Trends in Pediatric Attention-Deficit Hyperactive Disorder Diagnoses and Prescription Utilization: 2016 to 2019.

OBJECTIVE: Attention-deficit hyperactive disorder (ADHD) is one of the most common psychiatric disorders among children, with estimated prevalence of 7% to 15% worldwide. The aim of this analysis was to update and summarize trends in diagnosis, demographics, and drug utilization of pediatric patients with ADHD. METHODS: We used the Agency for Health care Research and Quality Medical Expenditure Panel Survey (MEPS), a survey of US individuals, families, their medical providers, and employers, using datasets from 2016 to 2019. The data sources from the MEPS database included the full-year consolidated files, medical conditions files, prescribed-medicines files, and condition-event link files for each year. We summarized trends in the proportion of children, ages 17 years and younger, with a diagnosis of ADHD, demographic information and a prescription for medication known to treat ADHD. In addition, we further stratified ADHD medication use by stimulant/nonstimulant categories. RESULTS: There was a 1.6% and 4.7% absolute increase in children with an ADHD diagnosis and those prescribed ADHD medications, respectively, from 2016 to 2019. Most of these children were male, non-Hispanic, and on public insurance. Of the children prescribed an ADHD medication and concomitant behavioral medications, stimulants-only use was the highest (60%-67%), followed by stimulants/nonstimulants (13%-15%), stimulant/antidepressants (6%-9%), and nonstimulants only (5%-9%). The proportion of patients with ADHD in the high-income and near-poor categories increased by 4% from 2016 to 2019. CONCLUSION: Diagnosis of ADHD among children is trending upward in the United States. Central nervous system stimulants, especially methylphenidate formulations, are the most prescribed ADHD medications for children 17 years and younger.

GLP-1 Receptor Agonist Discontinuation Among Patients With Obesity and/or Type 2 Diabetes.

This cohort study examines the prevalence of and factors associated with glucagon-like peptide 1 agonist discontinuation among new users.

Early Mortality After the First Dose of COVID-19 Vaccination: A Target Trial Emulation.

BACKGROUND: Vaccine hesitancy persists alongside concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines. We aimed to examine the effect of COVID-19 vaccination on risk of death among US veterans. METHODS: We conducted a target trial emulation to estimate and compare risk of death up to 60 days under two COVID-19 vaccination strategies: vaccination within 7 days of enrollment versus no vaccination through follow-up. The study cohort included individuals aged ≥18 years enrolled in the Veterans Health Administration system and eligible to receive a COVID-19 vaccination according to guideline recommendations from 1 March 2021 through 1 July 2021. The outcomes of interest included deaths from any cause and excluding a COVID-19 diagnosis. Observations were cloned to both treatment strategies, censored, and weighted to estimate per-protocol effects. RESULTS: We included 3 158 507 veterans. Under the vaccination strategy, 364 993 received vaccine within 7 days. At 60 days, there were 156 deaths per 100 000 veterans under the vaccination strategy versus 185 deaths under the no vaccination strategy, corresponding to an absolute risk difference of -25.9 (95% confidence limit [CL], -59.5 to 2.7) and relative risk of 0.86 (95% CL, .7 to 1.0). When those with a COVID-19 infection in the first 60 days were censored, the absolute risk difference was -20.6 (95% CL, -53.4 to 16.0) with a relative risk of 0.88 (95% CL, .7 to 1.1). CONCLUSIONS: Vaccination against COVID-19 was associated with a lower but not statistically significantly different risk of death in the first 60 days. These results agree with prior scientific knowledge suggesting vaccination is safe with the potential for substantial health benefits.

Disease-Modifying Medications in Patients with Rheumatoid Arthritis in the USA: Trends from 2016 to 2021.

