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In childhood and adolescent migraine, amitriptyline and topiramate were no better than placebo and not significantly different from each other in achieving a 50% or greater reduction in days with headache. The trial was stopped early for futility. More than 6 million children and adolescents in the United States have migraines. 1 – 3 The majority continue to have headaches into adulthood, taking a toll on the U.S. economy of approximately $36 billion and resulting in substantial effects on quality of life. 4 – 7 Pediatric clinical practice guidelines for migraine treatment are consensus based rather than evidence based, 8 , 9 with no Food and Drug Administration (FDA)–approved migraine prevention medication for children younger than 12 years of age. The Childhood and Adolescent Migraine Prevention (CHAMP) trial tested the effects of amitriptyline and topiramate in comparison with each other and with placebo in . . .

Objective This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA). Methods This prospective, multi‐center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits. Results Enrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP‐INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography (EIM) high‐frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts. Interpretation By the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit.

We assessed resistance rates and trends for important antimicrobial-resistant pathogens (oxacillin-resistant Staphylococcus aureus [ORSA], vancomycin-resistant Enterococcus species [VRE], ceftazidime-resistant Klebsiella species [K-ESBL], and ciprofloxacin-resistant Escherichia coli [QREC]), the frequency of outbreaks of infection with these resistant pathogens, and the measures taken to control resistance in a stratified national sample of 670 hospitals. Four hundred ninety-four (74%) of 670 surveys were returned. Resistance rates were highest for ORSA (36%), followed by VRE (10%), QREC (6%), and K-ESBL (5%). Two-thirds of hospitals reported increasing ORSA rates, whereas only 4% reported decreasing rates, and 24% reported ORSA outbreaks within the previous year. Most hospitals (87%) reported having implemented measures to rapidly detect resistance, but only ∼50% reported having provided appropriate resources for antimicrobial resistance prevention (53%) or having implemented antimicrobial use guidelines (60%). The most common resistant pathogen in US hospitals is ORSA, which accounts for many recognized outbreaks and is increasing in frequency in most facilities. Current practices to prevent and control antimicrobial resistance are inadequate.

Migraine is a common neurological disease that often begins in childhood and continues into adulthood; approximately 6 million children and adolescents in the United States cope with migraine, and many frequently experience significant disability and multiple headache days per week. Although pharmacological preventive treatments have been shown to offer some benefit to youth with migraine, additional research is needed to understand whether and how these benefits are sustained. To survey clinical status of youth with migraine who participated in the 24-week Childhood and Adolescent Migraine Prevention (CHAMP) trial over a 3-year follow-up period. This survey study used internet-based surveys collected from youth ages 8 to 17 years at 3, 6, 12, 18, 24, and 36 months after completion of the CHAMP trial, which randomized participants to amitriptyline, topiramate, or placebo. At the end of the trial, the study drug was stopped, and participants received clinical care of their choice thereafter. The CHAMP trial was conducted between May 2012 and November 2015, and survey follow-up was conducted June 2013 to June 2018. Participants in this survey study were representative of those randomized in the trial. Data were analyzed from March 2020 to April 2021. Survey completion. Headache days, disability (assessed using the Pediatric Migraine Disability Scale [PedMIDAS]), and self-report of ongoing use of prescription preventive medication. A total of 205 youth (mean [SD] age, 14.2 [2.3] years; 139 [68%] girls; mean [SD] history of migraine, 5.7 [3.1] years) participated in the survey. Retention of participants was 189 participants (92%) at month 6, 182 participants (88%) at month 12, 163 participants (80%) at month 18, 165 participants (80%) at month 24, and 155 participants (76%) at month 36. Over the course of the 3-year follow-up, participants consistently maintained meaningful reductions in headache days (mean [SD] headache days per 28 days: CHAMP baseline, 11.1 [6.0] days; CHAMP completion, 5.0 [5.7] days; 3-year follow-up, 6.1 [6.1] days) and disability (mean [SD] score: CHAMP baseline, 40.9 [26.4]; CHAMP completion, 17.9 [22.1]; 3-year follow-up, 12.3 [20.0]). At 3 years after completion of the CHAMP trial, headache days were approximately 1.5 per week (changed from about 3 per week at trial baseline) and disability had improved from the moderate range to the low mild range on the PedMIDAS. Longitudinal analyses showed that amitriptyline and topiramate did not explain intercept random effects for either mean rate of headache days per week (amitriptyline: estimate [SE], 0.07 [0.05]; P = .16; topiramate: estimate [SE], 0.04 [0.05]; P = .50) or headache disability PedMIDAS total score (amitriptyline: estimate [SE], 0.25 [0.38]; P = .52; topiramate: estimate [SE], -0.09 [0.39]; P = .82) changes over time. Of 153 participants who reported on prescription drug use at 3 years, only 1 participant (1%) reported using prevention medication, and most participants reported no medication use at most time points. These findings suggest that children and adolescents with longer than 5 years history of migraine who participated in the CHAMP trial may sustain positive clinical outcomes over time, even after discontinuing preventive pill-based treatment. This survey study could inform use and discontinuation timing of pharmacological preventive therapies for migraine in youth ages 8 to 17 years. Research is needed to examine mechanisms of treatment improvement and maintenance for preventive therapies, as well as placebo, in the pediatric population.

