A randomized, single-dose, crossover study of the effects of ulotaront on electrocardiogram intervals in subjects with schizophrenia.

This study (NCT04369391) evaluated the effects of ulotaront (SEP-363856), a novel trace amine-associated receptor 1 (TAAR1) agonist in development for schizophrenia, on electrocardiogram parameters. Study design was a randomized, single-dose, three-period crossover (ulotaront 150 mg, placebo, moxifloxacin 400 mg). Sixty subjects with schizophrenia completed all periods. Ulotaront had no clinically relevant effect on heart rate, PR interval, or QRS duration. In by-time-point analysis (secondary analysis), the upper bound of the two-sided 90% confidence interval for ΔΔQTcF (QT interval corrected for heart rate using Fridericia's formula) was below 10 ms at all time points for ulotaront. In concentration-QTc analysis (primary analysis), a linear mixed-effects model with ulotaront and its major metabolite SEP-383103 was selected as the primary model based on prespecified criteria. Effect on ∆∆QTcF exceeding 10 ms can be excluded within observed ranges of ulotaront and SEP-383103 plasma concentrations up to ~574 and ~272 ng/mL, respectively. The upper bound of 90% CI for ΔΔQTcF can be predicted to be below 10 ms at the highest anticipated clinical exposure, currently defined as steady-state mean Cmax at ulotaront 100 mg/day in CYP2D6 poor metabolizers, ~416 and ~211 ng/mL for ulotaront and SEP-383103, respectively. Assay sensitivity was demonstrated by the QTc effect caused by moxifloxacin. In conclusion, ulotaront is unlikely to cause clinically relevant QTc prolongation in patients with schizophrenia at the anticipated maximum therapeutic dose.

Serum neurofilament light levels in natalizumab-treated patients with multiple sclerosis who switch to extended interval dosing from every-4-week dosing in real-world clinical practice.

BACKGROUND: Serum levels of neurofilament light chain (sNfL) are a potentially useful biomarker for assessing the efficacy of multiple sclerosis (MS) treatments. OBJECTIVE: To compare levels of sNfL in patients with MS who switched from natalizumab every 4 weeks (Q4W) to extended interval dosing (EID) and patients who remained on Q4W dosing in real-world clinical practice. METHODS: This was a retrospective analysis of samples from patients treated with natalizumab from 2010 to 2015 at a single center in the United States. Levels of sNfL were compared in patients who stayed on Q4W dosing or who switched to EID (parallel-arm analyses) and during Q4W and EID periods in patients who switched to EID (pre- and post-switch analyses). RESULTS: The analysis included 139 patients (Q4W: n = 79; EID: n = 60). After adjustment, levels of sNfL did not significantly differ between patients who remained on Q4W dosing and those who switched to EID in parallel-arm analyses (adjusted Q4W-EID difference = 0.51 pg/mL; p = 0.60) or pre- and post-switch analyses (adjusted difference = 0.96 pg/mL; p = 0.10). CONCLUSION: These sNfL biomarker results suggest that the effectiveness of natalizumab is maintained in patients who switch from Q4W dosing to EID.

Development of a Highly Sensitive Neurofilament Light Chain Assay on an Automated Immunoassay Platform.

Background: Neurofilament light chain (NfL) is an axonal cytoskeletal protein that is released into the extracellular space following neuronal or axonal injury associated with neurological conditions such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and other diseases. NfL is detectable in the cerebrospinal fluid (CSF) and blood. Numerous studies on MS have demonstrated that NfL is correlated with disease activity, predicts disease progression, and is reduced by treatment with MS disease-modifying drugs, making NfL an attractive candidate to supplement existing clinical and imaging measures in MS. However, for NfL to achieve its potential as a clinically useful biomarker for clinical decision-making or drug development, a standardized, practical, and widely accessible assay is needed. Our objective was to develop a novel NfL assay on an automated, globally available immunoassay platform and validate its performance. Methods: A prototype NfL assay was first developed and evaluated on the ADVIA Centaur® XP immunoassay system from Siemens Healthineers. The lower limit of quantitation (LLoQ), within-lab precision, assay range, cross-reactivity with neurofilament medium and heavy chains, and effect of interfering substances were determined. NfL assay values in serum and CSF were compared with radiological and clinical disease activity measures in patients with MS and ALS, respectively. This assay was further optimized to utilize serum, plasma, and CSF sample types on the Atellica® IM system and transferred to Siemens' CLIA laboratory where it was analytically validated as a laboratory-developed test (LDT). Results: In this study, an LLoQ of 1.85 pg/mL, within-lab precision <6%, and an assay range of up to 646 pg/mL were demonstrated with the serum prototype assay. Cross-reactivity of <0.7% with the neurofilament medium and heavy chains was observed. Serum and CSF NfL assay values were associated with radiological and clinical disease activity measures in patients with MS and ALS, respectively. The optimized version of the NfL assay demonstrated specimen equivalence with additional plasma tube types and was analytically validated as an LDT. Conclusion: The analytical performance of the NfL assay fulfilled all acceptance criteria; therefore, we suggest that the assay is acceptable for use in both research and clinical practice settings to determine elevated NfL levels in patients.