BACKGROUND: Disease-modifying anti-rheumatic drugs (DMARDs), since their introduction in 1990, have revolutionized the management of rheumatoid arthritis. Newer DMARDs have recently been approved, influencing treatment patterns and clinical guidelines. OBJECTIVE: To update the current prescribing patterns of DMARDs in the pharmacotherapy of rheumatoid arthritis (RA) to include the pandemic era. METHODS: This was a retrospective cross-sectional multi-year study. Using Optum's Clinformatics® Data Mart Database, we summarized trends in the prevalence of DMARD use in the USA from 2016 to 2021 by year for adult patients ≥ 18 years old with at least one medical RA claim and one pharmacy/medical claim of a DMARD medication. Trends included type of DMARD, class of DMARD (conventional (csDMARDs), biologics [tumor necrosis factor (TNFi) and Non-TNFi), and Janus kinase inhibitors (JAKs)], and triple therapy [methotrexate (MTX), hydroxychloroquine (HCQ), sulfasalazine (SUL)] used. RESULTS: The total sample from 2016 to 2021 was 670,679 commercially insured patients. The average age was 63.7 years (SD 13.6), and 76.7% were female and 70% were White. csDMARDs remain the most prescribed (ranging from 77.2 to 79.2%). Although JAKs were the least prescribed DMARD class, their proportion more than doubled from 2016 (1.5%) to 2021 (4%). MTX utilization declined from 40% in 2016 to 34% in 2021. In contrast, HCQ use increased during the pandemic era from < 25% in 2018 to 30% in 2021. Although there is evidence of the therapeutic benefit of triple therapy, its use was very low (~ 1%) compared to biologics only (~ 17%) or biologics+MTX (~ 10%). CONCLUSION: About half of patients with RA were on DMARDs. As expected, csDMARDs were highly used consistently. The COVID-19 pandemic might have influenced the use of HCQ and infusion DMARDs. Triple therapy use remains low.

AAV-Mediated Delivery of Plakophilin-2a Arrests Progression of Arrhythmogenic Right Ventricular Cardiomyopathy in Murine Hearts: Preclinical Evidence Supporting Gene Therapy in Humans.

BACKGROUND: Pathogenic variants in PKP2 (plakophilin-2) cause arrhythmogenic right ventricular cardiomyopathy, a disease characterized by life-threatening arrhythmias and progressive cardiomyopathy leading to heart failure. No effective medical therapy is available to prevent or arrest the disease. We tested the hypothesis that adeno-associated virus vector-mediated delivery of the human PKP2 gene to an adult mammalian heart deficient in PKP2 can arrest disease progression and significantly prolong survival. METHODS: Experiments were performed using a PKP2-cKO (cardiac-specific, tamoxifen-activated PKP2 knockout murine model). The potential therapeutic, adeno-associated virus vector of serotype rh.74 (AAVrh.74)-PKP2a (PKP2 variant A; RP-A601) is a recombinant AAVrh.74 gene therapy viral vector encoding the human PKP2 variant A. AAVrh.74-PKP2a was delivered to adult mice by a single tail vein injection either before or after tamoxifen-activated PKP2-cKO. PKP2 expression was confirmed by molecular and histopathologic analyses. Cardiac function and disease progression were monitored by survival analyses, echocardiography, and electrocardiography. RESULTS: Consistent with prior findings, loss of PKP2 expression caused 100% mortality within 50 days after tamoxifen injection. In contrast, AAVrh.74-PKP2a-mediated PKP2a expression resulted in 100% survival for >5 months (at study termination). Echocardiographic analysis revealed that AAVrh.74-PKP2a prevented right ventricle dilation, arrested left ventricle functional decline, and mitigated arrhythmia burden. Molecular and histological analyses showed AAVrh.74-PKP2a-mediated transgene mRNA and protein expression and appropriate PKP2 localization at the cardiomyocyte intercalated disc. Importantly, the therapeutic benefit was shown in mice receiving AAVrh.74-PKP2a after disease onset. CONCLUSIONS: These preclinical data demonstrate the potential for AAVrh.74-PKP2a (RP-A601) as a therapeutic for PKP2-related arrhythmogenic right ventricular cardiomyopathy in both early and more advanced stages of the disease.

Ability change across multiple domains in mucopolysaccharidosis (Sanfilippo syndrome) type IIIA.