Background Hardware changes can be an unavoidable confound in imaging trials. Understanding the impact of such changes may play an important role in the analysis of imaging data. Objective To characterize the effect of equipment changes in a longitudinal, multi-site multiple sclerosis trial. Methods Using data from a clinical trial in progressive multiple sclerosis, we explored how major changes in imaging hardware affected data. We analyzed the extent to which these changes affected imaging biomarkers and the estimated treatment effects by including such changes as a time-dependent covariate. Results Significant differences whole brain atrophy (brain parenchymal fraction, BPF) and microstructure (transverse diffusivity, TD) between scans with and without changes were found and depended on the type of hardware change. A switch from GE HDxt to Siemens Skyra led to significant shifts in BPF (p < 0.04) and TD (p < 0.0001). However, we could not detect the influence of hardware changes on overall trial outcomes– differences between placebo and treatment arms in change over time of BPF and TD (p > 0.5). Conclusions The results suggest that differences among hardware types should be considered when planning and analyzing brain atrophy and diffusivity in a longitudinal clinical trial.

Positive relationships between hospital volume and outcomes have been demonstrated for several surgeries and medical conditions. However, little is known about the volume-outcome relationship in patients admitted to medical ICUs. To determine the relationship between hospital volume and risk-adjusted in-hospital mortality for patients admitted to ICUs with respiratory, neurologic, and GI disorders. Retrospective cohort study. Twenty-nine hospitals in a single metropolitan area. Adult ICU admissions from 1991 through 1997. Using Cox proportional hazards models, we compared in-hospital mortality between tertiles of hospital volume (high, medium, and low) for respiratory (n = 16,949), neurologic (n = 13,805), and GI (n = 12,881) diseases after adjusting for age, gender, admission severity of illness, admitting diagnosis, and source. Severity of illness was measured using the APACHE (acute physiology and chronic health evaluation) III methodology. Among respiratory and neurologic ICU admissions, hazard ratios were similar (p ≥ 0.05) in patients in low-, medium-, and high-volume hospitals. However, among GI diagnoses, risk of mortality was lower in high-volume hospitals, relative to low-volume hospitals (hazard ratio, 0.68; 95% confidence interval [CI], 0.54 to 0.85; p < 0.001), and was somewhat lower in medium-volume hospitals (hazard ratio, 0.83; 95% CI, 0.68 to 1.01; p = 0.06). Among subgroups based on severity of illness, high-volume hospitals had lower mortality, relative to low-volume hospitals, among sicker patients (APACHE III score > 57) in the respiratory cohort (hazard ratio, 0.77; 95% CI, 0.59 to 0.99) and the GI cohort (hazard ratio, 0.67; 95% CI, 0.53 to 0.85). Associations between ICU volume and risk-adjusted mortality were significant for patients with GI diagnoses and for sicker patients with respiratory diagnoses. However, associations were not significant for patients with neurologic diagnoses. The lack of a consistent volume-outcome relationship may reflect unmeasured patient complexity in higher-volume hospitals, relative standardization of care across ICUs, or lack of efficacy of some accepted ICU processes of care.

Background: Optimal diabetes management relies on providers adhering to evidence-based practice guidelines in the processes of care delivery and patients adhering to self-management recommendations to maximize patient outcomes. Purpose: To explore: (1) the degree to which providers adhere to the guidelines; (2) the extent of glycemic, lipid, and blood pressure control in patients with diabetes; and (3) the roles of organizational and patient population characteristics in affecting both provider adherence and patient outcome measures for diabetes. Design: Secondary data analysis of provider adherence and patient outcome measures from chart reviews, along with surveys of facility quality managers. Sample: We sampled 109 Veterans Affairs medical centers (VAMCs). Results: Analyses indicated that provider adherence to diabetes guidelines (ie, hemoglobin$A_{1c}$, foot, eye, renal, and lipid screens) and patient outcome measures (ie, glycemic, lipid, and hypertension control plus nonsmoking status) are comparable or better in VAMCs than reported elsewhere. VAMCs with higher levels of provider adherence to diabetes guidelines had distinguishing organizational characteristics, including more frequent feedback on diabetes quality of care, designation of a guideline champion, timely implementation of qualityof-care changes, and greater acceptance of guideline applicability. VAMCs with better patient outcome measures for diabetes had more effective communication between physicians and nurses, used educational programs and Grand Rounds presentations to implement the diabetes guidelines, and had an overall patient population that was older and with a smaller percentage of black patients. Conclusions: Healthcare organizations can adopt many of the identified organizational characteristics to enhance the delivery of care in their settings.

ObjectiveThis study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy (SMA).MethodsThis prospective, multi‐center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits.ResultsEnrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items (TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP‐INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude (CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography (EIM) high‐frequency reactance slope (Ohms/MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron (SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts.InterpretationBy the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington’s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington’s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression.