Faculty Bibliography

Many human genetic diseases, including Hutchinson-Gilford progeria syndrome (HGPS), are caused by single point mutations. HGPS is a rare disorder that causes premature aging and is usually caused by a de novo point mutation in the LMNA gene. Base editors (BEs) composed of a cytidine deaminase fused to CRISPR/Cas9 nickase are highly efficient at inducing C to T base conversions in a programmable manner and can be used to generate animal disease models with single amino-acid substitutions. Here, we generated the first HGPS monkey model by delivering a BE mRNA and guide RNA (gRNA) targeting the LMNA gene via microinjection into monkey zygotes. Five out of six newborn monkeys carried the mutation specifically at the target site. HGPS monkeys expressed the toxic form of lamin A, progerin, and recapitulated the typical HGPS phenotypes including growth retardation, bone alterations, and vascular abnormalities. Thus, this monkey model genetically and clinically mimics HGPS in humans, demonstrating that the BE system can efficiently and accurately generate patient-specific disease models in non-human primates.

In response to the need to better define the natural history of emerging consciousness after traumatic brain injury (TBI) and to better describe the characteristics of the condition commonly labeled Post-traumatic Amnesia, a case definition and diagnostic criteria for the Post- traumatic Confusional State (PTCS) were developed. This project was completed by the Confusion Workgroup of the American Congress of Rehabilitation Medicine Brain Injury Interdisciplinary Special Interest group. The case definition was informed by an exhaustive literature review and expert opinion of workgroup members from multiple disciplines. The workgroup reviewed 2,466 abstracts and extracted evidence from 44 articles. Consensus was reached through teleconferences, face-to-face meetings, and three rounds of modified Delphi voting. The case definition provides detailed description of PTCS (1) core neurobehavioral features, (2) associated neurobehavioral features, (3) functional implications, (4) exclusion criteria, (5) lower boundary, and (6) criteria for emergence. Core neurobehavioral features include disturbances of attention, orientation, and memory as well as excessive fluctuation. Associated neurobehavioral features include emotional and behavioral disturbances, sleep-wake cycle disturbance, delusions, perceptual disturbances and confabulation. The lower boundary distinguishes PTCS from the minimally conscious state while upper boundary is marked by significant improvement in the four core and five associated features. Key research goals are establishment of cut-offs on assessment instruments and determination of levels of behavioral function that distinguish persons in PTCS from those who have emerged to the period of continued recovery.

Acute limb ischemia caused by peripheral venoarterial extracorporeal membrane oxygenation (ECMO) cannulation is associated with increased mortality. Early detection of limb hypoperfusion may lead to timely intervention and prevent irreversible muscle damage. Methods to determine the adequacy of tissue oxygenation in cannulated extremities include bedside physical examination, trending serum biochemical markers, and somatic near-infrared spectroscopy. To prevent ECMO-related limb ischemia events, interventions include the addition of distal antegrade perfusion catheters to the arterial ECMO canula, minimizing arterial cannula diameter, placing arterial and venous cannulae on opposite extremities, and adding a side-arm graft to the cannulated artery. If the limb develops early signs of ischemia, preventative measures such as distal perfusion catheter insertion or changing the location of the arterial cannula should be performed. Acute compartment syndrome requires emergency fasciotomy or amputation if the limb is unsalvageable. Opportunities for future research include improving monitoring technology and standardizing the use of the distal perfusion catheter.

OBJECTIVE:To determine the patient-perceived effectiveness and tolerability of mirabegron compared to solifenacin in a multiple sclerosis (MS) population with overactive bladder (OAB) symptoms. MATERIALS AND METHODS/METHODS:MS patients with OAB symptoms who were not on medication for their urinary symptoms at enrollment were prospectively recruited. Patients enrolled in years 1-2 were prescribed mirabegron, whereas patients enrolled in years 3-4 were prescribed solifenacin. At enrollment and 6-week followup, patients completed several patient reported outcome measures (PROMs). The primary outcome was change in Overactive Bladder Questionnaire Short Form (OAB-q SF) symptom severity and minimal clinically important difference (MCID) achievement. The Patient Assessment of Constipation Symptoms (PAC-SYM) was used to assess bowel function over the treatment period. RESULTS:61 patients were enrolled. The majority of the mirabegron (70%) and the solifenacin (69%) group achieved the OAB-q SF symptom severity MCID. The solifenacin group had a statistically significant greater decrease in its end of study OAB-q SF score (Δ = -37.87 versus -20.43, p=0.02). Constipation improved in the mirabegron group and worsened in the solifenacin group (ΔPAC-SYM =-0.38 versus +0.22; p=0.02), with 30% of patients prescribed solifenacin experiencing worsening above the MCID threshold. CONCLUSION/CONCLUSIONS:Among MS patients, we demonstrated similar response rates to mirabegron and solifenacin, with approximately 50-70% achieving each PROM's MCID. Though this small study showed some short-term evidence that improvement in urinary symptom severity was greater with solifenacin, this potential benefit must be weighed against the observed risk of worsening constipation. Further studies are needed to confirm these findings.

