Preliminary Report on the Train the Brain Project, Part II: Neuroplasticity of Augmented Neuromuscular Training and Improved Injury-Risk Biomechanics.

CONTEXT: Neuromuscular training (NMT) facilitates the acquisition of new movement patterns that reduce the anterior cruciate ligament injury risk. However, the neural mechanisms underlying these changes are unknown. OBJECTIVE: To determine the relationship between brain activation and biomechanical changes after NMT with biofeedback. DESIGN: Cohort study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Twenty female high school soccer athletes, with 10 in an augmented NMT group and 10 in a control (no training) group. MAIN OUTCOME MEASURE(S): Ten participants completed 6 weeks of NMT augmented with real-time biofeedback to reduce knee injury-risk movements, and 10 participants pursued no training. Augmented neuromuscular training (aNMT) was implemented with visual biofeedback that responded in real time to injury-risk biomechanical variables. A drop vertical jump with 3-dimensional motion capture was used to assess injury-risk neuromuscular changes before and after the 6-week intervention. Brain-activation changes were measured using functional magnetic resonance imaging during unilateral knee and multijoint motor tasks. RESULTS: After aNMT, sensory (precuneus), visual-spatial (lingual gyrus), and motor-planning (premotor) brain activity increased for knee-specific movement; sensorimotor cortex activity for multijoint movement decreased. The knee-abduction moment during landing also decreased (4.66 ± 5.45 newton meters; P = .02; Hedges g = 0.82) in the aNMT group but did not change in the control group (P > .05). The training-induced increased brain activity with isolated knee movement was associated with decreases in knee-abduction moment (r = 0.67; P = .036) and sensorimotor cortex activity for multijoint movement (r = 0.87; P = .001). No change in brain activity was observed in the control group (P > .05). CONCLUSIONS: The relationship between neural changes observed across tasks and reduced knee abduction suggests that aNMT facilitated recruitment of sensory integration centers to support reduced injury-risk mechanics and improve sensorimotor neural efficiency for multijoint control. Further research is warranted to determine if this training-related multimodal neuroplasticity enhances neuromuscular control during more complex sport-specific activities.

Preliminary Report on the Train the Brain Project, Part I: Sensorimotor Neural Correlates of Anterior Cruciate Ligament Injury Risk Biomechanics.

CONTEXT: Anterior cruciate ligament injury commonly occurs via noncontact motor coordination errors that result in excessive multiplanar loading during athletic movements. Preventing motor coordination errors requires neural sensorimotor integration activity to support knee-joint neuromuscular control, but the underlying neural mechanisms driving injury-risk motor control are not well understood. OBJECTIVE: To evaluate brain activity differences for knee sensorimotor control between athletes with high or low injury-risk mechanics. DESIGN: Case-control study. SETTING: Research laboratory. PATIENTS OR OTHER PARTICIPANTS: Of 38 female high school soccer players screened, 10 were selected for analysis based on magnetic resonance imaging compliance, injury-risk classification via 3-dimensional biomechanics during a drop vertical jump, and matching criteria to complete neuroimaging during knee motor tasks. MAIN OUTCOME MEASURE(S): Peak knee-abduction moment during landing was used for group allocation into the high (≥21.74 newton meters [Nm], n = 9) or low (≤10.6 Nm, n = 11) injury-risk classification (n = 11 uncategorized, n = 7 who were not compliant with magnetic resonance imaging). Ten participants (5 high risk, 5 low risk) with adequate data were matched and compared across 2 neuroimaging paradigms: unilateral knee-joint control and unilateral multijoint leg press against resistance. RESULTS: Athletes with high injury-risk biomechanics had less neural activity in 1 sensory-motor cluster for isolated knee-joint control (precuneus, peak Z score = 4.14, P ≤ .01, 788 voxels) and greater brain activity for the multijoint leg press in 2 cognitive-motor clusters: the frontal cortex (peak Z score = 4.71, P < .01, 1602 voxels) and posterior cingulate gyrus (peak Z score = 4.43, P < .01, 725 voxels) relative to the low injury-risk group. CONCLUSIONS: The high injury-risk group's lower relative engagement of neural sensory resources controlling the knee joint may elevate demand on cognitive motor resources to control loaded multijoint action. The neural activity profile in the high injury-risk group may manifest as a breakdown in neuromuscular coordination, resulting in elevated knee-abduction moments during landing.

