Development of a Novel Evidence-Based Practice-Specific Competency for Doctor of Physical Therapy Students in Clinical Education: A Modified Delphi Approach.

INTRODUCTION: Evidence-based practice (EBP) results in high-quality care and decreases unwarranted variation in practice. REVIEW OF THE LITERATURE: Few performance criteria related to EBP are included in physical therapy clinical education (CE) performance measures, despite EBP requirements in Doctor of Physical Therapy education. The purpose of this study was to develop EBP-specific competencies that may be used for Doctor of Physical Therapy students for use throughout CE. SUBJECTS: Thirteen subject matter experts (SME) participated in this study. METHODS: Subject matter experts were asked to rank each core EBP competency, from a previously described framework, using a 3-point Likert scale, which included "Not Essential," "Essential," and "Not Sure." A consensus of 70% or greater for the "Essential" rating advanced the competency to the final Delphi round, whereas a consensus of 70% or greater for the "Not Essential" rating was required for competency elimination. Subject matter experts voted to either "Accept" or "Modify" the competencies that had reached the inclusion consensus threshold. All competencies that reached consensus for inclusion after all 3 rounds were included in the final EBP Domain of Competence. RESULTS: Consensus was achieved in round one for 38% (n = 26) of items. In round 2, a consensus was achieved for 20% (n = 8) of items. Of the items remaining after rounds 1 and 2, 6 overarching competencies were identified, and all remaining items served as descriptions and specifications in the final EBP Domain of Competence. DISCUSSION AND CONCLUSIONS: The 6 competencies developed from this study constitute the EBP Domain of Competence and may be used throughout CE to assess students' EBP competency in clinical practice.

The impact of post-operative enteral nutrition on duodenal injury outcomes: A post hoc analysis of an EAST multicenter trial.

BACKGROUND: Leak following surgical repair of traumatic duodenal injuries results in prolonged hospitalization and oftentimes nil per os(NPO) treatment. Parenteral nutrition(PN) has known morbidity; however, duodenal leak(DL) patients often have complex injuries and hospital courses resulting in barriers to enteral nutrition(EN). We hypothesized EN alone would be associated with 1)shorter duration until leak closure and 2)less infectious complications and shorter hospital length of stay(HLOS) compared to PN. METHODS: This was a post-hoc analysis of a retrospective, multicenter study from 35 Level-1 trauma centers, including patients >14 years-old who underwent surgery for duodenal injuries(1/2010-12/2020) and endured post-operative DL. The study compared nutrition strategies: EN vs PN vs EN + PN using Chi-Square and Kruskal-Wallis tests; if significance was found pairwise comparison or Dunn's test were performed. RESULTS: There were 113 patients with DL: 43 EN, 22 PN, and 48 EN + PN. Patients were young(median age 28 years-old) males(83.2%) with penetrating injuries(81.4%). There was no difference in injury severity or critical illness among the groups, however there were more pancreatic injuries among PN groups. EN patients had less days NPO compared to both PN groups(12 days[IQR23] vs 40[54] vs 33[32],p = <0.001). Time until leak closure was less in EN patients when comparing the three groups(7 days[IQR14.5] vs 15[20.5] vs 25.5[55.8],p = 0.008). EN patients had less intra-abdominal abscesses, bacteremia, and days with drains than the PN groups(all p < 0.05). HLOS was shorter among EN patients vs both PN groups(27 days[24] vs 44[62] vs 45[31],p = 0.001). When controlling for predictors of leak, regression analysis demonstrated EN was associated with shorter HLOS(ß -24.9, 95%CI -39.0 to -10.7,p < 0.001). CONCLUSION: EN was associated with a shorter duration until leak closure, less infectious complications, and shorter length of stay. Contrary to some conventional thought, PN was not associated with decreased time until leak closure. We therefore suggest EN should be the preferred choice of nutrition in patients with duodenal leaks whenever feasible. LEVEL OF EVIDENCE: IV.

Managing career transitions in the profession of acute care surgery.

