Faculty Bibliography

Long-term opioid therapy has the potential for serious adverse outcomes and is often used in a vulnerable population. Because adverse effects or failure to maintain benefits is common with long-term use, opioid taper or discontinuation may be indicated in certain patients. Concerns about the adverse individual and population effects of opioids have led to numerous strategies aimed at reductions in prescribing. Although opioid reduction efforts have had generally beneficial effects, there have been unintended consequences. Abrupt reduction or discontinuation has been associated with harms that include serious withdrawal symptoms, psychological distress, self-medicating with illicit substances, uncontrolled pain, and suicide. Key questions remain about when and how to safely reduce or discontinue opioids in different patient populations. Thus, health care professionals who reduce or discontinue long-term opioid therapy require a clear understanding of the associated benefits and risks as well as guidance on the best practices for safe and effective opioid reduction. An interdisciplinary panel of pain clinicians and one patient advocate formulated recommendations on tapering methods and ongoing pain management in primary care with emphasis on patient-centered, integrated, comprehensive treatment models employing a biopsychosocial perspective.

OBJECTIVE:To estimate the relative frequency and relative risk of post-traumatic stress disorder (PTSD) attributed to traumatic brain injury (TBI). DATA SOURCES/METHODS:PubMed and Embase were searched from database inception until January 26, 2019. STUDY SELECTION/METHODS:Two independent investigators screened titles, abstracts, and full texts. We selected studies that included subjects presenting with TBI, and where the number of subjects with TBI and PTSD could be extrapolated. There were no restrictions on study design. DATA EXTRACTION AND SYNTHESIS/METHODS:Data were extracted by two independent investigators and results were pooled using random-effects meta-analysis. RESULTS:= 99.9%). CONCLUSIONS AND RELEVANCE/CONCLUSIONS:TBI is a risk factor for PTSD in clinic-based civilian populations. There are insufficient data to assess the relative frequency or relative risk of PTSD in moderate to severe TBI. Due to significant between-study heterogeneity, the findings of our study should be interpreted with caution.

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.

OBJECTIVE:People with Multiple Sclerosis (pwMS) often exhibit generalized weakness that affects several activities of daily life, particularly those relying on balance and gait. While it is known that such a symptom has a strong impact on mobility, to what extent muscular strength is linked with functional mobility in men and women with MS remains mostly unexplored. The aim of this study is to assess the existence of possible sex-related differences in functional mobility in pwMS, also considering the muscular strength capacity. METHODS:Functional mobility and hand-grip strength (HGS) were assessed in 49 pwMS with mild-moderate disability using instrumental Timed-up-and-go (TUG) test carried out using an inertial sensor and digital dynamometry. We investigated the existence of sex-related differences in the duration of each TUG sub-phase and their correlation with the HGS. RESULTS:No sex-related differences in TUG performance (either in terms of overall or sub-phase time) were found. Similar large negative correlations were found in men and women with MS between HGS and overall TUG and walking phase duration. However, changes in strength have a more marked impact in women as indicated by the different slope of the HGS-TUG time relationship., In women, HGS also appears significantly correlated with all TUG sub-phases, while in men this occurs only for overall TUG and walking time. CONCLUSIONS:Rehabilitation and training programs for pwMS should take into account the peculiar features associated with the interaction between strength and mobility specific for each individual's sex to optimize their effectiveness.

Status epilepticus (SE) is associated with high mortality and morbidity. Although SE is frequently seen in elderly patients, there is a lack of a cohesive report of outcome measures and associated factors within this population. Our aim was to systematically review studies reporting outcomes of SE among elderly patients and factors influencing these outcomes. A literature search was conducted in PubMed/MEDLINE, EMBASE, CINAHL Complete, and Cochrane Library from database conception to April 22, 2018. A total of 85 studies were included in this systematic review. The included studies show that mortality is higher in elderly patients than in adult patients. Lesional etiologies, higher number of comorbidities, NCSE, RSE, longer hospital and intensive care unit stays, and infection during hospitalization are associated with poor outcome. Future studies should consider measuring functional outcomes, comparative studies between elderly and adults and AED clinical trials specific for elderly with SE.

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.