OBJECTIVE:Scalable, accessible forms of behavioral therapy for migraine prevention are needed. We assessed the feasibility and acceptability of progressive muscle relaxation (PMR) delivered by a smartphone application (app) in the Primary Care setting. METHODS:This pilot study was a non-blinded, randomized, parallel-arm controlled trial of adults with migraine and 4+ headache days/month. Eligible participants spoke English and owned a smartphone. All participants were given the RELAXaHEAD app which includes an electronic headache diary. Participants were randomized to receive 1 of the 2 versions of the app-one with PMR and the other without PMR. The primary outcomes were measures of feasibility (adherence to the intervention and diary entries during the 90-day interval) and acceptability (satisfaction levels). We conducted exploratory analyses to determine whether there was a change in Migraine Disability Assessment Scale (MIDAS) scores or a change in headache days. RESULTS:Of 139 participants (77 PMR, 62 control), 116 (83%) were female, mean age was 41.7 ± 12.8 years. Most patients 108/139 (78%) had moderate-severe disability. Using a 1-5 Likert scale, participants found the app easy to use (mean 4.2 ± 0.7) and stated that they would be happy to engage in the PMR intervention again (mean 4.3 ± 0.6). For the first 6 weeks, participants practiced PMR 2-4 days/week. Mean per session duration was 11.1 ± 8.3 minutes. Relative to the diary-only group, the PMR group showed a greater non-significant decline in mean MIDAS scores (-8.7 vs -22.7, P = .100) corresponding to a small-moderate mean effect size (Cohen's d = 0.38). CONCLUSION/CONCLUSIONS:Smartphone-delivered PMR may be an acceptable, accessible form of therapy for migraine. Mean effects show a small-moderate mean effect size in disability scores.

BACKGROUND:Despite innovations in left ventricular assist devices (LVAD) technology, stroke remains a leading cause of morbidity and mortality in this population. Major clinical trials of LVAD have used various definitions and approaches to measuring stroke outcomes which may limit comparison of stroke risk between different devices. METHODS:Data from the five major LVAD randomized, controlled, trials was abstracted to compare definitions of stroke (composite, ischemic, hemorrhagic and disabling) and stroke event rates across trials. Methodological limitations and suggestions to improve research and clinical practices for stroke and LVAD were identified. RESULTS:Comparison of stroke events across LVAD clinical trials is confounded by methodological variability including heterogeneity in stroke definitions, non-standardized evaluation of stroke etiology, oversimplification of stroke severity classification, and inconsistent event rate reporting due to data censoring at the time of death or transplant. Variability in the study of stroke in LVAD patients limits the ability to compare devices and design prevention strategies to mitigate stroke risk. CONCLUSIONS:Based on this review, we propose that future clinical trials: 1) utilize standardized stroke definitions and define stroke subtypes, 2) ensure that neurologists are integrated in study design and event adjudication, 3) include more thorough evaluations of stroke etiology using multimodality techniques, and 4) adopt the National Institutes of Health Stroke Scale to define stroke severity.