Career shifts are a naturally occurring part of the trauma and acute care surgeon's profession. These transitions may occur at various timepoints throughout a surgeon's career and each has their own specific challenges. Finding a good fit for your first job is critical for ensuring success as an early career surgeon. Equally, understanding how to navigate promotions or a change in job location mid-career can be fraught with uncertainty. As one progresses in their career, knowing when to take on a leadership position is oftentimes difficult as it may mean a change in priorities. Finally, navigating your path towards a fulfilling retirement is a complex discussion that is different for each surgeon. The American Association for the Surgery of Trauma (AAST) convened an expert panel of acute care surgeons in a virtual grand rounds session in August 2023 to address the aforementioned career transitions and highlight strategies for successfully navigating each shift. This was a collaboration between the AAST Associate Member Council (consisting of surgical resident, fellow and junior faculty members), the AAST Military Liaison Committee and the AAST Healthcare Economics Committee. Led by two moderators, the panel consisted of early, mid-career and senior surgeons, and recommendations are summarized below and in figure 1.

Primary Repair Versus Resection for AAST Grade I and II Colon Injuries: Does the Type of Repair Matter?

INTRODUCTION: The management of traumatic colon injuries has evolved over the past two decades. Recent evidence suggests that primary repair or resection over colostomy may decrease morbidity and mortality. Data comparing patients undergoing primary repair versus resection are lacking. We sought to compare the outcomes of patients undergoing primary repair versus resection for low-grade colon injuries. METHODS: A retrospective review of all patients who presented with American Association for the Surgery of Trauma grade I and II traumatic colon injuries to our Level I trauma center between 2011 and 2021 was performed. Patients were further dichotomized based on whether they underwent primary repair or resection with anastomosis. Outcome measures included length of stay data, infectious complications, and mortality. RESULTS: A total of 120 patients met inclusion criteria. The majority of patients (76.7%) were male, and the average age was 35.6 ± 13.1 y. Most patients also underwent primary repair (80.8%). There were no statistically significant differences between the groups in arrival physiology or in injury severity score. Length of stay data including hospital length of stay, intensive care unit length of stay, and ventilator days were similar between groups. Postoperative complications including pneumonia, surgical site infections, fascial dehiscence, the development of enterocutaneous fistulas, and unplanned returns to the operating room were also all found to be similar between groups. The group who underwent resection with anastomosis did demonstrate a higher rate of intra-abdominal abscess development (3.1% versus 26.1%, P < 0001). Mortality between both groups was not found to be statistically significant (7.2% versus 4.3%, P = 0.4) CONCLUSIONS: For low-grade (American Association for the Surgery of Trauma I and II) traumatic colon injuries, patients undergoing primary repair demonstrated a decreased rate of intra-abdominal abscess development when compared to patients who underwent resection with anastomosis.

Comparison of Erector Spinae Plane Blocks Versus Multimodal Pain Management for Traumatic Rib Fractures: A Matched Cohort Study.

INTRODUCTION: Erector spinae plane blocks (ESPBs) are frequently utilized when treating patients with multiple rib fractures. While previous work has demonstrated the efficacy of ESPB as an adequate method of pain control, there has been no work comparing a continuous ESPB to "best practice" multimodal pain control. We hypothesize that a continuous ESPB catheter combined with a multimodal pain regimen may be associated with a decrease in opioid requirements when compared to a multimodal pain regimen alone. METHODS: This was a retrospective observational cohort study at a level 1 trauma center from September 2016 through September 2021. Inclusion criteria included patients 18 y or older with at least three unilateral rib fractures who were not mechanically ventilated during admission. The primary outcome was the total morphine equivalents utilized throughout the index admission. RESULTS: A total of 142 patients were included in this study, 71 in each cohort. Patients included had a mean age of 52.5 y, and 18% were female. Demographic data including injury severity score, total number of rib fractures, and length of stay were similar. While there was a trend toward a decrease in morphine equivalents in the patient cohort undergoing ESPB catheter placement, this was not found to be statistically significant (284.3 ± 244.8 versus 412.6 ± 622.2, P = 0.5). CONCLUSIONS: While ESPB catheters are frequently utilized for analgesia in the setting of multiple rib fractures, there was no decrease in total opioid usage when compared with patients who were managed with a multimodal pain regimen alone. Further assessment comparing ESPB catheters to best practice multimodal pain control regimens through a prospective, multicenter trial is required to further validate these findings.

Reliability of the safety threats and adverse events in trauma (STAT) taxonomy using trauma video review.

