Faculty Bibliography

Background: To assess acute clinical effects and safety of single-dose oral ampreloxetine, a novel, long-acting, selective norepinephrine reuptake inhibitor in subjects with neurogenic orthostatic hypotension (nOH).
Method(s): In a 5-day dosing study, subjects received placebo on Day 1, followed by ascending doses of ampreloxetine (range:1-20 mg). A subset of subjects were randomized to placebo or ampreloxetine in a 1-day double-blind study. Assessments included change in seated and standing systolic blood pressure (SBP), and Orthostatic Hypotension Symptom Assessment-Item 1 (OHSA#1; dizziness, lightheadedness, feeling faint).
Result(s): Of 34 subjects (mean age, 66 years), 15 and 13 subjects received ampreloxetine 10 and 20 mg, respectively, as maximum tolerated dose. Ampreloxetine 10 mg showed the most consistent response for increase in seated SBP relative to placebo (mean [SD] change in seated SBP 4.9 [20.1] mmHg more than placebo 4 hours post-dose). In the double-blind study (ampreloxetine, n=5 [median dose, 10 mg]; placebo, n=5), relative to placebo, for the ampreloxetine treatment group, increase in seated (mean difference from placebo, 29.9 mmHg at 4 hours post-dose; p < 0.05) and 3-minute standing SBP (mean difference, 35.0 mmHg at 4 hours post-dose) was more pronounced for the ampreloxetine treatment group to 9 hours and 10 hours post-dose, respectively, and 3-minute standing SBP was more pronounced for subjects randomized to ampreloxetine up to 10 hours post-dose. Twice as many subjects in the ampreloxetine treatment arm reported symptom improvement on OHSA#1. Most common adverse events were headache and urinary tract infection, with no serious events.
Conclusion(s): In subjects with nOH, 10 mg ampreloxetine produced a consistent increase in seated SBP relative to placebo. Compared to placebo, ampreloxetine showed greater increase in seated and standing SBP up to 10 hours post-dose, and greater symptom improvement. Ampreloxetine was well tolerated. These results support assessment of longer-term effects of ampreloxetine in nOH.
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BACKGROUND:Little is known about the effect of the Coronavirus disease 2019 pandemic on stroke care and the impact of the epidemic on acute stroke hospitalizations has not been described. METHODS:We analyze the stroke admission rate in three hospitals in New York City from January 1, 2020 through April 17, 2020, identifying all cases of acute ischemic stroke, intraparenchymal hemorrhage and subarachnoid hemorrhage. RESULTS:We confirmed 518 cases of out-of-hospital stroke. During the baseline period up to February 25, 2020, the daily stroke admission rate was stable, with the slope of the regression describing the number of admissions over time equal to -0.33 (se = 1.21), not significantly different from 0 (p = 0.79), with daily admissions averaging 41. During the pandemic period, the slope was -4.4 (se = 1.00); i.e., the number of stroke admissions decreased an average of 4.4 per week, (p = 0.005), with weekly admissions averaging 23, a reduction of 44% versus baseline. This general result was not different by patient age, sex, or race/ethnicity. CONCLUSIONS:The weekly stroke admission rate started declining two weeks prior to the local surge of coronavirus admissions. The consequences of lack of diagnosis and treatment of a large proportion of acute stroke patients are likely severe and lasting.

Objective; To analyze a case of complex multisite carbapenems-resistant Klebsiella pneumoniae (CRKP) infection,and to evaluate the rationality of the treatment scheme,so as to provide reference for rational use of drugs.
Method(s): The clinical and laboratory data of the patient were collected,and the clinical efficacy was observed,laboratory indexes and the results of etiological examination were compared, treatment effect was evaluated and relevant literature was reviewed. Results and
Conclusion(s): In the treatment of the patient,meropenem,amikacin combined with fosfomycin were used. Literature retrieval revealed that there were many kinds of antimicrobial therapy options for CRKP infection, but cure rate was not clear. The prevalence of CRKP was more feasible in the intensive care unit(ICU). Reducing irrational use of broad-spectrum antibacterials and unnecessary invasive manipulation were effective strategies for the control of CRKP prevalence and reduction of economic burden on patients.
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INTRODUCTION/BACKGROUND:Hereditary transthyretin-mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO-TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients' neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score. METHODS:Stage 1/2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline, 35, and 66 weeks. RESULTS:At 66 weeks, inotersen-treated patients experienced symptom stabilization versus worsening in patients receiving placebo in NSC total score; the subdomains of muscle weakness, sensory, pain, and autonomic symptoms; and for various individual items. DISCUSSION/CONCLUSIONS:Inotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR based on the NSC score, which may be an effective assessment of neuropathy progression and patients' neuropathy experience in clinical practice. This article is protected by copyright. All rights reserved.

