Implementation of an Advanced Practice Registered Nurse-Led Clinic to Improve Follow-up Care for Post-Ischemic Stroke Patients.

ABSTRACT: BACKGROUND: Ischemic stroke continues to be a leading cause of serious disability within the United States, affecting 795 000 people annually. Approximately 12% to 21% of post-ischemic stroke patients will be readmitted to the hospital within 30 days of discharge. Studies suggest that implementation of a follow-up appointment within 7 to 14 days of discharge improves 30-day readmission rates; however, implementation of these guidelines is uncommon, and follow-up visits within the recommended window are not often achieved. The purpose of this project was to evaluate the impact of an advanced practice registered nurse (APRN)-led stroke clinic on follow-up care for post-ischemic stroke patients. The aims were to improve time to follow-up visit and reduce 30-day unplanned readmissions. METHODS: A pre/post intervention design was used to evaluate the impact of a process to access the APRN-led stroke clinic. The intervention included a scheduling process redesign, and subsequent APRN and scheduler education. RESULTS: The time to clinic follow-up preintervention averaged 116.9 days, which significantly reduced to 33.6 days post intervention, P = .0001. Unplanned readmissions within 30 days declined from 11.5% to 9.9%; however, it was not statistically significant, P = .149. Age was not statistically different between preintervention and postintervention groups, P = .092, and other demographics were similar between the groups. CONCLUSION: An APRN-led clinic can improve follow-up care and may reduce unplanned 30-day readmissions for post-ischemic stroke patients. Further work is needed to determine the impact of alternative approaches such as telehealth.

BioSphincters to treat Fecal Incontinence in Nonhuman Primates.

Loss of anorectal resting pressure due to internal anal sphincter (IAS) dysfunctionality causes uncontrolled fecal soiling and leads to passive fecal incontinence (FI). The study is focused on immediate and long-term safety and potential efficacy of bioengineered IAS BioSphincters to treat passive FI in a clinically relevant large animal model of passive FI. Passive FI was successfully developed in Non-Human Primates (NHPs) model. The implantation of autologous intrinsically innervated functional constructs resolved the fecal soiling, restored the resting pressure and Recto Anal Inhibitory Reflex (RAIR) within 1-month. These results were sustained with time, and efficacy was preserved up to 12-months. The histological studies validated manometric results with the regeneration of a well-organized neuro-muscular population in IAS. The control groups (non-treated and sham) remained affected by poor anal hygiene, lower resting pressure, and reduced RAIR throughout the study. The pathological assessment of implants, blood, and the vital organs confirmed biocompatibility without any adverse effect after implantation. This regenerative approach of implanting intrinsically innervated IAS BioSphincters has the potential to offer a better quality of life to the patients suffering from FI.

Instructive feedback embedded within group instruction for children diagnosed with autism spectrum disorder.

The present study evaluated the effects of instructive feedback embedded within a group discrete trial teaching to teach tact relations to nine children diagnosed with autism spectrum disorder using a nonconcurrent multiple-baseline design. Dependent variables included correct responses for: primary targets (directly taught), secondary targets (taught via instructive feedback), primary observational targets (directly taught to other members of the group), and secondary observational targets (taught via instructive feedback provided to other members of the group). Results showed that all nine participants reached the mastery criterion for the primary targets, as well as acquired the secondary and observational targets without direct teaching. Clinical implications and areas for future research are provided.

Evaluation of multiple-alternative prompts during tact training.

This study compared 2 methods of fading prompts while teaching tacts to 3 individuals who had been diagnosed with autism spectrum disorder (ASD). The 1st method involved use of an echoic prompt and prompt fading. The 2nd method involved providing multiple-alternative answers and fading by increasing the difficulty of the discrimination. An adapted alternating-treatments design showed that both procedures were more effective than a no-intervention control condition. Providing multiple alternatives did not increase error rates or teaching time, and better maintenance was shown for tacts taught with the multiple-alternative prompt.

