.147), overall asthma control (OR: 1.04; 95% CI: 0.956 to 1.135), and treatment stability (OR: 1.04; 95% CI: 0.949 to 1.115) did not differ between the DPP-4i and non-DPP-4i cohorts. A difference was not found between cohorts in severe asthma exacerbation rates during the 12 months following initiation of antidiabetes treatment (mean = 0.32 vs. 0.34 exacerbations per subject-year, respectively; p=0.064). Conclusion: Asthma control was similar between patients initiating DPP-4i and non-DPP-4i antidiabetes medications, suggesting no association between DPP-4i use and asthma control. Keywords: asthma control, DPP-4i, type 2 diabetes

th , 2015 ABSTRACT The choice of a model in the analysis of patient health care costs and utilization is critical for a clear understanding of the behavior and estimation of quantities like incremental costs or cost-effectiveness. In studying heath care claims related to pregnancy, it would not be surprising that a small portion of the women have costs associated with their care and treatment that might be extreme or outlying. Many strategies exist for accommodating outliers; however, is one approach superior to the others because it may be implemented over a broader set of conditions without making unreasonable assumptions about the prevailing data characteristics? In this study, the author will show an example of a data set based on the medical claims for over 300K pregnant women, aged 15-49, where the traditional, or widely used Generalized Linear Model (GLM) approach to modeling costs may be less than optimal due to the presence of patients with very large, or very small expenditure values. These values, in some sense "con- taminate" the typically employed GLM and cause it to violate its underlying requisite statistical assumptions.

Introduction While there is a substantial body of literature on the comparative healthcare costs of biologics used to treat rheumatoid arthritis (RA), nearly all of these investigations have been exclusively focused on anti-tumor necrosis factor-α (anti-TNF) agents in the setting of first-line biologic treatment. This study compared healthcare costs between RA patients treated with infused biologics after previously using at least one other biologic agent. Methods Using a large US administrative claims dataset, adult RA patients initiating an infused biologic (abatacept, infliximab, tocilizumab) between January 1, 2010 and January 1, 2012 (initiation = index) were identified. Rituximab was excluded because of unique dosing intervals, which make it difficult to determine treatment discontinuation using a claims database. Patients were required to have used one or more other biologic (infused or injected) at any time before index. Patients could contribute multiple observations to the dataset; one for each infused biologic they initiated between January 1, 2010 and January 1, 2012. A 6-month period before index was used to measure patient characteristics. A variable-length follow-up period after index was used to measure per-patient per-month (PPPM) healthcare costs, including biologic costs, RA-related healthcare costs, and all-cause healthcare costs. Generalized estimating equations models compared healthcare costs between the biologic agents, adjusting for patients’ demographics and clinical characteristics. Results The sample comprised 3,771 infused biologic initiations (abatacept = 1,759; infliximab = 922; tocilizumab = 1,090); the mean age of participants was 55 years, 82 % were female, and the median follow-up ranged from 251 to 280 days. Compared with other patients, patients treated with tocilizumab had significantly lower (all P

Study objectives were to compare the treatment patterns and clinical outcomes among metastatic breast cancer (mBC) patients by receipt of HER2-targeted agents and among subgroups of HER2-targeted agent users.Adult women newly diagnosed with mBC (index date) during 2008-2012 were selected from the Truven MarketScan databases and followed until end of enrollment or inpatient death. Patients with12 months of data, pre-index primary cancers other than breast cancer, pregnancy, or HIV/AIDS were excluded. Study cohorts were users and nonusers of HER2-targeted agents and women with no treatment; and HER2-targeted agent subgroups by receipt of hormonal therapy (HT), de novo vs. recurrent status, and age group. Pre- and post-index breast cancer treatments were compared across cohorts. Relative risk of progression and death were evaluated among the subset of patients with mortality data.Of 18,059 eligible women selected, 14.6% were users of HER2-targeted agents, 71.1% were nonusers, and 14.3% untreated. HER2-targeted agent users received more aggressive cancer treatments compared to nonusers. HER2-targeted agent users were 33% more likely to progress and had a similar risk of death compared to nonusers. Among HER2-targeted agent subgroups, the risk of progression was 30% lower among HT+ patients vs. HT-, 32% lower for de novo vs. recurrent, and similar across age groups. The risk of death was 52% lower for HT+ vs. HT-, 35% lower for de novo vs. recurrent, and increased with age.Identification of distant metastasis, tumor receptor expression and disease progression were based on claims data rather than on clinical assessment.Receipt of HER2-targeted agents (vs. non-HER2-targeted agents) was significantly associated with receipt of pre- and post-index breast cancer treatments. HER2-targeted agent users were more likely to progress but had a similar risk of death during follow-up. Among HER2-targeted agent subgroups, HT+ and de novo status were associated with a reduced risk of progression and death.