BACKGROUND/OBJECTIVE/OBJECTIVE:Desmopressin (DDAVP) has been suggested for antiplatelet medication reversal in patients with traumatic brain injury (TBI) but there are limited data describing its effect on clinical outcomes. The purpose of this study was to evaluate the effect of DDAVP on hematoma expansion and thrombosis in patients with TBI who were prescribed pre-injury antiplatelet medications. METHODS:Consecutive adult patients who were admitted to our level I trauma center and prescribed pre-injury antiplatelet medications between July, 2012, and May, 2018, were retrospectively identified. Patients were excluded if their hospital length of stay was < 24 h, if DDAVP was administered by any route other than intravenous, if they received a DDAVP dose < 0.3 mcg/kg or there was no evidence of brain hemorrhage on computed tomography (CT) scan. Patients were stratified based on the use of DDAVP, and the incidence of hematoma expansion was compared between groups. Thrombotic events were reviewed as a secondary outcome. Multivariate analysis was utilized to control for confounding variables. RESULTS:Of 202 patients included in analysis, 158 (78%) received DDAVP. The mean age was 76 ± 12 years; the most common injury mechanism was falls (76%); 69% had acute subdural hematoma, and 49% had multi-compartmental hemorrhage. Initial Glasgow coma score was between 13 and 15 for 91% of patients. Aspirin was the most common antiplatelet regimen prescribed (N = 151, 75%), followed by dual antiplatelet regimens (N = 26, 13%) and adenosine diphosphate (ADP)-receptor inhibitors (N = 25, 12%). The incidence of hematoma expansion was 14% and 30% for patients who did and did not receive DDAVP, respectively (p = 0.015). After controlling for age, injury severity score, multi-compartmental hemorrhage, and receipt of pre-injury high-dose aspirin (> 81 mg), ADP-receptor inhibitors, oral anticoagulants, prothrombin complex concentrates or platelets in a multivariate analysis, the association between DDAVP and hematoma expansion remained significant (adjusted OR 0.259 [95% CI 0.103-0.646], p = 0.004). Thrombotic events were similar between the two groups (DDAVP, 2.5%, no DDAVP, 4.5%; p = 0.613). CONCLUSIONS:DDAVP was associated with a lower incidence of hematoma expansion in patients with mild TBI who were prescribed pre-injury antiplatelet medications. These results justify a randomized controlled trial to further evaluate the role of DDAVP for this indication.

Introduction: The FOCUS study of fremanezumab, a fullyhumanized monoclonal antibody (IgG2DELTAa) that selectively targets calcitonin gene-related peptide (CGRP), was the first and largest study of a migraine preventive treatment in adults with both chronic and episodic migraine (CM and EM) and documented inadequate response to 2-4 classes of migraine preventive medications. Efficacy in a subgroup of patients with medication overuse (use of any acute medication on >=15 days/month or triptans/ergots/combination medications on >=10 days/month) at baseline was evaluated.
Method(s): Patients were randomized (1:1:1) to quarterly fremanezumab (Month 1: 675mg; Month 2 and 3: placebo), monthly fremanezumab (Month 1: CM, 675mg; EM, 225mg; Month 2 and 3: 225mg), or matched monthly placebo for 12 weeks. Changes from baseline in monthly migraine days and headache days of at least moderate severity at 4 weeks and during 12 weeks of treatment were compared using a mixed-effect model for repeated measures.
Result(s): Of 838 randomized patients, 427 had medication overuse. Treatment with quarterly and monthly fremanezumab versus placebo resulted in significantly greater reductions from baseline in the monthly average number of migraine days at 4 weeks (least-squares mean [SE] change from baseline, -3.7 [0.62] and -4.5 [0.57] vs -0.0 [0.62]; P<0.0001) and over 12 weeks (-3.3 [0.62] and -4.5 [0.57] vs -0.5 (0.62); P<0.0001). With quarterly and monthly fremanezumab versus placebo, significant reductions from baseline were also observed in the monthly average number of headache days of at least moderate severity at 4 weeks (-4.3 [0.62] and -5.1 [0.56] vs -0.2 [0.62]; P<0.0001) and over 12 weeks (-4.0 [0.62] and -5.0 [0.56] vs -0.8 [0.62]; P<0.0001).
Conclusion(s): Quarterly and monthly fremanezumab provided early and sustained reductions in migraine and headache days vs placebo in patients with medication overuse and documented inadequate response to 2-4 classes of migraine preventive medications