Stage-specific control of oligodendrocyte survival and morphogenesis by TDP-43.

Generation of oligodendrocytes in the adult brain enables both adaptive changes in neural circuits and regeneration of myelin sheaths destroyed by injury, disease, and normal aging. This transformation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes requires processing of distinct mRNAs at different stages of cell maturation. Although mislocalization and aggregation of the RNA-binding protein, TDP-43, occur in both neurons and glia in neurodegenerative diseases, the consequences of TDP-43 loss within different stages of the oligodendrocyte lineage are not well understood. By performing stage-specific genetic inactivation of Tardbp in vivo, we show that oligodendrocyte lineage cells are differentially sensitive to loss of TDP-43. While OPCs depend on TDP-43 for survival, with conditional deletion resulting in cascading cell loss followed by rapid regeneration to restore their density, oligodendrocytes become less sensitive to TDP-43 depletion as they mature. Deletion of TDP-43 early in the maturation process led to eventual oligodendrocyte degeneration, seizures, and premature lethality, while oligodendrocytes that experienced late deletion survived and mice exhibited a normal lifespan. At both stages, TDP-43-deficient oligodendrocytes formed fewer and thinner myelin sheaths and extended new processes that inappropriately wrapped neuronal somata and blood vessels. Transcriptional analysis revealed that in the absence of TDP-43, key proteins involved in oligodendrocyte maturation and myelination were misspliced, leading to aberrant incorporation of cryptic exons. Inducible deletion of TDP-43 from oligodendrocytes in the adult central nervous system (CNS) induced the same progressive morphological changes and mice acquired profound hindlimb weakness, suggesting that loss of TDP-43 function in oligodendrocytes may contribute to neuronal dysfunction in neurodegenerative disease.

The accuracy of a novel sonographic scanning and reporting protocol to survey for soft tissue sarcoma local recurrence.

OBJECTIVE: This study aims to determine the accuracy of a novel ultrasonography (US) scanning and reporting protocol to detect recurrences. The secondary aim is to compare US and MRI accuracy and agreement. MATERIALS AND METHODS: In this IRB-approved prospective study, consecutive patients presenting for MRI surveillance after resection were enrolled and underwent same-day US. Blinded to clinical information and the MRI, the US scanner characterized lesions using a proposed novel lexicon. Outcome was defined either by histology or a subsequent MRI scan confirming the presence or absence of recurrence. Fisher's exact test and Kappa test were performed to assess of the significance and agreement between US, MRI, and outcome. RESULTS: A total of 68 US scans were performed on 55 patients. The overall accuracy to diagnose recurrence was the same for US and MRI (92.6%) while US was less sensitive (75.0% vs. 91.7%) but more specific (97.6% vs. 92.9%) than MRI. The two lesions missed by US but not MRI were an entirely intraosseous metastasis and a subcentimeter skin nodule. There was strong agreement between US and MRI with outcome (k = 0.787 and 0.801, respectively). CONCLUSIONS: These pilot data suggest the accuracy of this novel US local recurrence surveillance method is comparable to MRI. A multi-institutional prospective trial would increase power and determine reproducibility.

Managing Urology Consultations During COVID-19 Pandemic: Application of a Structured Care Pathway.

OBJECTIVE: To describe and evaluate a risk-stratified triage pathway for inpatient urology consultations during the SARS-CoV-2 (COVID-19) pandemic. This pathway seeks to outline a urology patient care strategy that reduces the transmission risk to both healthcare providers and patients, reduces the healthcare burden, and maintains appropriate patient care. MATERIALS AND METHODS: Consultations to the urology service during a 3-week period (March 16 to April 2, 2020) were triaged and managed via one of 3 pathways: Standard, Telemedicine, or High-Risk. Standard consults were in-person consults with non COVID-19 patients, High-Risk consults were in-person consults with COVID-19 positive/suspected patients, and Telemedicine consults were telephonic consults for low-acuity urologic issues in either group of patients. Patient demographics, consultation parameters and consultation outcomes were compared to consultations from the month of March 2019. Categorical variables were compared using Chi-square test and continuous variables using Mann-Whitney U test. A P value <.05 was considered significant. RESULTS: Between March 16 and April 2, 2020, 53 inpatient consultations were performed. By following our triage pathway, a total of 19/53 consultations (35.8%) were performed via Telemedicine with no in-person exposure, 10/53 consultations (18.9%) were High-Risk, in which we strictly controlled the urology team member in-person contact, and the remainder, 24/53 consultations (45.2%), were performed as Standard in-person encounters. COVID-19 associated consultations represented 18/53 (34.0%) of all consultations during this period, and of these, 8/18 (44.4%) were managed successfully via Telemedicine alone. No team member developed COVID-19 infection. CONCLUSION: During the COVID-19 pandemic, most urology consultations can be managed in a patient and physician safety-conscious manner, by implementing a novel triage pathway.

