Relation of Magnetic Resonance Elastography to Fontan Circulatory Failure in a Cohort of Pediatric and Adult Patients.

Elevated magnetic resonance elastography (MRE)-derived liver stiffness may be associated with worse outcomes in people with Fontan circulation. We sought to evaluate the association between liver stiffness and Fontan failure or portal hypertension. Single center cross-sectional retrospective study of people with Fontan circulation who underwent MRE between 2011 and 2020. The cohort was divided into adult (age ≥ 21 years) and pediatric (< 21 years) groups. Fontan circulatory failure (FF) was defined as any of the following: death, transplantation, ventricular assist device, heart failure symptoms requiring escalation of diuretics. Radiologic portal hypertension was defined as the presence of one or more of the following: splenomegaly, ascites, or gastrointestinal varices. 128 patients were included (average age = 22.6 ± 8.7 years) and 58 (45%) were children. Median liver stiffness was 4.3 kPa (interquartile range (IQR) 3.8-5.8) for the entire cohort. Thirty patients (23%) developed FF (16 adults, 14 children). Liver stiffness was higher in adults with FF compared to those without FF (4.9 (IQR 4.0-6.0) vs. 4.2 (IQR 3.8-4.7) kPa, p = 0.04). There was no difference in liver stiffness between pediatric patients with and without FF (4.4 (IQR 4.1-5.4) vs. 4.4 (IQR 3.8-5.0), p = 0.5). Adults with radiologic portal hypertension and adults with moderate or severe atrioventricular valve regurgitation had higher liver stiffness than adults without. MRE-derived liver stiffness is associated with atrioventricular valve regurgitation, portal hypertension, and poor clinical outcomes in adults with Fontan circulation. There was no association between liver stiffness and FF in pediatric patients. This difference may be due to the progressive nature of Fontan-associated liver disease.

Non-spatial pre-training in the water maze as a clinically relevant model for evaluating learning and memory in experimental TBI.

Explicit and implicit learning and memory networks exist where each network can facilitate or inhibit cognition. Clinical evidence suggests that implicit networks are relatively preserved after traumatic brain injury (TBI). Non-spatial pre-training (NSPT) in the Morris Water Maze (MWM) provides the necessary behavioral components to complete the task, while limiting the formation of spatial maps. Our study utilized NSPT in the MWM to assess implicit and explicit learning and memory system deficits in the controlled cortical impact (CCI) model of TBI. 76 adult male Sprague-Dawley rats were divided: CCI vs. sham surgery, NSPT vs. No-NSPT, and cued vs. non-cued groups. NSPT occurred for 4d prior to surgery (dynamic hidden platform location, extra-maze cues covered, static pool entry point). Acquisition (d14-18), Probe/Visible Platform (d19), and Reversal (d20-21) trials were conducted with or without extra-maze cues. Novel time allocation and search strategy selection metrics were utilized. Results indicated implicit and explicit learning/memory networks are distinguishable in the MWM. In the cued condition, NSPT reduced thigmotaxis, improved place learning, and largely eliminated the apparent injury-induced deficits typically observed between untrained CCI and sham rats. However, among NSPT groups, incorporation of cues into search strategy selection for CCI rats was relatively impaired compared to shams. Non-cued condition performance showed sham/NSPT and CCI/NSPT rats perform similarly, suggesting implicit memory networks are largely intact 2weeks after CCI. Place learning differences between CCI/NSPT and sham/NSPT rats more accurately reflect spatial deficits in our CCI model compared to untrained controls. These data suggest NSPT as a clinically relevant construct for evaluating potential neurorestorative and neuroprotective therapies. These findings also support development of non-spatial cognitive training paradigms for evaluating rehabilitation relevant combination therapies.

Patent Ductus Arteriosus Stent Versus Surgical Aortopulmonary Shunt for Initial Palliation of Cyanotic Congenital Heart Disease with Ductal-Dependent Pulmonary Blood Flow: A Systematic Review and Meta-Analysis.