AIMS The prevalence of OAB increases with age and is associated with several chronic comorbidities. However, the impact of OAB on the healthcare costs of patients with such comorbidities is not well-understood. This study aimed to quantify the impact of OAB on healthcare costs and assess the potential moderating effects of OAB on the costs of patients with chronic comorbidities. METHODS Adults with evidence of OAB/OAB-related therapy between 1/1/2008-12/31/2013 were identified from two large, administrative claims databases. Per-patient-per-month (PPPM) expenditures for OAB cases were estimated and compared to those of propensity score-matched subjects without OAB. Costs were modeled using ordinary least squares regression including main effects and interactions of chronic depression, dementia, diabetes, hypertension, and osteoporosis with OAB. Values for the comparisons were calculated on the original dollar scale using smearing estimators. RESULTS A total of 110 059 pairs of OAB cases and matched non-OAB controls were identified. The mean, multivariable-adjusted, PPPM all-cause costs of OAB cases from the model without interactions were $3003, compared to $1123 for matched controls (P

Summary This retrospective, observational study assessed 2-year persistence and compliance by treatment, route of administration, and dosing frequency in postmenopausal women initiating a new osteoporosis therapy. Two-year persistence and compliance rates were higher in women receiving injectables compared with oral agents. Purpose This study extends previous studies limited to 1-year follow-up by examining persistence with osteoporosis therapies over a 2-year period and compares short- and long-term trends in persistence and compliance among postmenopausal women with commercial or Medicare supplemental insurance in the USA. Methods This retrospective, observational cohort study enrolled women ≥50 years newly initiating osteoporosis therapy between January 1 and December 31, 2012 (i.e., the index date), with continuous enrollment ≥14 months before and ≥24 months after their index date. Persistence (continuous therapy without a >60-day gap) and compliance with the index therapy were evaluated at 2 years of follow-up. Multivariable logistic regression was used to compare the odds of persistence and compliance across treatment and dosing regimens. Results This study included 43,543 patients with mean (standard deviation) age 65 (10) years. At 2 years of follow-up, persistence and compliance were higher for patients treated with injectable agents (ranging from 34 to 41%, excluding an every-3-month injection) than those treated with oral agents (ranging from 20 to 31%). Additionally, patients initiating oral bisphosphonates (except risedronate once daily), raloxifene (daily), or zoledronic acid (annually) had significantly lower odds of persistence compared with denosumab (every 6 months). Conclusions Patients initiating injectable therapies had greater persistence and compliance at 2 years than those initiating oral therapies. Patients initiating an every-6-month injection had significantly higher persistence compared with those initiating more frequently dosed (e.g., daily and weekly) oral or injectable agents.

**Objectives:** To evaluate the total and outpatient economic burden of aspergillosis, and to describe the outpatient antifungal treatment of aspergillosis within a large, commercially-insured population in the United States. **Methods:** Adults with at least one medical claim with an aspergillosis diagnosis (International Classification of Disease 9th Revision Clinical Modification [ICD-9-CM] code 117.3 or 484.6) between 07/01/04-03/01/11 were identified from the MarketScan Research Databases. Patients had ≥6 months of pre-index and ≥1 month of post-index continuous health plan and pharmacy benefit enrollment and no pre-index diagnosis of aspergillosis. Aspergillosis cases were propensity score-matched to a sample of controls without aspergillosis. Outpatient antifungal therapy and total and outpatient healthcare resource utilization were evaluated in the post-index period. General linear models were used to estimate costs, which were adjusted by the length of follow-up. Incremental costs were calculated between cohorts and a bootstrap procedure was used to produce corresponding variation and 95% confidence interval estimates. **Results:** Aspergillosis cases (N=5,499; mean age: 57.8 years; 48.6% female; 64.2% with cancer) were matched to 5,499 controls (mean age: 58.3 years; 48.4% female; 60.6% with cancer). Two-thirds of the aspergillosis cases had no outpatient prescription for an antifungal within 30 days of index; for those with outpatient antifungal therapy, voriconazole was the most commonly prescribed agent (60.9%). Average adjusted total and outpatient expenditures were greater for aspergillosis patients during follow-up than those of the matched controls ($26,680 and $9,248 greater, respectively). **Conclusions:** The economic burden of aspergillosis is substantial. Patients with aspergillosis utilize significantly more healthcare resources and thus incur greater healthcare costs than do similar patients without aspergillosis.