PURPOSE: The STAT (Safety Threats and Adverse Events in Trauma) taxonomy was developed through expert consensus, and groups 65 identified trauma resuscitation adverse events (AEs) into nine distinct categories. It provides a framework for standardized analysis of trauma resuscitations and creates a foundation for targeted quality improvement and patient safety initiatives. This study aims to evaluate the reliability of the STAT taxonomy in identifying AEs during video-recorded trauma resuscitations. METHODS: High-definition audiovisual data from 30 trauma resuscitations were reviewed. Videos were assessed and scored by four independent reviewers (two trainees and two staff). The STAT taxonomy was used to identify AEs based on binary responses: yes and no. Inter-rater reliability was calculated using Gwet's AC1. The frequencies of AEs were tallied and reported as counts and percentages. RESULTS: The most common AEs identified in the videos were failure to measure temperature (86.7%) and inadequate personal protective equipment (86.7%), followed by inability to use closed-loop communication (76.7%). The agreement on all AEs between reviewers was 0.94 (95% CI: 0.93-0.95). The Gwet's AC1 agreement across the 9 AE categories was paramedic handover (0.82), airway and breathing (0.99), circulation (0.95), assessment of injuries (0.91), management of injuries (0.96), procedure-related (0.97), patient monitoring and IV access (0.99), disposition (0.98), team communication and dynamics (0.87). CONCLUSION: The STAT taxonomy demonstrated excellent inter-rater reliability between reviewers and can be used to identify AEs in video-recorded trauma resuscitations. These results provide a foundation for adapting video review to objectively quantify and assess AEs in the trauma bay.

Outcomes among trauma patients with duodenal leak following primary versus complex repair of duodenal injuries: An Eastern Association for the Surgery of Trauma multicenter trial.

BACKGROUND: Duodenal leak is a feared complication of repair, and innovative complex repairs with adjunctive measures (CRAM) were developed to decrease both leak occurrence and severity when leaks occur. Data on the association of CRAM and duodenal leak are sparse, and its impact on duodenal leak outcomes is nonexistent. We hypothesized that primary repair alone (PRA) would be associated with decreased duodenal leak rates; however, CRAM would be associated with improved recovery and outcomes when leaks do occur. METHODS: A retrospective, multicenter analysis from 35 Level 1 trauma centers included patients older than 14 years with operative, traumatic duodenal injuries (January 2010 to December 2020). The study sample compared duodenal operative repair strategy: PRA versus CRAM (any repair plus pyloric exclusion, gastrojejunostomy, triple tube drainage, duodenectomy). RESULTS: The sample (N = 861) was primarily young (33 years) men (84%) with penetrating injuries (77%); 523 underwent PRA and 338 underwent CRAM. Complex repairs with adjunctive measures were more critically injured than PRA and had higher leak rates (CRAM 21% vs. PRA 8%, p < 0.001). Adverse outcomes were more common after CRAM with more interventional radiology drains, prolonged nothing by mouth and length of stay, greater mortality, and more readmissions than PRA (all p < 0.05). Importantly, CRAM had no positive impact on leak recovery; there was no difference in number of operations, drain duration, nothing by mouth duration, need for interventional radiology drainage, hospital length of stay, or mortality between PRA leak versus CRAM leak patients (all p > 0.05). Furthermore, CRAM leaks had longer antibiotic duration, more gastrointestinal complications, and longer duration until leak resolution (all p < 0.05). Primary repair alone was associated with 60% lower odds of leak, whereas injury grades II to IV, damage control, and body mass index had higher odds of leak (all p < 0.05). There were no leaks among patients with grades IV and V injuries repaired by PRA. CONCLUSION: Complex repairs with adjunctive measures did not prevent duodenal leaks and, moreover, did not reduce adverse sequelae when leaks did occur. Our results suggest that CRAM is not a protective operative duodenal repair strategy, and PRA should be pursued for all injury grades when feasible. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Using Arterial Pressure Index to Predict Arterial Injuries in Penetrating Trauma to the Upper Extremities.

BACKGROUND: Upper extremity (UE) vascular injuries account for 18.4% of all traumatic vascular injuries. Arterial pressure index (API) use in lower extremity injuries to determine the need for further investigations is well established. However, due to collateral circulation in UEs, it is unclear if the same algorithm can be applied. The purpose of this study was to determine if APIs can be used to determine the need for computed tomography angiogram (CTA) in penetrating UE trauma. METHODS: All adult trauma patients with penetrating UE trauma and APIs from 2006 to 2016 were identified at 3 urban US level 1 trauma centers. Sensitivity, specificity, and positive and negative predictive values of APIs <.9 in detecting UE arterial injuries were calculated. RESULTS: During the 11-year study period, 218 patients met our inclusion criteria. Gunshot wounds comprised 76.6% and stab wounds 17.9%. Median injury severity score and API were 9 and 1, respectively. Seventy-two of our patients underwent evaluation with CTA. Of the injuries, the most common were thrombus or occlusion (46.7%), transection (23.1%), and dissection (15.4%), radiographically. Ultimately, 32 patients underwent surgical.

