Faculty Bibliography

Abstract Background: Loss of hand dexterity is disabling and reduces quality of life. People living with progressive forms of MS have marked neurologic disabilities but limited rehabilitation options. Transcranial direct current stimulation (tDCS) is a method of noninvasive brain stimulation in which stimulation delivered during motor training can strengthen outcomes. We have established a remotely supervised tDCS (RS-tDCS) protocol that delivers multiple stimulation sessions paired with training to participants at home.
Objective(s): To evaluate a blinded randomized sham-controlled clinical trial of active vs. sham tDCS paired with manual dexterity training for people with progressive MS.
Method(s): We recruited right-hand dominant individuals with progressive MS and hand dexterity impairment. Participants completed 20 sessions of daily (M-F) manual dexterity and were randomized to either active (2.0 mA) or sham primary motor cortex (M1-SO) tDCS. Manual dexterity was measured with the Nine-Hole Peg Test (9HPT) and Dellon-Modified Moberg Pick-Up test (MMPUT) at baseline and study end and transformed to normative z-scores for comparison.
Result(s): Participants were n=60 with primary (32%) or secondary (68%) progressive MS (52% female, ages 37-72 years, and a median Expanded Disability Status Scale (EDSS) score of 5.0 [1.5-7.5]). The intervention was safe and well tolerated, with n=59/60 (98%) completing 18/20 daily sessions. Combining hands and tasks, the full group improved following the manual dexterity training (mean z-score improvement 1.64+/-9.53, p=0.016). Active tDCS led to greater improvement (mean z-score improvement 4.51+/-8.78, p=0.001). Analyzing those with right- or left-hand impairment at baseline, the active tDCS group had significant improvement on the 9HPT (Right: p=0.036, Left: p=0.028) and trended towards significant improvement for the MMPUT (Right: p=0.071, Left: p=0.079).
Conclusion(s): At-home manual dexterity training paired with tDCS is a safe, tolerable, and feasible intervention for people with progressive MS and hand impairment. Training outcomes are augmented with simultaneous M1-SO tDCS. Research Category and Technology and Methods Clinical Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: tDCS, motor training, multiple sclerosis, teleintervention
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Abstract Objectives: Evaluate feasibility and preliminary efficacy of remotely supervised transcranial Direct Current Stimulation (RS-tDCS) interventions for persistent post-traumatic headache (PPTH) secondary to mild TBI (mTBI).
Method(s): Veterans with PPTH completed a 28-day baseline observation of headache days and received either active or sham RS-tDCS paired with mindfulness meditation. This 4-week intervention of 20-minutes daily (M-F) RS-tDCS (anodal stimulation dlPFC) was monitored via VA Video Connect. Feasibility was determined by the number of participants completing >=80% of the intervention. Efficacy was measured by changes in number of moderate/severe headache days from baseline period to the end of treatment phase, and 4-week post-treatment follow-up. Secondary endpoints included total number of headache days, acute pain medication use, as well as headache- and mTBI-related disability.
Result(s): Twenty-six veterans (46.6+/-8.7 years) with PPTH completed baseline observations and were randomized to either active (n=13) or sham (n=13) treatment groups. A total of 22/25 (88%) participants fully completed either active (10/12) or sham (12/13) interventions (p=.0.59). Within-group analyses reveled significant reductions in moderate/severe headache days in the active (p=0.04) but not sham (p=0.54) groups. This resulted in a trend towards significant reductions in moderate/severe headache days in the active vs. sham groups (p = 0.07). Active participants also demonstrated a reduction in total number of headache days during treatment (p=0.04) where the sham group did not (p=0.70). There is statistically significant reduction in total number of headache days during treatment for active vs. sham participants (p=0.03). No significant differences were maintained during the 4-week post-treatment follow-up (p's>0.05).