IntroductionTardive dyskinesia (TD) is an often-irreversible movement disorder that usually results from prolonged use of antipsychotics. Although the burden of TD on patients’ quality of life has been reported, there is limited evidence of its impact on the healthcare system.ObjectiveTo assess healthcare utilization and costs between TD and non-TD patients in a sample of patients from the commercially insured and Medicare Supplemental US populations.MethodsA retrospective cohort analysis was conducted using Truven MarketScan Commercial/Medicare claims data. For each patient included in the analysis, the index date was set as the first TD diagnosis between 1/1/2008 and 9/30/2014. Patients with TD were then matched to similar patients without TD to compare resource utilization andcosts. Descriptive statistics on the incidence of resource utilization and costs of healthcare were reported.ResultsA total of 1020 patients were included in this analysis. TD patients had significantly greater annual all-cause (TD: $54,656; non-TD: $28,777) and mental health-related (TD: $10,199; non-TD: $2,605) healthcare costs compared with non-TD patients (PConclusionsPatients identified as being diagnosed with TD demonstrate significantly higher healthcare utilization and costs in the 12 months after diagnosis than do similar patients without TD.Presented at: Psych Congress; September 16–19, 2017; New Orleans, Louisiana, USA.Funding AcknowledgementsThis study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.

The present study examined real-world direct health care costs for metastatic colorectal cancer (mCRC) patients initiating first-line (1L) bevacizumab (BEV)- or cetuximab (CET)-containing regimen in 1L or 1L-through-second-line (1L-2L) therapy.Using a large US insurance claims database, patients with mCRC initiating 1L BEV- or 1L CET-containing regimen from January 1, 2008 to September 30, 2014 were identified. The per-patient per-month (PPPM) all-cause health care costs (2014 US dollars) were measured during 1L therapy and, for patients continuing to a 2L biologic-containing regimen, 1L-2L therapy. Multivariable regression analyses were used to compare PPPM total health care costs between patients initiating a 1L BEV- versus 1L CET-containing regimen.A total of 6095 patients initiating a 1L BEV- and 453 initiating a 1L CET-containing regimen were evaluated for 1L costs; 2218 patients initiating a 1L BEV- and 134 initiating a 1L CET-containing regimen were evaluated for 1L-2L costs. In 1L therapy, 1L CET had adjusted PPPM costs that were $3135 (95% confidence interval [CI], $1174-$5040; P .001) greater on average than 1L BEV. In 1L-2L therapy, 1L BEV-2L CET had adjusted PPPM costs that were $1402 (95% CI, $1365-$1442; P = .010) greater than those for 1L BEV-2L BEV, and 1L CET-2L BEV had adjusted PPPM costs that were $4279 (95% CI, $4167-$4400; P = .001) greater on average than those for 1L BEV-2L BEV. The adjusted PPPM cost differences for 1L BEV-2L other biologic or 1L CET-2L other biologic agent were numerically greater but statistically insignificant.PPPM total health care costs for 1L and 2L therapy tended to be greater for patients treated with 1L CET-containing regimens than for 1L BEV-containing regimens. Also, continuing treatment with BEV-containing regimens 1L-2L was less costly than switching between BEV and CET. The cost differences between BEV and CET hold important implications for treatment decisions of mCRC patients in real-world clinical practice.