Maltreatment Related Hospitalizations Among Children Ages 17 Years and Younger: New York State, 2011-2013.

BACKGROUND: Child maltreatment is an important societal and public health problem. However, there are limited data on the epidemiology of maltreatment related hospitalizations. OBJECTIVE: The objective of this study was to describe maltreatment related hospitalizations among children ages 17 and younger in New York State (NYS). METHODS: Using 2011-2013 statewide planning and research cooperative system (SPARCS) inpatient hospital discharge data, maltreatment related hospitalizations among children ages 17 years and younger were identified using international classification of diseases, ninth revision, clinical modification codes for diagnoses and external cause of injury. Distributions of demographic and inpatient care characteristics were compared between hospitalizations for maltreatment and those for other causes, and between different types of maltreatment, using chi-square tests (for categorical variables) and t-tests (for continuous variables). RESULTS: During 2011-2013, a total of 853 maltreatment related hospitalizations among 836 children ages 17 years and younger were documented in NYS SPARCS. Infants (children < 1) had the highest rates of hospitalization. Overall, physical abuse was the most prevalent maltreatment type reported. CONCLUSIONS: This is the first study in NYS to describe the epidemiology of child maltreatment hospitalizations; it establishes a statewide baseline for this public health and societal issue.

Efficacy of Nebulized Glycopyrrolate on Lung Hyperinflation in Patients with COPD.

INTRODUCTION: Lung hyperinflation in chronic obstructive pulmonary disease (COPD) is associated with activity limitation, impaired cardiac output, and mortality. Several studies have demonstrated that long-acting muscarinic antagonists (LAMAs) delivered by dry powder inhalers can promote lung deflation; however, the potential of nebulized LAMAs on improving hyperinflation in COPD is currently unknown. METHODS: This single-center, randomized, double-blind, two-way crossover study (NCT04155047) evaluated the efficacy of a single dose of nebulized LAMA [glycopyrrolate (GLY) 25 µg] versus placebo in patients with COPD and lung hyperinflation. Patients with moderate-to-severe COPD and a residual volume (RV) ≥ 130% of predicted normal were included. The primary endpoint was changed from baseline in RV at 6 h post-treatment. Other endpoints included changes from baseline in spirometric and plethysmographic measures up to 6 h post-treatment. RESULTS: A total of 22 patients (mean pre-bronchodilator RV, 153.7% of predicted normal) were included. The primary objective of the study was not met; the placebo-adjusted least squares (LS) mean [95% confidence interval (CI) change from baseline in RV with GLY at 6 h post-treatment was - 0.323 l (- 0.711 to 0.066); p = 0.0987]. A post hoc evaluation of the primary analysis was conducted after excluding a single statistical outlier; substantial improvements in RV with GLY compared with placebo was observed after exclusion of this outlier [placebo-adjusted LS mean change from baseline (95% CI) in RV was - 0.446 l (- 0.741 to - 0.150)]. Improvements from baseline were also observed with GLY compared with placebo in spirometric and plethysmographic measures up to 6 h post-treatment. GLY was generally safe, and no new safety signals were detected. CONCLUSIONS: This is the first study to evaluate the effect of nebulized GLY on lung deflation. Nebulized GLY resulted in marked improvements in RV up to 6 h post-treatment, compared with placebo. Improvements were also observed with GLY in spirometric and plethysmographic parameters of lung function. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT04155047.