The objective of this paper is 1) to expand the scope of the domains previously published in a natural history study of Mucopolysaccharidosis IIIA (Sanfilippo syndrome type A) (MPS IIIA) and 2) to present evidence regarding the capacity of a new metric, Growth Scale Values (GSVs), in comparison with traditional metrics, to show changes in skills as assessed by the Bayley Scales of Infant Development -III (BSID-III) and the Vineland Adaptive Behavior Scales, Second Edition (VABS-II). We re-analyzed a cohort of 25 children, 20 with rapid progressing disease and 5 with slow progression, who had been followed over two years using the BSID-III, and the VABS-II. Previously findings were reported using age equivalent scores; now we are also presenting findings with GSVs. For the re-analysis, Language and Motor scores were added to the Cognitive scale on the BSID-III, and Domain- and Subdomain-level scores added to the Total VABS-II score (i.e., ABC Composite). We evaluated raw scores, age equivalent scores, and GSVs (and standard scores for the VABS-II only). Individual patient data can be found in the appendices to this publication. Results indicate that 1) Cognition as measured by GSVs was the most sensitive to decline; 2) GSVs showed significant decline in the range of 4 to 6 years of age; 3) For children under 4 years of age, positive growth occurs on most scales and most metrics, with the exception of language which slows somewhat earlier; 4) Other than the Cognitive scale, Receptive Language on the BSID-III and Receptive Communication on the VABS-II showed the most sensitivity to change; 5) Gross Motor skills showed the least decline over time and appeared to lack sensitivity to MPS IIIA motor concerns; and 6) No evidence for sensitivity to change for any metric was found in time intervals less than one year. We conclude that GSVs are a precise measurement of change to detect decline in function, and they are a valuable method for future clinical trials in MPS IIIA. Evidence continues to support cognition as a primary endpoint. Additional work is needed to identify sensitive measures of meaningful endpoints to families.

Quantitative brain morphometry identifies cerebellar, cortical, and subcortical gray and white matter atrophy in late-onset Tay-Sachs disease.

Cerebellar atrophy is a characteristic sign of late-onset Tay-Sachs disease (LOTS). Other structural neuroimaging abnormalities are inconsistently reported. Our study aimed to perform a detailed whole-brain analysis and quantitatively characterize morphometric changes in LOTS patients. Fourteen patients (8 M/6F) with LOTS from three centers were included in this retrospective study. For morphometric brain analyses, we used deformation-based morphometry, voxel-based morphometry, surface-based morphometry, and spatially unbiased cerebellar atlas template. The quantitative whole-brain morphometric analysis confirmed the finding of profound pontocerebellar atrophy with most affected cerebellar lobules V and VI in LOTS patients. Additionally, the atrophy of structures mainly involved in motor control, including bilateral ventral and lateral thalamic nuclei, primary motor and sensory cortex, supplementary motor area, and white matter regions containing corticospinal tract, was present. The atrophy of the right amygdala, hippocampus, and regions of occipital, parietal and temporal white matter was also observed in LOTS patients in contrast with controls (p < 0.05, FWE corrected). Patients with dysarthria and those initially presenting with ataxia had more severe cerebellar atrophy. Our results show predominant impairment of cerebellar regions responsible for speech and hand motor function in LOTS patients. Widespread morphological changes of motor cortical and subcortical regions and tracts in white matter indicate abnormalities in central motor circuits likely coresponsible for impaired speech and motor function.

Assessing the impact of a financial incentive and refill reminder program on medication adherence and costs.

BACKGROUND: Improving medication adherence remains an important goal to improve therapeutic outcomes and lower health care costs. Point-of-sale prescription costs and forgetfulness remain top reasons why patients do not adhere to medications. Programs using both text message-based reminders and financial incentives may encourage patients to refill their prescriptions on time by reducing copays through discounts at the point of sale. Sempre Health, the subject of our analysis, provides both text message refill reminders and a dynamic discount incentive program to improve medication adherence. OBJECTIVE: To evaluate the impact of a financial incentive/refill reminder program on medication adherence and total cost of care for patients taking the antithrombotic agents ticagrelor, apixaban, or rivaroxaban in a large regional health plan. METHODS: After propensity-score matching on demographics, socioeconomic status, baseline copay, prior pharmacy/medical spend, and morbidity, we compared-using a difference-in-differences analytic approach-adherence (measured by proportion of days covered), unplanned health care utilization, and costs (total cost of care, medical, and pharmacy cost) of health plan members who did and did not enroll in the financial incentive/refill reminder program between February 1, 2019, and October 31, 2021, over 1 and 2 years. Because of differences in patient characteristics, we analyzed patients on ticagrelor (the antiplatelet group), apixaban, and rivaroxaban (the anticoagulant group) separately. RESULTS: There were a total of 1,292 one-to-one program and control propensity-matched patients: 166 each for the antiplatelet group and 480 each for the anticoagulant group. The average age of the anticoagulant group was 62 years; more than 60% were male, and approximately 45% had no prior unplanned care events. In contrast, the average age of the antiplatelet group was 57 years; more than 70% were male, and approximately 21% had no prior unplanned care events. In the antiplatelet group, the proportions adherent (proportion of days covered ≥80%) were 63.3% vs 42.8% (P = 0.0002) for program vs controls. Similarly, in the anticoagulant group, the proportion adherent was 77.9% vs 60.2% (P < 0.0001) for program vs controls. Reflecting improved adherence, costs of apixaban and rivaroxaban increased by $79 per member per month (PMPM) (P < 0.0001), with no statistically significant differences in other costs. Similarly, the cost of ticagrelor increased by $77 PMPM (P = 0.0102) with no statistically significant differences in other costs. Finally, there was a 16% (P = 0.032) reduction in emergency department use for those in the program. CONCLUSIONS: The financial incentive and refill reminder program was associated with improved adherence to antithrombotic medications, reduced emergency department use, and increased medication costs, but not in total pharmacy, medical, or total cost of care in both subgroups.