This study examined the effect of increasing material-specific verbal and visual memory impairment severity on Rey 15-Item Test (RFIT) and RFIT/Recognition Trial performance. Data from 146 clinically referred patients (109 valid/37 invalid) who completed the RFIT, Brief Visuospatial Memory Test-Revised, and Rey Auditory Verbal Learning Test were analyzed. Rey Auditory Verbal Learning Test/BVMT memory impairment was operationalized as ≥40T (no memory impairment), 30T-39T (mild memory impairment), or ≤29T (severe memory impairment). Medium-to-large correlations emerged between the RFIT and memory measures. Significantly more patients with impaired visual memory, and to a lesser extent verbal memory, failed the RFIT and RFIT/Recognition. RFIT and RFIT/Recognition produced areas under the curve = .80-.90 for detecting invalidity and strong associated psychometric properties among patients without memory impairment, but both yielded low and largely unacceptable accuracy (areas under the curve = .57-.71) when verbal or visual memory impairment of any severity was present. In sum, RFIT performance was significantly affected by increasing material-specific memory deficits, such that it produced acceptable accuracy among unimpaired patients, but accuracy greatly diminished with memory impairment, which is antithetical to a sound performance validity test. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Children with Congenital Zika Syndrome and microcephaly are at high risk for epilepsy; however, the risk is unclear in normocephalic children with prenatal Zika virus (ZIKV) exposure [Exposed Children (EC)]. In this prospective cohort study, we performed epilepsy screening in normocephalic EC alongside a parallel group of normocephalic unexposed children [Unexposed Children (UC)]. We compared the incidence rate of epilepsy among EC and UC at one year of life to global incidence rates. Pregnant women were recruited from public health centers during the ZIKV outbreak in Grenada, West Indies and assessed for prior ZIKV infection using a plasmonic-gold platform that measures IgG antibodies in serum. Normocephalic children born to mothers with positive ZIKV results during pregnancy were classified as EC and those born to mothers with negative ZIKV results during and after pregnancy were classified as UC. Epilepsy screening procedures included a pediatric epilepsy screening questionnaire and video electroencephalography (vEEG). vEEG was collected using a multi-channel microEEG® system for a minimum of 20 minutes along with video recording of participant behavior time-locked to the EEG. vEEGs were interpreted independently by two pediatric epileptologists, who were blinded to ZIKV status, via telemedicine platform. Positive screening cases were referred to a local pediatrician for an epilepsy diagnostic evaluation. Epilepsy screens were positive in 2/71 EC (IR: 0.028; 95% CI: 0.003-0.098) and 0/71 UC. In both epilepsy-positive cases, questionnaire responses and interictal vEEGs were consistent with focal, rather than generalized, seizures. Both children met criteria for a clinical diagnosis of epilepsy and good seizure control was achieved with carbamazepine. Our results indicate that epilepsy rates are modestly elevated in EC. Given our small sample size, results should be considered preliminary. They support the use of epilepsy screening procedures in larger epidemiological studies of children with congenital ZIKV exposure, even in the absence of microcephaly, and provide guidance for conducting epilepsy surveillance in resource limited settings.

OBJECTIVE:To evaluate whether multiple sessions of transcranial direct current stimulation (tDCS) applied to the primary motor (M1) cortex paired with aerobic exercise can improve walking functions in multiple sclerosis (MS). METHODS:MS participants were recruited for a double-blind, parallel-arm, randomized, sham-controlled trial and assigned to 10 sessions (5 d/wk for 2 weeks) of either active or sham tDCS paired with unloaded cycling for 20 minutes. Stimulation was administered over the left M1 cortex (2.5 mA; anode over C3/cathode over FP2). Gait spatiotemporal parameters were assessed using a wearable inertial sensor (10-meter and 2-minute walking tests). Measurements were collected at baseline, end of tDCS intervention, and 4-week postintervention to test for duration of any benefits. RESULTS:A total of 15 participants completed the study, nine in the active and six in the sham condition. The active and sham groups were matched according to gender (50% vs. 40% female), neurologic disability (median EDSS 5.5 vs. 5), and age (mean 52.1 ± 12.9 vs. 53.7 ± 9.8 years). The active group had a significantly greater increase in gait speed (0.87 vs. 1.20 m/s, p < 0.001) and distance covered during the 2-minute walking test (118.53 vs. 133.06 m, p < 0.001) at intervention end compared to baseline. At 4-week follow-up, these improvements were maintained (baseline vs. follow-up: gait speed 0.87 vs. 1.18 m/s, p < 0.001; distance traveled 118.53 vs. 143.82 m, p < 0.001). INTERPRETATION/CONCLUSIONS:Multiple sessions of tDCS paired with aerobic exercise lead to cumulative and persisting improvements in walking and endurance in patients with MS.