Objective: Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted a safety trial of a neutralizing antibody to myostatin, MYO-029, in adult muscular dystrophies (Becker muscular dystrophy, facioscapulohumeral dystrophy, and limb-girdle muscular dystrophy). Methods: This double-blind, placebo-controlled, multinational, randomized study included 116 subjects divided into sequential dose-escalation cohorts, each receiving MYO-029 or placebo (Cohort 1 at 1mg/kg; Cohort 2 at 3mg/kg; Cohort 3 at 10mg/kg; Cohort 4 at 30mg/kg). Safety and adverse events were assessed by reported signs and symptoms, as well as by physical examinations, laboratory results, echocardiograms, electrocardiograms, and in subjects with facioscapulohumeral dystrophy, funduscopic and audiometry examinations. Biological activity of MYO-029 was assessed through manual muscle testing, quantitative muscle testing, timed function tests, subject-reported outcomes, magnetic resonance imaging studies, dual-energy radiographic absorptiometry studies, and muscle biopsy. Results: MYO-029 had good safety and tolerability with the exception of cutaneous hypersensitivity at the 10 and 30mg/kg doses. There were no improvements noted in exploratory end points of muscle strength or function, but the study was not powered to look for efficacy. Importantly, bioactivity of MYO-029 was supported by a trend in a limited number of subjects toward increased muscle size using dual-energy radiographic absorptiometry and muscle histology. Interpretation: This trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate safety margin for clinical studies. Further evaluation of more potent myostatin inhibitors for stimulating muscle growth in muscular dystrophy should be considered. Ann Neurol 2008;63:561–571

Nicole Meyer,1 Yanni Hao,2 Pamela Landsman-Blumberg,1 William Johnson,1 Paul Juneau,3 Jaqueline Willemann Rogerio2 1Truven Health Analytics, Cambridge, MA, USA; 2Novartis Pharmaceuticals, East Hanover, NJ, USA; 3Truven Health Analytics, Washington, DC, USA Background: This retrospective administrative claims study of women diagnosed with advanced or metastatic breast cancer compared health care costs by receipt of HER2-targeted agents and by disease stage and age group among patients using HER2-targeted agents. Methods: Women aged ≥18 years and diagnosed with stage III or IV breast cancer were selected from the 2008–2012 Truven Health MarketScan® databases (Truven Health Analytics Inc., Cambridge, MA, USA) databases using ICD-9-CM (International Classification of Diseases, 9th Revision, Clinical Modification) codes for nondiagnostic medical claims corresponding to breast cancer and local or distant metastases (earliest diagnosis of stage III or stage IV metastasis was designated as the index date). The 12 months prior to the index date were defined as the pre-index period. The post-index period was variable in length, beginning on the index date and continuing through the end of enrolment, inpatient death, or December 31, 2012, whichever occurred first. Receipt of HER2-targeted agents was defined as at least one claim for trastuzumab or lapatinib in the pre-index or post-index period. The study cohorts were women using or not using HER2-targeted agents, women with stage III or IV breast cancer using HER2-targeted agents, and women using HER2-targeted agents and aged 18–44 years, 45–64 years, or 65+ years at index. Health care costs and utilization were calculated on a per patient per month basis for all-cause and breast cancer-related services by place of service. Generalized linear models were used to estimate total all-cause and breast cancer-related costs. Results: A total of 30,660 eligible women met the study selection criteria, 14.4% of whom received HER2-targeted agents. Users of HER2-targeted agents had significantly lower inpatient utilization but higher outpatient utilization than nonusers, except for emergency room visits. Adjusted total costs were higher for users of HER2-targeted agents than nonusers (US$12,919 versus $8,822, respectively). Among users of HER2-targeted agents, utilization was typically higher for stage IV patients than for stage III patients. Adjusted incremental total per patient per month costs were significantly higher for stage IV patients than for stage III patients (incremental cost $4,519; 95% confidence interval 3,855–5,183), and were highest in patients aged 18–44 years, declining with age. Conclusion: Among patients with advanced or metastatic breast cancer, receipt of HER2-targeted agents was associated with greater levels of costs and utilization. Higher costs and utilization in younger patients may indicate receipt of more aggressive treatments. Keywords: human epithelial growth factor receptor-2, resource utilization