Pathology of fractionated whole-brain irradiation in rhesus monkeys ( Macaca mulatta ).

Fractionated whole-brain irradiation (fWBI), used to treat brain metastases, often leads to neurologic injury and cognitive impairment. The cognitive effects of irradiation in nonhuman primates (NHP) have been previously published; this report focuses on corresponding neuropathologic changes that could have served as the basis for those effects in the same study. Four rhesus monkeys were exposed to 40 Gy of fWBI [5 Gy × 8 fraction (fx), 2 fx/week for four weeks] and received anatomical MRI prior to, and 14 months after fWBI. Neurologic and histologic sequelae were studied posthumously. Three of the NHPs underwent cognitive assessments, and each exhibited radiation-induced impairment associated with various degrees of vascular and inflammatory neuropathology. Two NHPs had severe multifocal necrosis of the forebrain, midbrain and brainstem. Histologic and MRI findings were in agreement, and the severity of cognitive decrement previously reported corresponded to the degree of observed pathology in two of the animals. In response to fWBI, the NHPs showed pathology similar to humans exposed to radiation and show comparable cognitive decline. These results provide a basis for implementing NHPs to examine and treat adverse cognitive and neurophysiologic sequelae of radiation exposure in humans.

Guiding intramuscular diaphragm injections using real-time ultrasound and electromyography.

INTRODUCTION: We describe a unique method that combines ultrasound and electromyography to guide intramuscular diaphragm injections in anesthetized large animals. METHODS: Ultrasound was used to visualize the diaphragm on each side of spontaneously breathing, anesthetized beagle dogs and cynomolgus macaques. An electromyography (EMG) needle was introduced and directed by ultrasound to confirm that the needle entered the muscular portion of the diaphragm, and methylene blue was injected. Injection accuracy was confirmed upon necropsy by tracking the spread of methylene blue. RESULTS: All methylene blue injections were confirmed to have been placed appropriately into the diaphragm. CONCLUSIONS: This study demonstrates the feasibility and accuracy of using ultrasound and EMG to guide injections and to reduce complications associated with conventional blind techniques. Ultrasound guidance can be used for clinical EMG of the diaphragm. Future applications may include targeted diaphragm injections with gene replacement therapy in neuromuscular diseases.

Ultrasound assessment of the diaphragm: Preliminary study of a canine model of X-linked myotubular myopathy.

INTRODUCTION: We tested the feasibility of using neuromuscular ultrasound for non-invasive real-time assessment of diaphragmatic structure and function in a canine model of X-linked myotubular myopathy (XLMTM). METHODS: Ultrasound images in 3 dogs [wild-type (WT), n=1; XLMTM untreated, n=1; XLMTM post-AAV8-mediated MTM1 gene replacement, n=1] were analyzed for diaphragm thickness, change in thickness with respiration, muscle echogenicity, and diaphragm excursion amplitude during spontaneous breathing. RESULTS: Quantitative parameters of diaphragm structure were different among the animals. WT diaphragm was thicker and less echogenic than the XLMTM control, whereas the diaphragm measurements of the MTM1-treated XLMTM dog were comparable to those of the WT dog. CONCLUSIONS: This pilot study demonstrates the feasibility of using ultrasound for quantitative assessment of the diaphragm in a canine model. In the future, ultrasonography may replace invasive measures of diaphragm function in canine models and in humans for non-invasive respiratory monitoring and evaluation of neuromuscular disease.

Gene therapy prolongs survival and restores function in murine and canine models of myotubular myopathy.