Ticagrelor versus clopidogrel for recurrent myocardial infarction: An outcomes-based agreement.

Background: Outcomes-based agreements (OBA) are performance-based risk-sharing agreements between manufacturers and payers which provide the opportunity for collection and evaluation of real-world outcomes to supplement clinical trials. Objectives: To describe an OBA comparing ticagrelor to clopidogrel in patients admitted with acute coronary syndrome (ACS) and proportion of recurrent myocardial infarction (MI) in a real-world setting. Methods: Commercial (CM) and Medicare (MC) insurance patients of a large regional health plan, who presented with ACS and were prescribed either ticagrelor or clopidogrel were prospectively analyzed. The cohort consisted of adults (18-85 years) discharged between January 1, 2019, and December 31, 2020, who were adherent to the study medications, within the confines of the OBA. The primary outcome of interest was the proportion of recurrent MI hospitalizations within one year of discharge. Results: There were 500 patients who met inclusion criteria in the ticagrelor cohort and 648 in the clopidogrel cohort. The mean age of patients in the ticagrelor cohort was 61.5 ± 10.5 years old and 66.5 ± 10.2 years in the clopidogrel cohort. The proportion of patients with type 2 diabetes, hypertension, or a history of congestive heart failure at baseline in the ticagrelor cohort was 31%, 85%, 14% respectively, and 43%, 90%, and 32% respectively in the clopidogrel cohort. The overall proportion of hospitalization for recurrent MI was 1.00% in the ticagrelor and 3.13% in the clopidogrel cohorts. In the follow-up propensity-matched analysis, although recurrent MI hospitalization was higher in the clopidogrel cohort (1.69% vs 1.21%) it was not statistically significant (p-value 0.5242). Conclusion: Patients presenting with ACS and treated with ticagrelor had a lower rate of hospitalization for recurrent MI compared to patients treated with clopidogrel cohort within the confines of an OBA in a real-world setting.

Association of PCSK9 Inhibitor Initiation on Statin Adherence and Discontinuation.

Background PCSK9is (proprotein convertase subtilisin/kexin type 9 inhibitors) are well tolerated, potently lower cholesterol, and decrease cardiovascular events when added to statins. However, statin adherence may decrease after PCSK9i initiation and alter clinical outcomes. We evaluate the association of PCSK9i initiation on statin discontinuation and adherence. Methods and Results In this retrospective pre-post difference-in-difference analysis, new PCSK9i claims were propensity matched with statin-alone users (April 2017-September 2019). The primary outcomes were statin adherence (proportion of days covered) and statin discontinuation (absence of statin coverage for at least 60 days) 12 months following PCSK9i initiation. Secondary outcomes included low-density lipoprotein cholesterol levels after 1 year. A total of 220 538 statin users and 700 PCSK9i users were identified, from which 178 on PCSK9i were included and matched to 712 on statins alone. At 12 months, mean statin proportion of days covered decreased from 67% to 48% in the PCSK9i group but increased from 68% to 86% in the statin-alone groups (P<0.0001). Statin discontinuation rates increased from 11% to 39% in the PCSK9i group and from 7% to 9% in the statin-alone group (P=0.0041). Patients with low-density lipoprotein cholesterol <70 mg/dL increased from 5% to 68% with PCSK9i but increased from 16% to 24% with statins alone (P<0.0001). Changes in hospitalization rates were similar between both groups during the follow-up period. Conclusions PCSK9i initiation was associated with decreased low-density lipoprotein cholesterol, higher statin discontinuation, and reduced statin adherence.