Background In patients with ductal-dependent pulmonary blood flow, initial palliation includes catheter-based patent ductus arteriosus (PDA) stent or surgical aortopulmonary shunt (APS). This meta-analysis aimed to compare outcomes between PDA stent and APS. Methods and Results A comprehensive literature search yielded six retrospective observational studies. Pooled adjusted hazard ratios (HR) were included to control for covariates and assess time to event analysis. Of 757 patients, 243 (32.1%) underwent PDA stent and 514 (67.9%) underwent APS. Pulmonary atresia with intact ventricular septum and expected biventricular repair were more common with PDA stent compared with APS (39.6% versus 21.2%, P<0.001 and 57.9% versus 46.6%, P=0.007, respectively). There was no statistically significant difference in mortality between PDA stent and APS (HR, 0.71; [95% CI, 0.26-1.93]; P=0.50). PDA stent was associated with lower risk of postprocedural complications (odds ratio [OR], 0.45; [95% CI, 0.25-0.81]; P=0.008), mechanical circulatory support (OR, 0.27; [95% CI, 0.09-0.79]; P=0.02), and shorter intensive care unit length of stay (-4.03 days; [95% CI, -5.99 to -2.07]; P<0.001), hospital length of stay (-5.54 days; [95% CI, -9.20 to -1.88]; P=0.003), and duration of mechanical ventilation (-3.41 days; [95% CI, -5.29 to -1.52]; P<0.001). There was no difference in pulmonary artery growth or hazard of unplanned reintereventions. Conclusions PDA stent has a similar hazard of mortality compared with APS. Benefits to PDA stent include shorter duration of mechanical ventilation, shorter hospital length of stay, and fewer complications. Differences in patient characteristics exist with more patients with pulmonary atresia with intact ventricular septum and expected biventricular repair undergoing PDA stent.

Enterococcus hirae Bacteremia in an Infant: Case Report and Review of the Literature.

Enterococcus hirae is a gram-positive coccus that is rarely implicated in human disease and has not been reported in pediatric patients. We report a case of catheter-associated bloodstream infection and prolonged bacteremia in a 7-month-old infant dependent on total parenteral nutrition. The species was identified by the VITEK2 system and confirmed by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry. The organisms was susceptible to ampicillin, vancomycin, and high-level gentamicin. The patient was treated with vancomycin and gentamicin with adjunctive vancomycin lock therapy but had persistent bacteremia. Therapy was changed to dual ß-lactam therapy of ampicillin and ceftriaxone with synergistic gentamicin, which led to clearance of the enterococcal bacteremia. E hirae is an unusual species that may be difficult for the microbiology laboratory to identify. This is the first pediatric case and the second case of invasive E hirae in the United States.

Ritonavir-boosted protease inhibitor based therapy: a new strategy in chronic hepatitis C therapy.

Chronic hepatitis C virus (HCV) infection is a worldwide health issue. All oral therapies are quickly replacing peg-interferon-based treatment regimens. Developing effective, well tolerated, treatments accessible for difficult to treat populations remains an unmet need. Ritonavir, an HIV-1 protease inhibitor, has pharmacokinetic properties that enhance the activity of concomitantly administered direct acting antivirals against HCV. Ritonavir inhibits Cytochrome P450 isozyme 3A4, diminishing first pass effect and hepatic metabolism, changing the pharmacokinetic parameters of Cytochrome P450 isozyme 3A4 substrates. When combined with the HCV protease inhibitor paritaprevir, ritonavir increases mean area under the curve, allowing once daily dosing. While Phase II and III clinical trials with ritonavir-boosted paritaprevir, ombitasvir, and dasabuvir demonstrated high efficacy in those with HCV infection, drug-drug interactions warrant cautious use of ritonavir in specific patient populations. Consideration of the patients' full medication list is imperative due to the ubiquitous nature of the Cytochrome P450 isozyme 3A4 system.

Developing a clinically relevant model of cognitive training after experimental traumatic brain injury.