Laparoscopic-Assisted Pancreatic Necrosectomy: Technique and Initial Outcomes.

BACKGROUND: Necrotizing pancreatitis (NP) may result de novo or following procedures such as ERCP or partial pancreatectomy (post-procedural), and may require surgical debridement. Video-assisted retroperitoneal debridement (VARD) is a standard approach for NP that employs a 5 cm incision with varying degrees of blind and open debridement. We describe our technique and outcomes of a modified VARD called laparoscopic-assisted pancreatic necrosectomy (LAPN) performed through a single 12 mm incision that uses direct laparoscopic visualization during debridement. METHODS: At one medical center, all LAPN patients (2012-2020) were assessed for demographics, disease factors, and outcomes. Bivariate logistic regression analyses were performed to identify factors independently associated with recovery after LAPN for patients with de novo vs post-procedural necrosum. RESULTS: Over 9 years, 60 patients underwent LAPN for NP. Median age was 57 years (IQR: 47-66) and 43 (69%) were men. Pancreas necrosum was de novo in 39 (63%) patients and post-procedural in 23 (37%). NP resolved with a median of 1 LAPN procedure and median hospitalization was 33 days. The LAPN major morbidity rate and in-hospital mortality rate were 47% and 5%. No significant differences were seen between NP etiology cohorts, although post-procedure NP patients trended towards a faster clinical recovery to baseline compared to de novo patients (193 vs 394 days; p-value = .07). CONCLUSIONS: LAPN offers a smaller incision with excellent visualization and non-inferior outcomes, regardless of etiology, with likely faster recovery for patients with post-procedural vs de novo necrotizing pancreatitis.

Faith Leaders' Views on Collaboration with Mental Health Professionals.

When faced with experiences of mental struggle, Americans often turn to faith leaders as their first recourse. Although studies have explored religious leaders' mental health literacy, few studies have investigated how religious leaders believe faith communities and mental health professionals should collaborate. The data gathered for this research is from in-depth and focus group interviews with faith leaders from Christian, Jewish, Buddhist, and Sikh communities in South Texas and the Mid-Atlantic region between 2017-2019 (n=67). This research analyzed faith leaders' response to the question "How can mental health professionals and faith communities better work together" by utilizing the flexible coding approach (Deterding and Waters 2018). Four distinct themes emerged from the faith leaders' responses: education, relationship building, external factors, and dismissal. By learning about how faith leaders believe they can better work together with mental health professionals we can help bridge the gap between religion and mental health further by fostering a much-needed dialogue between these two groups.

Traumatic Blunt Injuries to the Celiac Artery: A 5-Year Review From a Level I Trauma Center.

BACKGROUND: Injury to the celiac artery secondary to a blunt mechanism of trauma is an extremely rare injury that accounts for only 1%-2% of all visceral vascular lesions. Although rare, this injury is associated with significant mortality. Despite this high mortality, there are currently only a few published case series of blunt celiac artery injuries in the literature. This study sought to review all cases of blunt celiac artery injuries that presented to our Level I trauma center over a 5-year period. METHODS: This was a retrospective chart review of all patients who presented with a traumatic blunt celiac artery injury between January 2012 and March 2017. RESULTS: A total of 10 patients met the inclusion criteria for this study. The majority of patients were male (7/10, 70%), the average age was 38.3 ± 16.1 years, and overall mortality was 20% (2/10). On average, patients spent 10.2 ± 6.5 days in the hospital, 4.4 ± 4.5 days in the ICU, and 1.6 ± 2.0 days on the ventilator. The majority of patients presented with either an intimal dissection (3/10, 30%) or an intraluminal thrombus (3/10, 30%). Other injuries included pseudoaneurysms (2/10, 20%), complete avulsion (1/10, 10%), and an intimal dissection with thrombus (1/10, 10%). Of these injuries, 2 (20%) were noted to have retrograde flow on imaging studies including computed tomography angiography and a visceral angiogram. The majority of patients (8/10, 80%) were managed nonoperatively, and 5 (50%) patients were discharged home on aspirin. One patient who was initially managed nonoperatively required an unplanned return to the operating room for ischemic bowel, liver, and stomach. There were no other complications noted. DISCUSSION: Traumatic blunt injury to the celiac artery is rare. Although there are multiple treatment options, there is currently no consensus in regard to management guidelines. In this case series, the majority of patients were successfully managed nonoperatively suggesting that a selective approach for intervention on patients with a blunt celiac artery injury should be considered.

