Objective To compare early routine pharmacologic treatment of moderate-to-large patent ductus arteriosus (PDA) at the end of week 1 with a conservative approach that requires prespecified respiratory and hemodynamic criteria before treatment can be given. Study design A total of 202 neonates of <28 weeks of gestation age (mean, 25.8 ± 1.1 weeks) with moderate-to-large PDA shunts were enrolled between age 6 and 14 days (mean, 8.1 ± 2.2 days) into an exploratory randomized controlled trial. Results At enrollment, 49% of the patients were intubated and 48% required nasal ventilation or continuous positive airway pressure. There were no differences between the groups in either our primary outcome of ligation or presence of a PDA at discharge (early routine treatment [ERT], 32%; conservative treatment [CT], 39%) or any of our prespecified secondary outcomes of necrotizing enterocolitis (ERT, 16%; CT, 19%), bronchopulmonary dysplasia (BPD) (ERT, 49%; CT, 53%), BPD/death (ERT, 58%; CT, 57%), death (ERT,19%; CT, 10%), and weekly need for respiratory support. Fewer infants in the ERT group met the rescue criteria (ERT, 31%; CT, 62%). In secondary exploratory analyses, infants receiving ERT had significantly less need for inotropic support (ERT, 13%; CT, 25%). However, among infants who were ≥26 weeks gestational age, those receiving ERT took significantly longer to achieve enteral feeding of 120 mL/kg/day (median: ERT, 14 days [range, 4.5-19 days]; CT, 6 days [range, 3-14 days]), and had significantly higher incidences of late-onset non-coagulase-negative Staphylococcus bacteremia (ERT, 24%; CT,6%) and death (ERT, 16%; CT, 2%). Conclusions In preterm infants age <28 weeks with moderate-to-large PDAs who were receiving respiratory support after the first week, ERT did not reduce PDA ligations or the presence of a PDA at discharge and did not improve any of the prespecified secondary outcomes, but delayed full feeding and was associated with higher rates of late-onset sepsis and death in infants born at ≥26 weeks of gestation. Trial registration ClinicalTrials.gov: NCT01958320.

Background Memantine has been used off-label to treat frontotemporal lobar degeneration (FTD). A previous 26 week open label study suggested a transient, modest benefit on neuropsychiatric symptoms as measured by the Neuropsychiatric Inventory (NPI). Methods We performed a randomized, parallel group, double blind, placebo controlled trial of 20 mg memantine taken orally daily for 26 weeks in FTD. Participants met Neary criteria for behavioral variant (bvFTD) or semantic dementia (SD) and had characteristic brain atrophy. Use of cholinesterase inhibitors was prohibited. The objective of the study was to determine whether memantine is an effective treatment for FTD. Individuals were randomized to memantine or matched placebo tablets in blocks of two and four. Primary endpoints were the change in total NPI score and Clinical Global Impression of Change (CGIC) scores after 26 weeks. Secondary outcomes included a neuropsychological battery, and other cognitive, global and activity of daily living measures. Clinicaltrials.gov identifier: NCT00545974 Findings 100 subjects were screened, 81 were randomized, 5 (6%) discontinued and 76 completed all visits. Enrollment numbers were lower than planned due to many subjects’ preference to take memantine or cholinesterase inhibitors off-label rather than participate in a clinical trial. 39 memantine and 42 placebo subjects entered the primary intent to treat analysis. There was no effect of memantine treatment on either the NPI (mean difference [MD] 2.2, 95%CI: −3.9, 8.3, p = 0.47) or CGIC (MD 0, 95%CI: −0.4, 0.4, p = 0.90) after 26 weeks of treatment. Memantine was generally well tolerated, however there were more frequent cognitive adverse events in the memantine group. Interpretation There was no benefit of memantine treatment in bvFTD or SD. These data do not support memantine use in FTD. Funding Forest Research Institute