Impact of natalizumab on quality of life in a real-world cohort of patients with multiple sclerosis: Results from MS PATHS.

BACKGROUND: Optimizing multiple sclerosis treatment warrants understanding of changes in physical, mental, and social health. OBJECTIVE: To assess the impact of natalizumab on Quality of Life in Neurological Disorders (Neuro-QoL) scores. METHODS: Annualized change in T-scores and likelihood of ≥5-point improvement over baseline were calculated for each Neuro-QoL domain after natalizumab initiation. Comparisons with ocrelizumab-treated patients were conducted after propensity score weighting and adjustment for relevant co-medications, year, and drug-year interaction. RESULTS: Among 164 natalizumab patients analyzed, 8 of 12 Neuro-QoL domains improved significantly, with greater improvement in patients with abnormal baseline Neuro-QoL. In the subgroup comparison of natalizumab-treated (n = 145) and ocrelizumab-treated (n = 520) patients, significant improvement occurred in 9 of 12 and 4 of 12 domains, respectively. The difference between groups was statistically significant for positive affect and well-being (p = 0.02), sleep (p = 0.003), and satisfaction with social roles and activities (SRA) (p = 0.03) in the overall population and for emotional and behavioral dyscontrol (p = 0.01), participation in SRA (p = 0.0001), and satisfaction with SRA (p = 0.02) in patients with abnormal baseline Neuro-QoL. CONCLUSIONS: Natalizumab can produce clinically meaningful improvements in mental and social health. Such improvements are unlikely to be primarily driven by expectation bias, as their magnitude exceeded improvements with another high-efficacy therapy, ocrelizumab.

Matching comparisons of therapeutic efficacy suggest better clinical outcomes for patients treated with peginterferon beta-1a than with glatiramer acetate.

BACKGROUND: Peginterferon beta-1a and glatiramer acetate (GA) are approved first-line therapies for the treatment of relapsing forms of multiple sclerosis, but their therapeutic efficacy has not been compared directly. METHODS: Clinical outcomes at 2 years, including no evidence of disease activity (NEDA), for patients receiving peginterferon beta-1a 125 mcg every 2 weeks (Q2W) or GA 20 mg/ml once daily (QD) were compared by propensity score matching analysis using individual patient data from ADVANCE and CONFIRM phase III clinical trials. In addition, clinical outcomes at 1-3 years for patients receiving peginterferon beta-1a Q2W or GA 40 mg/ml three times a week (TIW) were evaluated using a matching-adjusted comparison analysis of individual patient data from ADVANCE and the ADVANCE extension study, ATTAIN, and aggregate patient data from the phase III GALA and the GALA extension studies. RESULTS: Propensity-score-matched peginterferon beta-1a patients (n = 336) had a significantly lower annualized relapse rate [ARR (0.204 versus 0.282); rate ratio = 0.724; p = 0.045], a significantly lower probability of 12-week confirmed disability worsening (10.0% versus 14.6%; hazard ratio = 0.625; p = 0.048), and a significantly higher rate of NEDA (20.3% versus 11.5%; p = 0.047) compared with GA 20 mg/ml QD patients after 2 years of treatment. Matching-adjusted peginterferon beta-1a patients (effective n = 276) demonstrated a similar ARR at 1 year (0.278 versus 0.318; p = 0.375) and significantly lower ARR at 2 years (0.0901 versus 0.203; p = 0.032) and 3 years (0.109 versus 0.209; p = 0.047) compared with GA 40 mg/ml TIW patients (n = 834). CONCLUSION: Results from separate matching comparisons of phase III clinical trials and extension studies suggest that peginterferon beta-1a 125 mcg Q2W may provide better clinical outcomes than GA (20 mg/ml QD or 40 mg/ml TIW).

Statewide Initiative to Reduce Postnatal Growth Restriction among Infants <31 Weeks of Gestation.

OBJECTIVE: To decrease the incidence of postnatal growth restriction, defined as discharge weight <10th percentile for postmenstrual age, among preterm infants cared for in New York State Regional Perinatal Centers. STUDY DESIGN: The quality improvement cohort consisted of infants <31 weeks of gestation admitted to a New York State Regional Perinatal Center within 48 hours of birth who survived to hospital discharge. Using quality improvement principles from the Institute for Healthcare Improvement and experience derived from successfully reducing central line-associated blood stream infections statewide, the New York State Perinatal Quality Collaborative sought to improve neonatal growth by adopting better nutritional practices identified through literature review and collaborative learning. New York State Regional Perinatal Center neonatologists were surveyed to characterize practice changes during the project. The primary outcome-the incidence of postnatal growth restriction-was compared across the study period from baseline (2010) to the final (2013) years of the project. Secondary outcomes included differences in z-score between birth and discharge weights and head circumferences. RESULTS: We achieved a 19% reduction, from 32.6% to 26.3%, in postnatal growth restriction before hospital discharge. Reductions in the difference in z-score between birth and discharge weights were significant, and differences in z-score between birth and discharge head circumference approached significance. In survey data, regional perinatal center neonatologists targeted change in initiation of feedings, earlier breast milk fortification, and evaluation of feeding tolerance. CONCLUSIONS: Statewide collaborative quality improvement can achieve significant improvement in neonatal growth outcomes that, in other studies, have been associated with improved neurodevelopment in later infancy.

A Statewide Quality Improvement Initiative to Reduce Non-Medically Indicated Scheduled Deliveries.

Objectives To evaluate a large two-phase, statewide quality improvement (QI) collaborative to decrease non-medically indicated (N-MI) deliveries scheduled between 36 and 38 weeks gestation (early). Methods The New York State Department of Health (NYSDOH) convened a Perinatal Quality Collaborative to devise a two-phase QI initiative using a rapid cycle incremental learning model. Phase 1 included Regional Perinatal Centers (RPCs), and Phase 2 added their affiliated perinatal hospitals. Maternal demographics, delivery characteristics, medical indications, and stillbirths were collected on scheduled inductions and cesarean section (CS) deliveries between 36 and 38 weeks. Results There were 35,091 scheduled 36-38 week deliveries reported during the collaborative's 4 years. The percentage of early N-MI scheduled deliveries decreased 41-fold in RPCs (Phase 1 and Phase 2), and 17-fold in affiliates (Phase 2). There was a significant statewide increase in deliveries at ≥39 weeks (P < 0.001), with an estimated 23,732 early deliveries averted. Stillbirths did not increase over time (P = 0.42), although reporting was incomplete. Conclusions A two-phase, statewide QI collaborative in a large state with regionalized perinatal care effectively lowered the number of N-MI deliveries scheduled between 36 and 38 weeks gestation. Associated improvements in neonatal and early childhood developmental outcomes should translate to significant cost savings. This model can effectively be used for similar as well as other obstetrical QI.

Variation in Enteral Feeding Practices and Growth Outcomes among Very Premature Infants: A Report from the New York State Perinatal Quality Collaborative.

BACKGROUND: Extrauterine growth restriction (EUGR) is inversely related to neurodevelopmental outcome. We analyzed growth outcomes and enteral nutrition practices among preterm infants at New York State (NYS) regional perinatal centers (RPCs) to identify practices associated with risk of EUGR. METHODS: Surviving infants < 31 weeks' gestation admitted to a NYS RPC during 2010 were identified and data collected on their growth and enteral nutrition from a statewide database. Neonatologists at NYS RPCs were surveyed to identify center-specific nutritional practices. Survey responses, nutrition, and growth data were then analyzed to identify factors associated with risk of EUGR. RESULTS: Of the 1,387 infants, 32.6% were discharged with EUGR. Incidence of EUGR varied more than fivefold among RPCs. Nutritional practices directly related to EUGR included age at first enteral feeding and full enteral feedings. Among the surveyed nutrition practices, longer duration of trophic feeding before advancing was associated with an increased risk of EUGR while later discontinuation of total parenteral nutrition and larger trophic feeding volume were associated with lower risk. CONCLUSION: Our study found marked variation in nutrition practices and incidence of EUGR among preterm infants at NYS RPCs. A statewide quality improvement initiative to reduce practice variation and improve growth in preterm infants is underway.

Comparison of 2 Clostridium difficile surveillance methods: National Healthcare Safety Network's laboratory-identified event reporting module versus clinical infection surveillance.