Mapping brain networks in MPS I mice and their restoration following gene therapy.

Mucopolysaccharidosis type I (MPS I) is an inherited lysosomal disorder that causes syndromes characterized by physiological dysfunction in many organs and tissues. Despite the recognizable morphological and behavioral deficits associated with MPS I, neither the underlying alterations in functional neural connectivity nor its restoration following gene therapy have been shown. By employing high-resolution resting-state fMRI (rs-fMRI), we found significant reductions in functional neural connectivity in the limbic areas of the brain that play key roles in learning and memory in MPS I mice, and that adeno-associated virus (AAV)-mediated gene therapy can reestablish most brain connectivity. Using logistic regression in MPS I and treated animals, we identified functional networks with the most alterations. The rs-fMRI and statistical methods should be translatable into clinical evaluation of humans with neurological disorders.

Association Between Weight Reduction and Employees' Healthcare Cost.

OBJECTIVE: The aim of the study is to assess the impact of ≥15% body mass index (BMI) reduction on employees' health expenditures. METHODS: We retrospectively analyzed health risk assessment surveys combined with insurance claims from January 2014 to December 2019. We compared costs of employees with baseline BMI > 30 who reported ≥15% BMI reduction in subsequent health risk assessment reports with employees who lost ≤5% BMI within the same period, matching the two cohorts on demographics and costs. RESULTS: The study cohort of 197 lost an average of 23% of their BMI from baseline. The average age was 44 years with majority females (approximately 80%). Group health insurance payments were similar at baseline; at year 1, the study cohort had a 33% payment reduction compared with 10% reduction in the control group. CONCLUSIONS: A ≥15% BMI reduction was associated with a substantial medical cost savings.

Disparities in late and lost: Pediatricians' role in following Pompe disease identified by newborn screening.

BACKGROUND AND OBJECTIVES: Pompe disease (PD) results from a deficiency of lysosomal acid α-glucosidase that leads to glycogen accumulation in lysosomes in multiple tissues. There are two phenotypes: infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD). The objective was to evaluate the diagnostic and follow-up outcomes of children identified with PD through newborn screening (NBS) in the state of Minnesota over a 4-year period. METHODS: This study is a retrospective analysis of infants born in Minnesota between August 1, 2017, and July 31, 2021, by the Minnesota Department of Health NBS Program for Pompe disease. Newborn screening and clinical diagnostic data are summarized for all newborns with positive newborn screens for Pompe disease. RESULTS: Children with IOPD had abnormal biomarkers necessitating immediate initiation of treatment. Children with LOPD are asymptomatic to date (1.25-4.58 years) with normal biomarkers including creatine kinase, urine glucotetrasaccharides, liver function tests, and echocardiogram. The estimated birth prevalence of PD is 1:15,160. The positive predictive value for PD was 81% with a false positive rate of 1.9 per 10 positive screens. 32% of the children with LOPD were lost to follow up among which 66% were from minority ethnic groups. CONCLUSION: This emphasizes the disparity in access to health care among specific demographics, as well as the importance of a primary care provider's early involvement in educating these families. To accomplish this, and ensure equality in follow-up care, the Minnesota Pompe Disease Consortium has been formed.

Denitrification potential of surface soils of constructed wetlands in Newtown Creek, an urban superfund site.