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Background and Relevance: Atherosclerotic stenosis of the major intracranial arteries is an important cause of transient ischemic attack (TIA) or stroke. Of the 900,000 patients who suffer a TIA or stroke each year in the USA, intracranial stenosis is responsible for approximately 10%, i.e. 90,000 patients. There have been no prospective trials evaluating antithrombotic therapies for preventing recurrent vascular events in these patients. The main objective of this trial is to compare warfarin [International Normalized Ratio (INR) 2–3] with aspirin (1,300 mg/day) for preventing stroke (ischemic and hemorrhagic) and vascular death in patients presenting with TIA or stroke caused by stenosis of a major intracranial artery. Study Design: Prospective, randomized, double-blind, multicenter trial. The sample sizerequired will be 403 patients per group, based on stroke and vascular death rates of 33% per 3 years in the aspirin group vs. 22% per 3 years in the warfarin group, a p value of 0.05, power of 80%, a 24% rate of ‘withdrawal of therapy’, and a 1% rate of ‘lost to follow-up’. Conduct of Trial: Patients with TIA or nondisabling stroke caused by ≧50% stenosis of a major intracranial artery documented by catheter angiography are randomized to warfarin or aspirin. Patients are contacted monthly by phone and examined every 4 months until a common termination date. Mean follow-up in the study is expected to be 3 years. Conclusion: This study will determine whether warfarin or aspirin is superior for patients with symptomatic intracranial arterial stenosis. Furthermore, it will identify patients whose rate of ischemic stroke in the territory of the stenotic intracranial artery on best medical therapy is sufficiently high to justify a subsequent trial comparing intracranial angioplasty/stenting with best medical therapy in this subset of patients.

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Studies in premature animals suggest that 1) prolonged tight constriction of the ductus arteriosus is necessary for permanent anatomic closure and 2) endogenous nitric oxide (NO) and prostaglandins both play a role in ductus patency. We hypothesized that combination therapy with an NO synthase (NOS) inhibitor [N G -monomethyl-L-arginine (L-NMMA)] and indomethacin would produce tighter ductus constriction than indomethacin alone. Therefore, we conducted a phase I and II study of combined treatment with indomethacin and L-NMMA in newborns born at Ͻ28 weeks' gestation who had persistent ductus flow by Doppler after an initial three-dose prophylactic indomethacin course (0.2, 0.1, 0.1 mg/kg/24 h). Twelve infants were treated with the combined treatment protocol [three additional indomethacin doses (0.1 mg/kg/24 h) plus a 72-hour L-NMMA infusion]. Thirty-eight newborns received three additional indomethacin doses (without L-NMMA) and served as a comparison group. Ninety-two percent (11/12) of the combined treatment group had tight ductus constriction with elimination of Doppler flow. In contrast, only 42% (16/38) of the comparison group had a similar degree of constriction. L-NMMA infusions were limited in dose and duration by acute side effects. Doses of 10 -20 mg/kg/h increased serum creatinine and systemic blood pressure. At 5 mg/kg/h, serum creatinine was stable but systemic hypertension still limited L-NMMA dose. We conclude that combined inhibition of NO and prostaglandin synthesis increased the degree of ductus constriction in newborns born at Ͻ28 weeks' gestation. However, the combined administration of L-NMMA and indomethacin was limited by acute side effects in this treatment protocol. Studies in premature animals demonstrate that prolonged, tight constriction of the ductus arteriosus is necessary to produce ischemia of the ductus wall, anatomic remodeling, and permanent closure (1-3). A persistent patent ductus arteriosus (PDA) in premature infants is due in large part to the increased sensitivity of the ductus to endogenous vasodilators like prostaglandins. Prostaglandin synthesis inhibitors, such as indomethacin, are the only drugs currently approved for treatment of PDA. Unfortunately, a three-dose course of indomethacin frequently fails to close the PDA in infants of Ͻ28 weeks gestational age (GA). Previous studies have shown that infants delivered before 28 weeks GA who still have evidence of ductus flow on Doppler examination (performed after a standard three-dose course of indomethacin), are unlikely to eliminate Doppler flow through their ductus even if a prolonged six-dose indomethacin course is administered (2).

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Background Progressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off‐label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence‐based knowledge to guide future treatment decisions. Objectives To describe an open‐label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP‐Richardson's syndrome (PSP‐RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies. Methods For 6 months, 10 PSP‐RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP‐RS patients from the davunetide clinical trial and the 4‐Repeat Tauopathy Neuroimaging Initiative. Results Salsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (–0.07 ± 0.03), young plasma (–0.06 ± 0.03), and historical controls (–0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint. Conclusions Neither salsalate nor young plasma had a detectable effect on disease progression in PSP‐RS. Focused open‐label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP‐directed therapies.