OBJECTIVE: To determine whether the Centers for Disease Control and Prevention's National Healthcare Safety Network (NHSN) laboratory-identified (LabID) event reporting module for Clostridium difficile infection (CDI) is an adequate proxy measure of clinical CDI for public reporting purposes by comparing the 2 surveillance methods. DESIGN: Validation study. SETTING: Thirty New York State acute care hospitals. METHODS: Six months of data were collected by 30 facilities using a clinical infection surveillance definition while also submitting the NHSN LabID event for CDI. The data sets were matched and compared to determine whether the assigned clinical case status matched the LabID case status. A subset of mismatches was evaluated further, and reasons for the mismatches were quantified. Infection rates determined using the 2 definitions were compared. RESULTS: A total of 3,301 CDI cases were reported. Analysis of the original data yielded a 67.3% (2,223/3,301) overall case status match. After review and validation, there was 81.3% (2,683/3,301) agreement. The most common reason for disagreement (54.9%) occurred because the symptom onset was less than 48 hours after admission but the positive specimen was collected on hospital day 4 or later. The NHSN LabID hospital onset rate was 29% higher than the corresponding clinical rate and was generally consistent across all hospitals. CONCLUSIONS: Use of the NHSN LabID event minimizes the burden of surveillance and standardizes the process. With a greater than 80% match between the NHSN LabID event data and the clinical infection surveillance data, the New York State Department of Health made the decision to use the NHSN LabID event CDI data for public reporting purposes.

Longitudinal functional recovery after postacute rehabilitation in older hip fracture patients: the role of cognitive impairment and implications for long-term care.

OBJECTIVE: To compare functional recovery patterns of cognitively impaired and nonimpaired older adults who had hip fracture surgeries, and to identify associated long-term care needs. METHODS: Longitudinal study (n = 231). Data were collected within 72 hours of admission to and before discharge from the postacute rehabilitation facilities and at 2, 6, and 12 months following postacute rehabilitation discharge. Six functional independence measures (FIM) were used to assess functional recovery. Mini-mental status examination was used to gauge cognitive function. Mixed-effects analyses quantify differences of FIM functional recovery patterns between groups while adjusting for potential confounders. RESULTS: Multivariate results showed that patients with impaired cognition had notably different functional recovery patterns and significantly worse overall FIM scores (P < .001) than their counterparts in all 6 FIM functions. For locomotion function at 1 year, cognitively nonimpaired patients needed little supervision (mean FIM = 5.6), whereas patients with impaired cognition needed 50% human assistance (FIM = 3.9). In addition to needing locomotion assistance, cognitively impaired patients also required 25% human assistance in transfers (FIM = 4.8), 25% in self-care (FIM mean = 5.3), and 25% in sphincter control (FIM mean = 5.0). CONCLUSION: Cognitively impaired patients experienced recovery at 2 and 6 months but were unable to retain rehabilitation gains in locomotion, transfers, self-care, and sphincter control at 1 year following postacute rehabilitation discharge, and they still required human assistance to stay in their homes within the community. To prevent or delay nursing home entry, it is suggested that appropriate long-term care planning and social support for caregivers are needed for cognitively impaired hip fracture patients.

Examining heterogeneity of functional recovery among older adults with hip fractures.

OBJECTIVE: To examine heterogeneity in 1-year functional recovery following postacute rehabilitation among older adults with hip fracture. METHODS: Two hundred twenty-five community-dwelling older adults with hip fracture who received postacute rehabilitation in 5 rehabilitation facilities in Baltimore, Maryland, were recruited during postacute rehabilitation (baseline) and follow-up at 2, 6, and 12 months following postacute rehabilitation discharge. Functional recovery was measured by the activities of daily living (ADL) and instrumental activities of daily living (IADL) scores. A mixed-effect model was used to examine factors associated with postacute rehabilitation functional recovery; fixed and random effects estimates from the models were used to demonstrate heterogeneity in functional recovery. RESULTS: Results indicated that there was an overall trend in both ADL and IADL functional improvement at 2 months following postacute rehabilitation, with continued improvement to 6 months, after which functional recovery slowed down and remained constant through the year. Individuals whose functional recovery did not conform to these patterns were identified and their functional recovery that deviated substantially from the group mean was demonstrated. CONCLUSIONS: Functional recovery patterns in elderly hip fracture patients are heterogeneous. To foster functional independence, health care professionals should consider individual recovery trajectories using a modeling approach appropriate for longitudinal or repeated measurement data such as a linear mixed-effects model when designing individualized rehabilitation and postacute rehabilitation care plans.