CT can stratify patients as low risk for tibial neuropathy following a talus fracture.

OBJECTIVE: Determine the incidence of tibial neuropathy following talus fractures and CT's ability to stratify patients at risk for developing post-traumatic neuropathy. MATERIALS AND METHODS: In this IRB-approved retrospective analysis, 71 talus fractures and 8 contralateral control ankle CTs were reviewed by one observer blinded to clinical information. CT evidence suggestive of tibial neurovascular bundle injury included nerve displacement, perineural fat effacement/edema, and bone touching nerve. The association between these CT findings and clinically evident tibial neuropathy was analyzed. A semi-quantitative likelihood score was assigned based on the degree of the CT findings around the nerve. Interobserver agreement was calculated between 2 other readers. RESULTS: Twenty-five percent of patients in this cohort had clinical evidence of tibial neuropathy. There was a high specificity (0.87-0.93) and negative predictive value (0.83-0.87), a moderate accuracy (0.80-0.82), but a lower sensitivity (0.33-0.56) associated with the CT findings. Among the CT findings, nerve displacement (p < 0.0001) and bone touching nerve (p = 0.01) were associated with tibial neuropathy. A likelihood score of 2-5 was associated (p = 0.007-0.015) with tibial neuropathy. The presence of tibial neuropathy and nerve recovery were not associated with hospital length of stay, while CT findings were. There was substantial agreement between the three readers: likelihood scores 2+ (k = 0.78) and 3+ (k = 0.72). CONCLUSIONS: Tibial neuropathy occurs following talus fractures, and CT findings may help surgeons narrow down the number of patients requiring close neurological follow-up.

Choosing Wisely Canada-Top Five List in Hepatology: Official Position Statement of the Canadian Association for the Study of the Liver (CASL) and Choosing Wisely Canada (CWC).

INTRODUCTION AND AIM: The prevalence and incidence of chronic liver disease is increasing resulting, in substantial direct and indirect medical costs. Overuse of investigations, treatments and procedures contribute to rising health care costs and can expose patients to unnecessary harm and delay in receiving care. The Choosing Wisely Canada (CWC) campaign has encouraged professional societies to develop statements that are directly actionable by their members in an effort to promote higher-value health care that will lead to downstream effect on how other practitioners make decisions. MATERIAL AND METHODS: The Canadian Association for the Study of the Liver (CASL) established its Choosing Wisely top five list of recommendations using the framework put forward by CWC. CASL convened a task force that developed a list of draft recommendations and shared this with CASL membership electronically with eventual ranking of the top five recommendations by consensus at Canadian Digestives Disease Week (CDDW) 2017. Following revisions, the CASL Executive Committee endorsed the final list, which was disseminated online by CWC (July 2017). RESULTS: The top five recommendations physicians and patients should question include: 1) Don't order serum ammonia to diagnose or manage hepatic encephalopathy (HE). 2) Don't routinely transfuse fresh frozen plasma, vitamin K, or platelets to reverse abnormal tests of coagulation in patients with cirrhosis prior to abdominal paracentesis, endoscopic variceal band ligation, or any other minor invasive procedures. 3) Don't order HFE genotyping based on serum ferritin values alone to diagnose hereditary hemochromatosis. 4) Don't perform computed tomography (CT) or magnetic resonance imaging (MRI) routinely to monitor benign focal liver lesions. 5) Don't repeat hepatitis C viral load testing in an individual who has established chronic infection, outside of anti-viral treatment. CONCLUSION: The Choosing Wisely recommendations will foster patient-physician discussions, reduce unnecessary treatment and testing, avert adverse effects from testing and treatment along with reducing medical expenditure in hepatology.