OBJECTIVE:To investigate differences between flail limb syndrome (FLS) and amyotrophic lateral sclerosis (ALS). DESIGN/METHODS:Retrospective chart review identified 16 cases of ALS and 16 of FLS. Revised ALS Functional Rating Scale (ALSFRS-R), compound muscle action potential (CMAP) amplitudes, and rate of loss of vital capacity (ΔVC) were compared. RESULTS:Comparing ALS and FLS patients, ΔVC was 5.26% ± 0.33% vs. 0.54% ± 0.06%, respectively (p<0.05). No patient in FLS group had a ΔVC more that 0.65% per month. No patient in ALS group had a ΔVC less than 4.6% per month. Average ulnar nerve CMAP amplitudes were significantly lower in FLS (p<0.05). No significant difference was observed in rate of ALSFRS-R decline or average peroneal, tibial, and median nerve CMAP amplitudes. CONCLUSION/CONCLUSIONS:In FLS, an average monthly decrease in VC exceeding 0.65% may suggest a spread of motor neuron loss to higher cervical anterior horn areas and raise the possibility of progression to ALS. Larger prospective studies are needed to investigate the rate of VC decline in FLS and limb-onset ALS and to establish whether a cut-off score combining ΔVC and CMAP amplitude mainly of the ulnar nerve might predict progression of FLS to ALS, the knowledge of which can facilitate appropriate patient counseling.

OBJECTIVES/OBJECTIVE:Guidelines recommend to initiate anticoagulation within 4-14 days after cardioembolic stroke. Data supporting this did not account for key factors potentially affecting the decision to initiate anticoagulation such as infarct size, hemorrhagic transformation, or high risk features on echocardiography. METHODS:We pooled data from stroke registries of 8 comprehensive stroke centers across the United States. We included consecutive patients admitted with ischemic stroke and atrial fibrillation. The primary predictor was timing of initiating anticoagulation (0-3 days, 4-14 days, or >14 days) and outcomes were recurrent stroke/TIA/systemic embolism, symptomatic intracerebral hemorrhage (sICH), and major extracranial hemorrhage (ECH) within 90 days. RESULTS:Among 2084 patients, 1289 met the inclusion criteria. The combined endpoint occurred in 10.1% (n = 130) subjects (87 ischemic events, 20 sICH, and 29 ECH). Overall, there was no significant difference in the composite endpoint between the three groups: 0-3 days [10.3% (64/617)], 4-14 days [(9.7%) 52/535)], >14 days [10.2% (14/137), p=0.933]. In adjusted models, patients started on anticoagulation between 4-14 days did not have a lower rate of sICH (vs. 0-3 days) (OR 1.49 95% CI 0.50 - 4.43) neither did they have a lower rate of recurrent ischemic events (vs. > 14 days) (OR 0.76 95% CI 0.36 - 1.62, p = 0.482). INTERPRETATION/CONCLUSIONS:In this multicenter real world cohort, the recommended (4-14 days) time frame to start oral anticoagulation was not associated with reduced ischemic and hemorrhagic outcomes. Randomized trials are required to determine the optimal timing of anticoagulation initiation. This article is protected by copyright. All rights reserved.

Acute-onset and severe sensory and autonomic deficits with no motor dysfunction, typically preceded by a febrile illness, with poor recovery, and often fatal outcome are the hallmark features of acute sensory and autonomic neuronopathy (ASANN). Pathologically and electrophysiologically, ASANN is characterized by an extensive ganglionopathy affecting sensory and autonomic ganglia with preservation of motor neurons. Consequently, patients, usually children or young adult, develop acute-onset profound widespread loss of all sensory modalities resulting in automutilations, as well as autonomic failure causing neurogenic orthostatic hypotension, neurogenic underactive bladder, and gastroparesis and constipation. The diagnosis is clinical with support of nerve conduction studies and autonomic testing, as well as spinal cord magnetic resonance imaging showing characteristic posterior cord hyperintensities. Although the presumed etiology is immune-mediated, further studies are required to clarify the physiopathology of the disease. We here performed a systematic review of the epidemiology, pathophysiology, diagnosis, and management of ASANN, with three representative cases that recently presented at our clinic. All three patients had the typical clinical manifestations of ASANN but in different combinations, illustrating the variable phenotype of the disorder. Immunosuppression is seldom effective. Management options are limited to supportive and symptomatic care with the goal of minimizing complications and preventing death.