Objective: Test the null hypothesis that Level III support measures do not differ between Chinese and Caucasian nulliparous women with normal support.
Method(s): Pelvic floor 3D MRIs at rest were analyzed (Image J, 3D slicer v. 4.10.1) from Chinese and Caucasian nulliparous women with no prolapse at/below the hymen. Urogenital hiatus (UGH), levator hiatus (LH), and levator bowl volume (LBV) were measured and levator plate (LP) was traced (Figure 1A-D). Perineal body (PB) location was measured relative to Pelvic Inclination Correction System (PICS) line, 34degree below the SCIPP line. Muscle fiber directions were traced for the pubococcygeus (PCM), puborectalis (PR), and external anal sphincter muscles (EAS) in parasagittal slides (Figure1E-F). LP shape was analyzed using principal component analysis (PCA) (Figure 2C-D). Student's t-test was used to compare measurements between groups.
Result(s): Eleven Chinese and 10 Caucasian women were included with average ages of 28+/-3 and 23+/-2 years, respectively (P<.001). BMI was lower in Chinese women (21.5+/-2.5kg/m2 vs 25.6+/-5.6kg/m2, P=.04) and height was similar (1.63 +/-0.06m vs 1.65+/-0.12m, P=.56). Chinese women had 18% smaller UGH, 10% smaller LH and 33% smaller LBV compared to Caucasian women at rest (Figure 2A). PB position was higher in Chinese versus Caucasian women (-2mm vs-12mm, P<.001). PCM fiber direction was more horizontal in Chinese women compared to Caucasian women (16+/-12degree vs 25+/-5degree, P=.047), while the direction of PR (-21+/-5degree vs-20+/-5degree, P=.91) and EAS (-49+/-9degree vs-51 +/-10degree, P=.80) are similar (Figure 2B). PCA showed the LP is significantly more horizontal in Chinese than Caucasian women (PC1 score for Chinese-6.5 vs Caucasian 7.1, P=.020).
Conclusion(s): We reject our null hypothesis. In nulliparas with normal support, Chinese women have a smaller hiatus size and LBV than Caucasian women and their PCM fiber direction and LP shape are oriented more horizontally. Comment: This analysis is consistent with the hypothesis that PCM fiber direction varies with LP shape and bowl volume. These baseline differences in anatomy may influence birth injury, mechanism of prolapse, and treatment outcomes

BACKGROUND:Ideal timing of postoperative beta-blockers is unclear. We hypothesized that patients who do not receive beta-blockers immediately after cardiac surgery would have increased in-hospital mortality (primary outcome) and postoperative hemodynamic, pulmonary, neurologic, or respiratory complications (secondary outcomes). METHODS:We performed a retrospective cohort study evaluating patients who underwent cardiac surgery at our institution from January 1, 2013 to September 30, 2017. We compared outcomes between patients who received beta-blockers by postoperative day (POD) 5 with outcomes in patients who did not receive beta-blockers at any time or received them after POD 5. Inverse probability of treatment weighting was used to minimize confounding. Univariate logistic regression analyses were performed on the weighted sets using absent or delayed beta-blockers as the independent variable and each outcome as dependent variables in separate analyses. A secondary analysis was performed in patients prescribed preoperative beta-blockers. E-values were calculated for significant outcomes. RESULTS:All results were confounder adjusted. Among patients presenting for cardiac surgery, not receiving beta-blockers by POD 5 or at any time was not associated with the primary outcome in-hospital mortality, estimated odds ratio (OR; 99.5% confidence interval [CI]) of 1.6 (0.49-5.1), P = .28. Not receiving beta-blockers by POD 5 or at any time was associated with postoperative atrial fibrillation, estimated OR (99.5% CI) of 1.5 (1.1-2.1), P < .001, and pulmonary complications, estimated OR (99.5% CI) of 3.0 (1.8-5.2), P < .001. E-values were 2.4 for postoperative atrial fibrillation and 5.6 for pulmonary complications. Among patients presenting for cardiac surgery taking preoperative beta-blockers, not receiving beta-blockers by POD 5 or at any time was not associated with the primary outcome mortality, with estimated OR (99.5% CI) of 1.3 (0.43-4.1), P = .63. In this subset, not receiving beta-blockers by POD 5 or at any time was associated with increased adjusted ORs of postoperative atrial fibrillation (OR = 1.6; 99.5% CI, 1.1-2.4; P < .001) and postoperative pulmonary complications (OR = 2.8; 99.5% CI, 1.6-5.2; P < .001). Here, e-values were 2.7 for postoperative atrial fibrillation and 5.1 for pulmonary complications. For the sensitivity analyses for secondary outcomes, exposure and outcome periods overlap. Outcomes may have occurred before or after postoperative beta-blocker administration. CONCLUSIONS: Among patients who undergo cardiac surgery, not receiving postoperative beta-blockers within the first 5 days after cardiac surgery or at any time is not associated with in-hospital mortality and is associated with, but may not necessarily cause, postoperative atrial fibrillation and pulmonary complications.

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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