A comparison of gait stability between younger and older adults while head turning.

Head turning while walking may challenge stability by altering visual and vestibular information. Whether there are age-related changes that affect gait stability while head turning during walking remains unknown. The aim of the current study was to compare gait stability between younger and older adults immediately following a head turn while walking. Ten younger [mean (SD)] [23.4 (3.3) years] and ten older [68.8 (6.0) years] healthy adults walked on a treadmill at their preferred gait velocity and performed head turns by responding to a visual cue. The margin of stability (MoS) in the mediolateral (MoSML), anterior (MoSA) and posterior (MoSP) directions, foot placement (mean step length and width) and rotation of the head, trunk and pelvis were calculated for the four steps immediately following a cue to head turn and compared to walking only. Older adults increased their MoSML and younger adults increased their MoSP immediately following a head turn. However, older adults had a significantly greater MoSP than younger adults during this time. Older adults also had greater pelvic rotation velocity and a trend towards smaller head-on-trunk rotation compared to younger adults. Age does not compromise the stability of healthy older compared to younger adults immediately following or when completing a head turn. However, older adults may use a different motor strategy to perform a head turn to limit isolated movement of the head and the effects of a changing sensory frame of reference.

Does hypertension at initial presentation adversely affect outcomes in pediatric traumatic brain injury?

BACKGROUND: Adults with traumatic brain injury (TBI) who present hypertensive suffer worse outcomes and increased mortality compared to normotensive patients. The purpose of this study is to determine if age-adjusted hypertension on presentation is associated with worsened outcomes in pediatric TBI. METHODS: A retrospective chart review was conducted on pediatric patients with severe TBI admitted to a single system pediatric tertiary care center. The primary outcome was mortality. Secondary outcomes included length of stay, need for neurosurgical intervention, duration of mechanical ventilation, and the need for inpatient rehabilitation. RESULTS: Of 150 patients, 70% were hypertensive and 30% were normotensive on presentation. Comparing both groups, no statistically significant differences were noted in mortality (13.3% for both groups), need for neurosurgical intervention (51.4% vs 48.8%, p = 0.776), length of stay (6 vs 8 days, p = 0.732), duration of mechanical ventilation (2 vs 3 days, p = 0.912), or inpatient rehabilitation rates (48.6% vs 48.9%, p = 0.972). In comparing just the hypertensive patients, there was a trend toward increased mortality in the 95th and 99th percentile groups at 15.8% and 14.1%, versus the 90th percentile group at 6.7% but the difference was not statistically significant (p = 0.701). CONCLUSIONS: Contrary to the adult literature, pediatric patients with severe TBI and hypertension on presentation do not appear to have worsened outcomes compared to those who are normotensive. However, a trend toward increased mortality did exist at extremes of age adjusted hypertension. Larger scale studies are needed to validate these findings. STUDY TYPE: Retrospective cohort study LEVEL OF EVIDENCE: III.

Screening for Harassment, Abuse, and Discrimination among Surgery Residents: An EAST Multicenter Trial.

Estimating the prevalence of harassment, verbal abuse, and discrimination among residents is difficult as events are often under-reported. The purpose of this study was to determine the prevalence of discrimination and abuse among surgical residents using the HITS (Hurt, Insulted, Threatened with harm or Screamed at) screening tool. A multicenter, cross-sectional, survey-based study was conducted at five academic teaching hospitals. Of 310 residents, 76 (24.5%) completed the survey. The HITS screening tool was positive in 3.9 per cent. The most common forms of abuse included sexual harassment (28.9%), discrimination based on gender (15.7%), and discrimination based on ethnicity (7.9%). There was a positive correlation between individuals who reported gender discrimination and racial discrimination (r = 0.778, n = 13, P = 0.002). Individuals who experienced insults were more likely to experience physical threats (r = 0.437, n = 79, P < 0.001) or verbal abuse (r = 0.690, n = 79, P < 0.001). Discrimination and harassment among surgical residents in academic teaching hospitals across the United States is not uncommon. Further research is needed to determine the impact of these findings on resident attrition.

Pharmacokinetics of furosemide after intravenous, oral and transdermal administration to cats.