BACKGROUND: Following traumatic brain injury (TBI), clinical cognitive training paradigms harness implicit and explicit learning and memory systems to improve function; however, these systems are differentially affected by TBI, highlighting the need for an experimental TBI model that can test efficacy of cognitive training approaches. OBJECTIVES: To develop a clinically relevant experimental cognitive training model using the Morris water maze (MWM) wherein training on implicitly learned task components was provided to improve behavioral performance post-TBI. METHODS: Eighty-one adult male rats were divided by injury status (controlled cortical impact [CCI]/Sham), non-spatial cognitive training (CogTrained/No-CogTrained), and extra-maze cues (Cued/Non-Cued) during MWM testing. Platform latencies, thigmotaxis, and search strategies were assessed during MWM trials. RESULTS: Cognitive training was associated with improved platform latencies, reduced thigmotaxis, and more effective search strategy use for Sham and CCI rats. In the Cued and Non-Cued MWM paradigm, there were no differences between CCI/CogTrained and Sham/No-CogTrained groups. During novel testing conditions, CogTrained groups applied implicitly learned knowledge/skills; however, sham-cued CogTrained/rats better incorporated extramaze cues into their search strategy than the CCI-Cued group. Cognitive training had no effects on contusion size or hippocampal cell survival. CONCLUSIONS: The results provide evidence that CCI-CogTrained rats that learned the nonspatial components of the MWM task applied these skills during multiple conditions of the place-learning task, thereby mitigating cognitive deficits typically associated with this injury model. The results show that a systematic application of clinically relevant constructs associated with cognitive training paradigms can be used with experimental TBI to affect place learning.

Visual Priming Enhances the Effects of Nonspatial Cognitive Rehabilitation Training on Spatial Learning After Experimental Traumatic Brain Injury.

Previous work demonstrates that spatial (explicit) and nonspatial (implicit) elements of place learning in the Morris water maze (MWM) task can be dissociated and examined in the context of experimental traumatic brain injury (TBI). Providing nonspatial cognitive training (CT) after injury can improve place learning compared with untrained controls. In the present study, we hypothesized that brief exposure to extra-maze cues, in conjunction with CT, may further improve MWM performance and extra-maze cue utilization compared with CT alone. Adult male Sprague-Dawley rats (n = 66) received controlled cortical impact (CCI) injury or sham surgery. Beginning day 8 postsurgery, CCI and sham rats received 6 days of no training (NT) or CT with/without brief, noncontextualized exposure to extra-maze cues (BE and CT, respectively). Acquisition (days 14-18), visible platform (VP; day 19), carryover (CO; days 20-26), and periodic probe trials were performed. Platform latencies, peripheral and target zone time allocation, and search strategies were assessed. CCI/BE rats had shorter acquisition trial latencies than CCI/NT (P < .001) and tended to have shorter latencies than CCI/CT rats (P < .10). Both BE and CT reduced peripheral zone swimming for CCI rats versus CCI/NT. CCI/BE animals increased spatial swim strategies from day 14 to day 18 relative to CCI/CT and showed similar swim strategy selection to the Sham/NT group. These data suggest that visual priming improves initial place learning in the MWM. These results support the visual priming response as another clinically relevant experimental rehabilitation construct, to use when assessing injury and treatment effects of behavioral and pharmacological therapies on cognition after TBI.

Neuroprotective, neuroplastic, and neurobehavioral effects of daily treatment with levetiracetam in experimental traumatic brain injury.

BACKGROUND: Prophylactic treatment with antiepileptic drugs (AEDs) has been recommended to prevent early seizure onset in patients with traumatic brain injury (TBI). However, the potential neuroprotective and/or detrimental effects of prophylactic AED treatment on behavioral and cognitive function after TBI are not well studied. OBJECTIVE: To investigate the effects of a novel AED, levitiracetam (LEV), on behavioral and cognitive function after experimental TBI in rats. METHODS: Adult male rats were administered LEV (intraperitoneal 50 mg/kg) or vehicle (saline; SL) daily for 20 days beginning 1 day after controlled cortical impact (CCI; 2.8 mm; 4 m/s) or sham surgery. Beam performance (days 1-6), Y-maze (day 7), and Morris water maze (days 14-19) postinjury testing was assessed. RESULTS: Daily LEV treatment improved motor function, increased novel arm exploration in the Y-maze, elicited greater hippocampal cell sparing, and decreased contusion volumes compared with CCI/SL rats. Daily LEV administration also reversed a TBI-induced decrease in regional glutamate transporter expression and neuroplastic marker proteins present 20 days post-CCI. Also, daily LEV treatment decreased regional IL-1ß expression after TBI. CONCLUSIONS: These results suggest that daily LEV treatment has beneficial effects on histological, molecular, and behavioral elements of neurological recovery after TBI, in part, via modulation of neuroinflammatory and excitatory pathways.