Hepatic ALECT-2 amyloidosis causing portal hypertension and recurrent variceal bleeding: a case report and review of the literature.

OBJECTIVES: To examine laser microdissection and mass spectrometry (LMD-MS), which has emerged as a new tool to aid in typing amyloid proteins. RESULTS: ALECT-2 is a potential cause of hepatic amyloidosis best detected by LMD-MS. METHODS: One of the more recently reported proteins is ALECT-2 (leukocyte cell-derived chemotaxin 2) amyloid, found in renal specimens of Hispanic patients. Here we report the first case of hepatic ALECT-2 amyloidosis diagnosed by LMD-MS from a liver biopsy specimen of a 52-year-old Hispanic man and causing portal hypertension with recurrent esophageal variceal bleeding. CONCLUSIONS: ALECT-2 can cause amyloidosis in organs other than the kidneys. It should be strongly considered in Hispanic patients and in those with a globular pattern of amyloid deposition. The incidence of ALECT-2 amyloidosis is likely underreported.

Physicians' practices for diagnosing liver fibrosis in chronic liver diseases: a nationwide, Canadian survey.

OBJECTIVE: To determine practices among physicians in Canada for the assessment of liver fibrosis in patients with chronic liver diseases. METHODS: Hepatologists, gastroenterologists, infectious diseases specialists, members of the Canadian Gastroenterology Association and/or the Canadian HIV Trials Network who manage patients with liver diseases were invited to participate in a web-based, national survey. RESULTS: Of the 237 physicians invited, 104 (43.9%) completed the survey. Routine assessment of liver fibrosis was requested by the surveyed physicians mostly for chronic hepatitis C (76.5%), followed by autoimmune/cholestatic liver disease (59.6%) and chronic hepatitis B (52.9%). Liver biopsy was the main diagnostic tool for 46.2% of the respondents, Fibroscan (Echosens, France) for 39.4% and Fibrotest (LabCorp, USA) for 7.7%. Etiology-specific differences were observed: noninvasive methods were mostly used for hepatitis C (63% versus 37% liver biopsy) and hepatitis B (62.9% versus 37.1% liver biopsy). For 42.7% of respondents, the use of noninvasive methods reduced the need for liver biopsy by >50%. Physicians' characteristics associated with higher use of noninvasive methods were older age and being based at a university hospital or in private practice versus community hospital. Physicians' main concerns regarding noninvasive fibrosis assessment methods were access/availability (42.3%), lack of guidelines for clinical use (26.9%) and cost/lack of reimbursement (14.4%). CONCLUSIONS: Physicians who manage patients with chronic liver diseases in Canada require routine assessment of liver fibrosis stage. Although biopsy remains the primary diagnostic tool for almost one-half of respondents, noninvasive methods, particularly Fibroscan, have significantly reduced the need for liver biopsy in Canada. Limitations in access to and availability of the noninvasive methods represent a significant barrier. Finally, there is a need for clinical guidelines and a better reimbursement policy to implement noninvasive tools to assess liver fibrosis.

A meta-analysis of nutritional supplementation for management of hospitalized alcoholic hepatitis.

BACKGROUND: Alcoholic liver disease (ALD) is associated with a high risk of morbidity and mortality. Malnutrition accompanies this condition and may be both a consequence of and contributor to the pathology. Many trials have investigated the benefits of providing supplemental nutrition in the management of patients with ALD. The present study is a meta-analysis of the available evidence. METHOD: A meta-analysis of randomized controlled studies comparing nutritional supplementation plus a normal hospital diet versus diet alone. RESULTS: Seven randomized controlled studies including 262 patients with ALD were identified. Pooled analysis revealed no statistical difference in mortality between groups given special nutritional therapy versus a normal balanced diet (OR 0.80 [95% CI 0.42 to 1.52]). In addition, nutrition did not significantly improve ascites (OR 1.29 [95% CI 0.52 to 3.20]) or any biochemical parameters. However, encephalopathy showed a significant improvement or resolution (OR 0.24 [95% CI 0.06 to 0.93]). CONCLUSION: Nutritional supplementation provided no mortality benefit in patients with ALD, and neither ascites nor biochemical parameters significantly improved. However, encephalopathy was significantly ameliorated and, therefore, nutritional supplementation should be encouraged in that setting.