Conclusion(s): RS-tDCS treatment feasible with high adherence and effective for veterans with PPTH. Findings suggest that active RS-tDCS via dlPFC reduce headache frequency and improve clinical outcomes. A larger phase II study is warranted to confirm these findings and inform evaluation for clinical use. Research Category and Technology and Methods Clinical Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: tDCS, Persistent Post-traumatic headache, Veterans, mTBI
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Background/Purpose: Home exercise programs (HEP) supplement treatment with the intent to promote retention and generalization of skills (Muratori et al., 2013). With an increased frequency of skill practice, neural connections have greater opportunity to restore and 'enhance the stability of recall and recognition schemas' (Maas et al., 2008). Unfortunately, psychosocial barriers can lead to inconsistent implementation of speech HEPs but minimal research exists identifying these factors. One study assessed HEP implementation for patients with childhood apraxia of speech, but psychosocial barriers experienced by parents of children with cleft palate and other craniofacial conditions has not been researched (Lim et al., 2020). Through this study, the authors aim to ascertain the barriers involved in suppressing the implementation of speech HEPs within the cleft and craniofacial population. Methods/Description: This is a single center survey study distributed in October 2022 consisting of 3 components including: demographics (e.g., ethnicity, diagnosis), speech services (e.g., frequency, additional services), and psychosocial barriers (e.g., mental health of parent, patient motivation). Approximately 30-40 parents/caregivers of children with cleft palate and/or other craniofacial conditions who were assigned speech HEPs submitted survey responses via Qualtrics. Parents/caregivers were presented with 20 items which included a combination of multiple choice and open-ended questions. The survey was translated into both English and Spanish. At the time of survey completion, patients had already undergone a speech evaluation and therapy was initiated as indicated by the treating speechlanguage pathologist (SLP). Descriptive statistics were utilized to analyze data and gather conclusions.
Result(s): Researchers analyzed preliminary data as responses continue to be collected at the time of abstract submission. Preliminary data suggests a diverse demographic sample comprised of a variety of ethnicities, religions, and places of residence. Receiving additional community-based speech services displayed as routine for all patients. To date, 100% of respondents identified at least one psychosocial barrier impacting their ability to execute HEPs. All respondents were mothers who indicated that the main barriers to implementation of their speech HEPs included parent fatigue, parent mental health, and child behavior/noncompliance of the task.
Conclusion(s): The preliminary findings from this study confirm the hypothesis that psychosocial barriers negatively impact a parent/caregiver's ability to execute a speech home exercise program. Data also provides insight into what specific barriers affect HEP fulfillment despite the foreseen benefits of the assigned tasks. Limitations include a small sample size and potential for selection bias, suggesting that additional multi-center studies should be conducted to gain further insight into these psychosocial barriers

Background: Decreased peak oxygen consumption during exercise (peak Vo2) is a well-established prognostic marker for mortality in ambulatory heart failure. After heart transplantation, the utility of peak Vo2 as a marker of post-transplant survival is not well established.
Methods and Results: We performed a retrospective analysis of adult heart transplant recipients at the Hospital of the University of Pennsylvania who underwent cardiopulmonary exercise testing within a year of transplant between the years 2000 to 2011. Using time-to-event models, we analyzed the hazard of mortality over nearly two decades of follow-up as a function of post-transplant percent predicted peak Vo2 (%Vo2). A total of 235 patients met inclusion criteria. The median post-transplant %Vo2 was 49% (IQR 42 to 60). Each standard deviation (+/-14%) increase in %Vo2 was associated with a 32% decrease in mortality in adjusted models (HR 0.68, 95% CI 0.53 to 0.87, p = 0.002). A %Vo2 below 29%, 64% and 88% predicted less than 80% survival at 5, 10, and 15 years, respectively.
Conclusion(s): Post-transplant peak Vo2 is a highly significant prognostic marker for long-term post-transplant survival. It remains to be seen whether decreased peak Vo2 post-transplant is modifiable as a target to improve post-transplant longevity.