To study the economic burden of pregnancy in the US, common complications during pregnancy, and the incremental costs attributable to these complications.A retrospective comparative cohort study was conducted of pregnant women aged 15-49 years using de-identified medical and pharmacy claims from the Truven Health MarketScan Commercial Claims and Encounters database incurred between January 1, 2007 and December 31, 2011. The total healthcare costs are reported (adjusted to 2011 dollars) from the date of the first pregnancy-related claim through to 3 months post-delivery and these costs were compared to matched controls of non-pregnant women. Pregnancy-related complications were categorized, and the incremental costs associated with each complication were estimated using multivariate analyses.A total of 322,141 eligible women with live births were studied. Compared to matched controls, the average costs of care for pregnant women were nearly $13,000 higher through 3 months post-delivery. A total of 46.9% of women had at least one pre-specified pregnancy complication; the most commonly observed were fetal abnormality (24.7%) and early or threatened labor (16.3%). Multiple gestation (1.9%) resulted in the highest adjusted incremental cost ($12,212; 95% CI = 11,298, 13,216); hypertension ($6152; 95% CI = 5312, 6992) and diabetes ($5081; 95% CI = 4244, 5918) were also among those complications that led to high incremental costs of care.Pregnancy and delivery are frequently compounded by complications that lead to increased costs and resource utilization.

The aim of this study is examine the impact of pregnancy and delivery complications on the healthcare costs of newborns during the first 3 months of life. We conducted a retrospective cohort study of newborns born to women ages 15-49 using de-identified medical and pharmacy claims from the Truven Health MarketScan Commercial Claims and Encounters database incurred between January 1, 2007 and December 31, 2011. Total healthcare costs and resource utilization were examined and compared for the first 3 months of life between cohorts of newborns either with or without evidence of categorized maternal complications. Incremental costs were also determined using multivariable analysis for the conditions found to be the most prevalent in the study population. A total of 137,040 infants were studied, 75.4% of which were born to mothers who had experienced at least one complication during pregnancy or delivery. Fetal abnormalities (26.2%), early or threatened labor (16.6%), and hemorrhage (10.8%) were the most frequently observed complications. Diabetes (8.0%) and hypertension (7.7%) were also common, with the majority of other conditions present in 1% or less of the study population. Adjusted analyses found significant differences for seven conditions where incremental costs ranged from $987 to $10,287. Complications are common during pregnancy and delivery and some complications may lead to increased healthcare costs for newborns immediately following birth.

Heat maps have been used as a means to visualize high-density information in settings as diverse as astronomy, business analysis, and meteorology. Discovery biology research teams have also used heat maps to visualize gene clusters in genomics investigations or to study amino acid distribution in protein sequence analysis. Commercially available software packages, like Spotfire® or SAS JMP® afford scientific investigators the ability to construct heat maps and visualize information from studies, yet do not offer any form of summary statistic that would be useful in high-throughput investigations comparing the results of a large number of data visualizations simultaneously or viewing changes in the display longitudinally (over time). Previously, Juneau suggested the usage of Plotnick’s characterization of lacunarity (1996) for two-dimensional heat map data displays in two colors or shades. For c (c>2) discrete shades (in a monochromatic map) or hues (in a full color display), the author will suggest a modification to Plotnick’s approach using the underlying gliding box approach developed by Allain and Cloitre , but with an alteration in the means of counting features.

Recent clinical trial data have shown that newer oral anticoagulants may reduce all-cause hospitalizations in patients with venous thromboembolism (VTE) who complete anticoagulation therapy for 6-12 months. To understand the potential cost implications of such hospitalization reductions, this study sought to quantify the real-world cost of all-cause hospitalizations over a 12-month period after acute VTE. This was a retrospective cohort study using U.S. health insurance claims data. Patients included in the study were aged ≥18 years, had experienced a non-fatal hospitalization or ED visit with a principal diagnosis of VTE between 1-Jan-2007 and 31-Mar-2013 (first visit=index) and had ≥1 claim for anticoagulation (warfarin, enoxaparin, rivaroxaban) or placement of an inferior vena cava filter ≤30 days after index. For up-to one year after discharge from the hospitalization or ED visit for acute VTE, patients were followed to identify the occurrence and costs of all-cause hospitalizations. Multivariable regressions were used to compare per-patient per-month (PPPM) total healthcare costs between patients with vs. without a hospitalization during follow-up. The final cohort included 123,665 patients (mean age 59 years, 50% male). During an overall mean follow-up of 284 days after discharge from the acute VTE event, 33,843 patients were hospitalized at least once for any cause within 1 year and 37% of these hospitalized patients had at least one hospitalization for VTE. Among patients who were hospitalized, mean (standard deviation) PPPM hospital length of stay and PPPM costs for hospitalizations were 1.4 (2.8) and $5,800 ($14,723) at 1 year. Adjusted incremental PPPM differences in total healthcare costs between patients with vs. without a hospitalization during the 1-year follow-up were $ $4,808 (P Conclusion: Hospitalizations within 1 year after acute VTE are common and costly. VTE treatments which reduce hospitalizations after acute VTE may confer substantial cost offsets.