OBJECTIVES: The aim of this study was to determine the pharmacokinetics of furosemide in cats following intravenous (IV), oral and transdermal administration. METHODS: This study used six healthy adult cats in a three-phase design to compare plasma furosemide concentrations in cats that received one IV 2 mg/kg dose of furosemide, one oral 2 mg/kg dose of furosemide and 3 days of q12h dosing with 2 mg/kg furosemide transdermally applied to the ear pinna. RESULTS: After IV administration the elimination half-life was (mean and coefficient of variation) 2.25 h (72%), systemic clearance was 149 ml/kg/h (27.4%) and volume of distribution was 227 ml/kg (22%). After oral administration the terminal half-life was 1.2 h (18.7%), peak concentration was 3.4 µg/ml (51.7%) and bioavailability was 48.4%. The transdermal plasma concentrations were undetectable or very low at most time points, and pharmacokinetics were not determined from the transdermal dose. CONCLUSIONS AND RELEVANCE: Furosemide was rapidly eliminated in cats after oral and IV administration and is probably best administered orally at least q12h in cats with heart failure. The oral dose absorbed was approximately 50%, but the absorption from transdermal administration was negligible.

Occupational exposure during emergency department thoracotomy: A prospective, multi-institution study.

BACKGROUND: Occupational exposure is an important consideration during emergency department thoracotomy (EDT). While human immunodeficiency virus/hepatitis prevalence in trauma patients (0-16.8%) and occupational exposure rates during operative trauma procedures (1.9-18.0%) have been reported, exposure risk during EDT is unknown. We hypothesized that occupational exposure risk during EDT would be greater than other operative trauma procedures. METHODS: A prospective, observational study at 16 US trauma centers was performed (2015-2016). All bedside EDT resuscitation providers were surveyed with a standardized data collection tool and risk factors analyzed with respect to the primary end point, EDT occupational exposure (percutaneous injury, mucous membrane, open wound, or eye splash). Provider and patient variables and outcomes were evaluated with single and multivariable logistic regression analyses. RESULTS: One thousand three hundred sixty participants (23% attending, 59% trainee, 11% nurse, 7% other) were surveyed after 305 EDTs (gunshot wound, 68%; prehospital cardiopulmonary resuscitation, 57%; emergency department signs of life, 37%), of which 15 patients survived (13 neurologically intact) their hospitalization. Overall, 22 occupational exposures were documented, resulting in an exposure rate of 7.2% (95% confidence interval [CI], 4.7-10.5%) per EDT and 1.6% (95% CI, 1.0-2.4%) per participant. No differences in trauma center level, number of participants, or hours worked were identified. Providers with exposures were primarily trainees (68%) with percutaneous injuries (86%) during the thoracotomy (73%). Full precautions were utilized in only 46% of exposed providers, while multiple variable logistic regression determined that each personal protective equipment item utilized during EDT correlated with a 34% decreased risk of occupational exposure (odds ratio, 0.66; 95% CI, 0.48-0.91; p = 0.010). CONCLUSIONS: Our results suggest that the risk of occupational exposure should not deter providers from performing EDT. Despite the small risk of viral transmission, our data revealed practices that may place health care providers at unnecessary risk of occupational exposure. Regardless of the lifesaving nature of the procedure, improved universal precaution compliance with personal protective equipment is paramount and would further minimize occupational exposure risks during EDT. LEVEL OF EVIDENCE: Therapeutic/care management study, level III.

AAVrh10 Gene Therapy Ameliorates Central and Peripheral Nervous System Disease in Canine Globoid Cell Leukodystrophy (Krabbe Disease).

Globoid cell leukodystrophy (GLD), or Krabbe disease, is an inherited, neurologic disorder that results from deficiency of a lysosomal enzyme, galactosylceramidase. Most commonly, deficits of galactosylceramidase result in widespread central and peripheral nervous system demyelination and death in affected infants typically by 2 years of age. Hematopoietic stem-cell transplantation is the current standard of care in children diagnosed prior to symptom onset. However, disease correction is incomplete. Herein, the first adeno-associated virus (AAV) gene therapy experiments are presented in a naturally occurring canine model of GLD that closely recapitulates the clinical disease progression, neuropathological alterations, and biochemical abnormalities observed in human patients. Adapted from studies in twitcher mice, GLD dogs were treated by combination intravenous and intracerebroventricular injections of AAVrh10 to target both the peripheral and central nervous systems. Combination of intravenous and intracerebroventricular AAV gene therapy had a clear dose response and resulted in delayed onset of clinical signs, extended life-span, correction of biochemical defects, and attenuation of neuropathology. For the first time, therapeutic effect has been established in the canine model of GLD by targeting both peripheral and central nervous system impairments with potential clinical implications for GLD patients.