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STUDY OBJECTIVES/OBJECTIVE:Obstructive sleep apnea (OSA) has been associated with more severe acute coronavirus disease-2019 (COVID-19) outcomes. We assessed OSA as a potential risk factor for Post-Acute Sequelae of SARS-CoV-2 (PASC). METHODS:We assessed the impact of preexisting OSA on the risk for probable PASC in adults and children using electronic health record data from multiple research networks. Three research networks within the REsearching COVID to Enhance Recovery initiative (PCORnet Adult, PCORnet Pediatric, and the National COVID Cohort Collaborative [N3C]) employed a harmonized analytic approach to examine the risk of probable PASC in COVID-19-positive patients with and without a diagnosis of OSA prior to pandemic onset. Unadjusted odds ratios (ORs) were calculated as well as ORs adjusted for age group, sex, race/ethnicity, hospitalization status, obesity, and preexisting comorbidities. RESULTS:Across networks, the unadjusted OR for probable PASC associated with a preexisting OSA diagnosis in adults and children ranged from 1.41 to 3.93. Adjusted analyses found an attenuated association that remained significant among adults only. Multiple sensitivity analyses with expanded inclusion criteria and covariates yielded results consistent with the primary analysis. CONCLUSIONS:Adults with preexisting OSA were found to have significantly elevated odds of probable PASC. This finding was consistent across data sources, approaches for identifying COVID-19-positive patients, and definitions of PASC. Patients with OSA may be at elevated risk for PASC after SARS-CoV-2 infection and should be monitored for post-acute sequelae.

Many conditions can present with accumulation of calcium in the brain and manifest with a variety of neurological symptoms. Brain calcifications can be primary (idiopathic or genetic) or secondary to various pathological conditions (e.g., calcium-phosphate metabolism derangement, autoimmune disorders and infections, among others). A set of causative genes associated with primary familial brain calcification (PFBC) has now been identified, and include genes such as SLC20A2, PDGFB, PDGFRB, XPR1, MYORG, and JAM2. However, many more genes are known to be linked with complex syndromes characterized by brain calcifications and additional neurologic and systemic manifestations. Of note, many of these genes encode for proteins involved in cerebrovascular and blood-brain barrier functions, which both represent key anatomical structures related to these pathological phenomena. As a growing number of genes associated with brain calcifications is identified, pathways involved in these conditions are beginning to be understood. Our comprehensive review of the genetic, molecular, and clinical aspects of brain calcifications offers a framework for clinicians and researchers in the field.

Stimulated Raman histology (SRH) is an ex vivo optical imaging method that enables microscopic examination of fresh tissue intraoperatively. The conventional intraoperative method uses frozen section analysis, which is labor and time intensive, introduces artifacts that limit diagnostic accuracy, and consumes tissue. SRH imaging allows rapid microscopic imaging of fresh tissue, avoids tissue loss, and enables remote telepathology review. This improves access to expert neuropathology consultation in both low- and high-resource practices. We clinically validated SRH by performing a blinded, retrospective two-arm telepathology study to clinically validate SRH for telepathology at our institution. Using surgical specimens from 47 subjects, we generated a data set composed of 47 SRH images and 47 matched whole slide images (WSIs) of formalin-fixed, paraffin-embedded tissue stained with hematoxylin and eosin, with associated intraoperative clinicoradiologic information and structured diagnostic questions. We compared diagnostic concordance between WSI and SRH-rendered diagnoses. Also, we compared the 1-year median turnaround time (TAT) of intraoperative conventional neuropathology frozen sections with prospectively rendered SRH-telepathology TAT. All SRH images were of sufficient quality for diagnostic review. A review of SRH images showed high accuracy in distinguishing glial from nonglial tumors (96.5% SRH vs 98% WSIs) and predicting final diagnosis (85.9% SRH vs 93.1% WSIs). SRH-based diagnosis and WSI-permanent section diagnosis had high concordance (κ = 0.76). The median TAT for prospectively SRH-rendered diagnosis was 3.7 minutes, approximately 10-fold shorter than the median frozen section TAT (31 minutes). The SRH-imaging procedure did not affect ancillary studies. SRH generates diagnostic virtual histologic images with accuracy comparable to conventional hematoxylin and eosin-based methods in a rapid manner. Our study represents the largest and most rigorous clinical validation of SRH to date. It supports the feasibility of implementing SRH as a rapid method for intraoperative diagnosis complementary to conventional pathology laboratory methods.