Objective: Evaluation of healthcare resource utilization (HRU) and costs in patients with neuropathic pain (NeP) secondary to spinal cord injury (SCI) in a Medicare population. Methods: Using data from the MarketScan Medicare Database between January 1, 2006 and June 30, 2011, patients with NeP following SCI (SCI-NeP cohort) were identified based on an ICD-9-CM diagnostic code indicative of SCI, and NeP (index event) within 12 months based on ICD-9-CM code 338.0x (central neuropathic pain) or a claim for an NeP-related antiepileptic or NeP-related antidepressant drug, and propensity score-matched to SCI patients without NeP (SCI-only). Pre-index demographic and clinical characteristics were compared between the cohorts. HRU and expenditures were compared for 12 months post-index. Generalized linear models and ordinary least squares models evaluated the association between characteristics and outcomes. Results: The matched cohorts included 1,418 patients (approximately 54% male, mean age 77 years). During the 12-month follow-up period, SCI-NeP patients showed significantly greater use of evaluated medications (P < 0.01), and significantly higher HRU (P < 0.05), including 20% and 18% increased odds of hospitalization and emergency department visits, respectively. Mean (SD) total all-cause healthcare expenditures for this period adjusted for covariates showed an annual incremental economic burden of $6,808 (95% confidence interval $4,143, $9,764) per patient with NeP. Conclusions: Medicare patients with NeP secondary to SCI have significantly higher HRU and costs relative to SCI patients without NeP. Medicare patients represent a population with special needs regarding therapeutic choices that may benefit from an integrated approach to NeP management.

To evaluate health care resource use, costs, and cost drivers among patients with neuropathic pain (NeP) after spinal cord injury (SCI) in a commercially insured population.Retrospective longitudinal cohort study comparing SCI patients with and without NeP.Truven Health MarketScan commercial claims database from 2005 through 2012.Commercially insured SCI patients with NeP (n=3524) propensity score matched to SCI patients without NeP (n=3524).Not applicable.Health care resource utilization and expenditures for the 12 months after NeP onset (index event; identified through International Classification of Diseases, 9th Revision, Clinical Modification diagnosis 338.0x or use of NeP-specific antiepileptic drugs or NeP-specific antidepressants) in patients with SCI compared with matched patients without NeP.Utilization over 12 months postindex among patients with SCI-associated NeP was higher than among SCI-only patients for inpatient admissions (27.4% vs 22.1%), emergency department visits (36.7% vs 26.4%), and office visits per patient (mean ± SD: 13.0±9.5 vs 9.5±8.3); all P values were.001. All-cause expenditures showed adjusted incremental costs of $22,545 (95% confidence interval, $19,010-$26,168) per patient with SCI-associated NeP during the 12-month postindex period.Patients with evidence of NeP secondary to SCI have significantly higher health care utilization and total costs compared with SCI patients without evidence of NeP. Factors contributing to NeP in patients with SCI need to be clinically assessed to determine the optimal approach for treating these individuals.

Objective: To estimate the medical and productivity-related cost burden of systemic lupus erythematosus (SLE) flares and comorbidities in a commercially insured population. Methods: Using administrative data, annual medical costs and indirect costs because of work loss were calculated for adult SLE patients, including flare severity and SLE-related comorbidity subsets, and a matched control group without SLE. Results: Adjusted annualized medical costs were $18,952, $4305, $914, and $441 greater for SLE patients with severe, moderate, mild, and no flares, respectively, during follow-up than those of the matched controls. Medical costs also varied by SLE-related comorbidity. Adjusted annualized indirect costs of work loss because of absence and short-term disability were $1867 and $1602 greater, respectively, for SLE patients than for controls. Conclusions: SLE imposes a substantial cost burden to both patients and their employers.