Alzheimer's therapeutics: translation of preclinical science to clinical drug development.

Over the past three decades, significant progress has been made in understanding the neurobiology of Alzheimer's disease. In recent years, the first attempts to implement novel mechanism-based treatments brought rather disappointing results, with low, if any, drug efficacy and significant side effects. A discrepancy between our expectations based on preclinical models and the results of clinical trials calls for a revision of our theoretical views and questions every stage of translation-from how we model the disease to how we run clinical trials. In the following sections, we will use some specific examples of the therapeutics from acetylcholinesterase inhibitors to recent anti-Aß immunization and γ-secretase inhibition to discuss whether preclinical studies could predict the limitations in efficacy and side effects that we were so disappointed to observe in recent clinical trials. We discuss ways to improve both the predictive validity of mouse models and the translation of knowledge between preclinical and clinical stages of drug development.

Liver transplant outcomes in HIV-infected patients: a systematic review and meta-analysis with synthetic cohort.

OBJECTIVES: The relative success of liver transplantation in those with HIV compared to HIV-uninfected individuals remains a point of intense debate. We aimed to evaluate the effectiveness of liver transplantation in HIV-hepatitis co-infected patients using a meta-analysis and individual patient data meta-analysis as a synthetic cohort. METHODS: We searched MEDLINE via PubMed, EMBASE, Cochrane CENTRAL, AIDSLINE (inception to 2010), AMED, CINAHL, TOXNET, Development and Reproductive Toxicology, Hazardous Substances Databank, Psych-info and relevant conferences. We included cohort studies and individual case-reports evaluating survival of co-infected transplant patients. We abstracted data on cohort and case demographics and outcomes. We pooled cohorts using a random-effects analysis and created a synthetic cohort of cases using individual patient data. We confirmed this with the pooled cohort analysis. RESULTS: We included 15 cohort studies and 49 case series with individual patient data. At 12 months, 84.4% [95% confidence interval (CI) 81.1-87.8%] of patients had survived. Within the HIV-infected population evaluated, HIV-hepatitis B virus (HBV) co-infection was associated with optimal survival. In an adjusted model, individuals positive for HBV were 8.28 (95% CI 2.26-30.33) times more likely to survive when compared to those without HBV. Further, individuals with an undetectable HIV viral load at the time of transplantation were 2.89 (95% CI 1.41-5.91) times more likely to survive when compared to those with detectable HIV viremia. Hepatitis C virus was not a predictor of patient survival when adjusted for by other key predictors [0.54 (95% CI 0.17-1.80)].

Association of preoperative parameters with postoperative mortality and long-term survival after liver transplantation.

BACKGROUND: The ability of Child-Turcotte-Pugh (CTP) or Model for End-Stage Liver Disease (MELD) scores to predict recipient survival after liver transplantation is controversial. This analysis aims to identify preoperative parameters that might be associated with early postoperative mortality and long-term survival after liver transplantation. METHODS: We studied a total of 15 parameters, using both univariate and multivariate models, among adults who underwent primary liver transplantation. RESULTS: A total of 458 primary adult liver transplants were performed. Fifty-seven (12.44%) patients died during the first 3 postoperative months and composed the early mortality group. The remaining 401 patients composed the long-term patient survival group. The parameters that were identified through univariate analysis to be associated with early postoperative mortality were CTP score, MELD score, bilirubin, creatinine, international normalized ratio and warm ischemia time (WIT). In all multivariate models, WIT retained its statistical significance. The 10-year long-term survival was 65%. The parameters that were identified to be independent predictors of long-term survival were the recipient's sex (improved survival in women, p = 0.005), diagnosis of hepatocellular cancer (p=0.015) and recipient's age (p=0.024). CONCLUSION: Either CTP or MELD score, in conjunction with WIT, might have a role in predicting early postoperative mortality after liver transplantation, whereas the recipient's sex and the absence of hepatocellular cancer are associated with improved long-term survival.

Liver transplantation for hepatic epithelioid hemangioendothelioma: the Canadian multicentre experience.