BACKGROUND AND OBJECTIVES:Functional outcomes after stroke are strongly related to focal injury measures. However, the role of global brain health is less clear. In this study, we examined the impact of brain age, a measure of neurobiological aging derived from whole-brain structural neuroimaging, on poststroke outcomes, with a focus on sensorimotor performance. We hypothesized that more lesion damage would result in older brain age, which would in turn be associated with poorer outcomes. Related, we expected that brain age would mediate the relationship between lesion damage and outcomes. Finally, we hypothesized that structural brain resilience, which we define in the context of stroke as younger brain age given matched lesion damage, would differentiate people with good vs poor outcomes. METHODS:We conducted a cross-sectional observational study using a multisite dataset of 3-dimensional brain structural MRIs and clinical measures from the ENIGMA Stroke Recovery. Brain age was calculated from 77 neuroanatomical features using a ridge regression model trained and validated on 4,314 healthy controls. We performed a 3-step mediation analysis with robust mixed-effects linear regression models to examine relationships between brain age, lesion damage, and stroke outcomes. We used propensity score matching and logistic regression to examine whether brain resilience predicts good vs poor outcomes in patients with matched lesion damage. RESULTS:= 0.004). DISCUSSION:We provide evidence that younger brain age is associated with superior poststroke outcomes and modifies the impact of focal damage. The inclusion of imaging-based assessments of brain age and brain resilience may improve the prediction of poststroke outcomes compared with focal injury measures alone, opening new possibilities for potential therapeutic targets.

Rationale: Adverse reactions following COVID-19 vaccination are common. We sought to characterize the most common cutaneous manifestations following COVID-19 vaccine administration and identify potential predictive factors.
Method(s): A retrospective chart review was conducted for patients seen in the allergy clinic between December 2020 and May 2021 for COVID-19 vaccine counseling. Details of reactions to either mRNA COVID-19 vaccine were noted. Cutaneous findings were defined as any local reaction including pain, redness or swelling, or generalized rash.
Result(s): Twenty-four patients out of 115 patients (20.9%) had any type of cutaneous reaction after vaccination. Most were female (n=21, 87.5%). Seven of these 24 patients had a local reaction alone. Two patients had immediate onset of generalized pruritus and rash (1 of these patients had symptom resolution by the next morning, the other resolved 8 days post-vaccination). Four patients (16.7%) had a delayed (>6 hours after vaccination) generalized pruritic rash, three of which resolved within 2 weeks and one resolved after 6 weeks. Four patients with a history of chronic urticaria (CU) had a flare of urticaria following vaccination beginning 1-2 days later. One additional patient with CU had delayed pruritus only. One patient developed urticaria 1 day after receiving vaccination with persistence of urticaria beyond 6 weeks.
Conclusion(s): Cutaneous ARs were common (20%) following COVID-19 vaccination. Most rashes were delayed and resolved within 2 weeks with no additional sequelae. In this cohort, patients with a history of CU were seen to have flares of symptoms following vaccination. Cutaneous reactions were more commonly seen in women.
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The radiation-attenuated Plasmodium falciparum sporozoites (PfSPZ) Vaccine has demonstrated safety and immunogenicity in 5-month-old to 50-year-old Africans in multiple trials. Except for one, each trial has restricted enrollment to either infants and children or adults < 50 years old. This trial was conducted in Equatorial Guinea and assessed the safety, tolerability, and immunogenicity of three direct venous inoculations of 1.8 × 106 or 2.7 × 106 PfSPZ, of PfSPZ Vaccine, or normal saline administered at 8-week intervals in a randomized, double-blind, placebo-controlled trial stratified by age (6-11 months and 1-5, 6-10, 11-17, 18-35, and 36-61 years). All doses were successfully administered. In all, 192/207 injections (93%) in those aged 6-61 years were rated as causing no or mild pain. There were no significant differences in solicited adverse events (AEs) between vaccinees and controls in any age group (P ≥ 0.17). There were no significant differences between vaccinees and controls with respect to the rates or severity of unsolicited AEs or laboratory abnormalities. Development of antibodies to P. falciparum circumsporozoite protein occurred in 67/69 vaccinees (97%) and 0/15 controls. Median antibody levels were highest in infants and 1-5-year-olds and declined progressively with age. Antibody responses in children were greater than in adults protected against controlled human malaria infection. Robust immunogenicity, combined with a benign AE profile, indicates children are an ideal target for immunization with PfSPZ Vaccine.