Denitrification, the anaerobic microbial conversion of nitrate (NO3 - ), a common water pollutant, to nitrogen (N) gases, is often high in the soil of natural wetlands. In areas where natural wetlands have been degraded or destroyed, constructed and restored wetlands have been used to restore ecosystem services like denitrification. Thus, denitrification in restored and constructed wetlands could play an important role in treating anthropogenic N sources such as combined sewer overflow discharges which can be high in NO3 - . In this study, we measured denitrification potential using an anaerobic slurry assay and made a suite of ancillary measurements (soil moisture content, microbial biomass carbon [C] and N content, potential net N mineralization and nitrification, soil inorganic N pools, and soil respiration) in four constructed salt marsh wetlands, and a series of wetland habitat basins in Newtown Creek, NY, an urban superfund site. Samples were also taken from natural salt marshes located at Paerdegat Basin, Jamaica Bay, NY. Our results show that constructed Spartina alterniflora marshes in ultra-urban Newtown Creek support denitrification potential equivalent to rates of natural marshes in Jamaica Bay and reference marshes in other urban estuaries. There were significant positive correlations between microbial biomass C and N content and organic matter content and denitrification potential. Results suggest that constructed wetlands can support wetland vegetation, soils, and microbial life and contribute to N removal under ultra-urban conditions.

Comparison of hospitalization costs for the same adverse reaction associated with different medications.

PURPOSE: Costs of hospitalization due to severe adverse drug reactions (ADRs) were previously estimated within the Veterans Health Administration (VHA), but additional analyses are needed to infer potential interventions to mitigate these negative outcomes. The objective of this study was to compare specific adverse reaction-related hospitalization costs between medications with similar indications. METHODS: Mean hospitalization costs associated with the same ADR symptom were compared for different drugs with similar indications using adjusted generalized linear models with a Bonferroni correction for multiple comparisons as well as a gamma distribution. RESULTS: Overall, hospitalization costs between medications with similar indications were not significantly different for specific adverse reactions. However, gastrointestinal hemorrhage-associated costs were higher for warfarin versus nonsteroidal anti-inflammatory drugs (model estimate of mean cost, $18,114 [range of lower and upper model estimates, $12,522-$26,202] vs $14,255 [estimate range, $9,710-$20,929]). Similarly, the estimated mean hospitalization cost associated with angioedema was higher for losartan versus lisinopril or lisinopril/hydrochlorothiazide: $14,591 (range, $9467-$22,488) versus $8,935 (range, $6,301-$12,669) and $8,022 (range, $5,424-$11,865), respectively. CONCLUSION: Although we found few differences in the cost of hospitalization when comparing drugs with similar indications and the same adverse reaction, there were specific drug-ADR pairs that merit attention and consideration of interventions to improve safe and appropriate medication use. Evaluation of the effect of those interventions on the incidence of ADRs is an area for future study.

Association of the Chantix Recall With US Prescribing of Varenicline and Other Medications for Nicotine Dependence.

This cross-sectional study evaluates the association between the 2021 varenicline tartrate recall and prescribing of varenicline and other medications for nicotine dependence in a large US national patient cohort.

Persistent bone and joint disease despite current treatments for mucopolysaccharidosis types I, II, and VI: Data from a 10-year prospective study.

The mucopolysaccharidosis (MPS) disorders have many potential new therapies on the horizon. Thus, historic control data on disease progression and variability are urgently needed. We conducted a 10-year prospective observational study of 55 children with MPS IH (N = 23), MPS IA (N = 10), non-neuronopathic MPS II (N = 13), and MPS VI (N = 9) to systematically evaluate bone and joint disease. Annual measurements included height, weight, and goniometry. Mixed effects modeling was used to evaluate changes over time. All participants had been treated with hematopoietic cell transplantation and/or enzyme replacement therapy. Height z-score decreased over time in MPS IH, MPS II, and MPS VI, but not MPS IA. Adult heights were 136 ± 10 cm in MPS IH, 161 ± 11 cm in MPS IA, 161 ± 14 cm in MPS II, and 128 ± 15 cm in MPS VI. Adult average BMI percentiles were high: 75 ± 30%ile in MPS IH, 71 ± 37%ile in MPS IA, 71 ± 25%ile in MPS II, and 60 ± 42%ile in MPS VI. Every participant had joint contractures of the shoulders, elbows, hips, and/or knees. Joint contractures remained stable over time. In conclusion, despite current treatments for MPS I, II, and VI, short stature and joint contractures persist. The elevation in average BMI may be related, in part, to physical inactivity due to the ongoing bone and joint disease. Data from this longitudinal historical control study may be used to expedite testing of experimental bone and joint directed therapies and to highlight the need for weight management as part of routine clinical care for patients with MPS.