INTRODUCTION: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare entity. At the present time, there is no standardized effective therapy. Liver transplantation (LT) has emerged as a treatment for this rare tumour. OBJECTIVE: To evaluate the outcome of liver transplantation for HEHE at eight centres across Canada. METHODS: The charts of patients who were transplanted for HEHE at eight centres across Canada were reviewed. RESULTS: A total of 11 individuals (eight women and three men) received a LT for HEHE. All LTs were performed between 1991 and 2005. The mean (+/- SD) age at LT was 38.7+/-13 years. One patient had one large liver lesion (17 cm x 14 cm x 13 cm), one had three lesions, one had four lesions and eight had extensive (five or more) liver lesions. One patient had spleen involvement and two had involved lymph nodes at the time of transplantation. The mean duration of follow-up was 78+/-63 months (median 81 months). Four patients (36.4%) developed recurrence of HEHE with a mean time to recurrence of 25+/-25 months (median 15.6 months) following LT. The calculated survival rate following LT for HEHE was 82% at five years. CONCLUSIONS: The results of LT for HEHE are encouraging, with a recurrence rate of 36.4% and a five-year survival rate of 82%. Further studies are needed to help identify patients who would benefit most from LT for this rare tumour.

Preoperative alpha-fetoprotein slope is predictive of hepatocellular carcinoma recurrence after liver transplantation.

BACKGROUND: Liver transplantation (LT) offers a possible cure for patients with hepatocellular carcinoma (HCC) and cirrhosis. However, tumour progression while on the waiting list and tumour recurrence after LT are common. The prognostic significance of various pre- and postoperative variables were investigated in regard to tumour recurrence, with an emphasis on the slope of preoperative serum alpha-fetoprotein (AFP) levels. patients and METHODS: Data from 48 patients who had HCC diagnosed preoperatively and underwent LT at the McGill University Health Centre (Montreal, Quebec) were reviewed retrospectively, and possible risk factors for tumour recurrence were examined. RESULTS: Univariate analysis revealed a positive correlation between the preoperative AFP slope and vascular invasion (P = 0.045), total tumour diameter at explant (P = 0.040), Cancer of the Liver Italian Program score (P = 0.017) and recurrence-free survival (P = 0.028). Of the preoperative variables examined, only the preoperative AFP slope was identified as an independent predictor of tumour recurrence by multivariate analysis. Receiver operating characteristic analysis showed that the best discriminant cut-off value, calculated as the value of the maximized likelihood ratio, was preoperative AFP slope greater than 50 microg/L per month. At this cut-off, sensitivity was 36%, and specificity was 97%. Patients with a preoperative AFP slope greater than 50 microg/L per month had a much worse one-year recurrence-free survival rate than those with a preoperative AFP slope 50 microg/L per month or less (40% versus 90%, P < 0.001). CONCLUSIONS: These results suggest that the preoperative AFP slope is an important predictor of HCC recurrence after LT and should be examined in future studies of patients receiving LT for HCC.

N-glycosylation of human nicastrin is required for interaction with the lectins from the secretory pathway calnexin and ERGIC-53.

The gamma-secretase complex, composed of four non-covalently bound transmembrane proteins Presenilin, Nicastrin (NCT), APH-1 and PEN-2, is responsible for the intramembranous cleavage of amyloid precursor protein (APP), Notch and several other type I transmembrane proteins. gamma-Secretase cleavage of APP releases the Abeta peptides, which form the amyloid plaques characteristic of Alzheimer's disease brains, and cleavage of Notch releases an intracellular signalling peptide that is critical for numerous developmental processes. NCT, a type I membrane protein, is the only protein within the complex that is glycosylated. The importance of these glycosylation sites is not fully understood. Here, we have observed that NCT N-linked oligosaccharides mediated specific interactions with the secretory pathway lectins calnexin and ERGIC-53. In order to investigate the role played by N-glycosylation, mutation of each site was performed. All hNCT mutants interacted with calnexin and ERGIC-53, indicating that the association was not mediated by any single N-glycosylation site. Moreover, the interaction with ERGIC-53 still occurred in PS1/2 double knockout cells as detected in immunoprecipitation as well as confocal immunofluorescence microscopy studies, which indicated that NCT interacted with ERGIC-53 prior to its association with the active gamma-secretase complex.