Loss-of-function mutations in the myotubularin gene (MTM1) cause X-linked myotubular myopathy (XLMTM), a fatal, congenital pediatric disease that affects the entire skeletal musculature. Systemic administration of a single dose of a recombinant serotype 8 adeno-associated virus (AAV8) vector expressing murine myotubularin to Mtm1-deficient knockout mice at the onset or at late stages of the disease resulted in robust improvement in motor activity and contractile force, corrected muscle pathology, and prolonged survival throughout a 6-month study. Similarly, single-dose intravascular delivery of a canine AAV8-MTM1 vector in XLMTM dogs markedly improved severe muscle weakness and respiratory impairment, and prolonged life span to more than 1 year in the absence of toxicity or a humoral or cell-mediated immune response. These results demonstrate the therapeutic efficacy of AAV-mediated gene therapy for myotubular myopathy in small- and large-animal models, and provide proof of concept for future clinical trials in XLMTM patients.

Muscle function in a canine model of X-linked myotubular myopathy.

INTRODUCTION: We established a colony of dogs that harbor an X-linked MTM1 missense mutation.Muscle from affected male dogs exhibits reduction and altered localization of the MTM1 gene product, myotubularin, and provides a model analogous to X-linked myotubular myopathy (XLMTM). METHODS: We studied hindlimb muscle function in age-matched canine XLMTM genotypes between ages 9 and 18 weeks. RESULTS: By the end of the study, affected dogs produce only ∼15% of the torque generated by normals or carriers (0.023 ± 0.005 vs. 0.152 ± 0.007 and 0.154 ± 0.003 N-m/kg body mass, respectively, P < 0.05) and are too weak to stand unassisted. At this age, XLMTM dogs also demonstrate an abnormally low twitch:tetanus ratio, a right-shifted torque-frequency relationship and an increase in torque during repetitive stimulation (P < 0.05). CONCLUSIONS: We hypothesize that muscle weakness results from impaired excitation-contraction (E-C) coupling. Interventions that improve E-C coupling might be translated from the XLMTM dog model to patients.

A novel antireflux procedure: gastroplasty with restricted antrum to control emesis (GRACE).

PURPOSE: Nissen fundoplication is the most commonly performed operation to treat gastroesophageal reflux disease and vomiting in children with neurologic impairment. However, failure rates of Nissen fundoplication in this population are higher, and alternatives to Nissen fundoplication have technical and functional disadvantages. We hypothesize that the novel gastroplasty with restricted antrum to control emesis (GRACE) would be more effective than Nissen fundoplication at reducing emetic reflux. METHODS: To compare the GRACE with Nissen fundoplication, 15 canine subjects were randomized to Nissen fundoplication or GRACE. All subjects underwent gastrostomy tube placement. Baseline gastric emptying, electrogastrography, and induced vomiting studies were performed. Nissen fundoplication or GRACE was then performed. Postoperatively, gastric emptying and vomiting studies were repeated. RESULTS: Gastric emptying before and after antireflux procedures was not significantly different between groups. Both Nissen fundoplication (38%, P = .04) and GRACE (69%, P < .01) procedures prevented reflux compared with baseline. However, the GRACE procedure significantly reduced reflux when compared with Nissen fundoplication (P = .03). CONCLUSIONS: In this canine model, GRACE appears to be significantly more effective than Nissen fundoplication at reducing emetic reflux. This novel procedure preserves gastric function and is well tolerated. The GRACE procedure may provide an alternative to Nissen fundoplication as a primary or repeat antireflux procedure for children with neurologic impairment.

Establishing clinical end points of respiratory function in large animals for clinical translation.

Respiratory dysfunction due progressive weakness of the respiratory muscles, particularly the diaphragm, is a major cause of death in the neuromuscular disease (NMD) X-linked myotubular myopathy (XLMTM). Methods of respiratory assessment in patients are often difficult, especially in those who are mechanically ventilated. The naturally occuring XLMTM dog model exhibits a phenotype similar to that in patients and can be used to determine quantitative descriptions of dysfunction as clinical endpoints for treatment and the development of new therapies. In experiments using respiratory impedance plethysmography (RIP), XLMTM dogs challenged with the respiratory stimulant doxapram displayed significant changes indicative of diaphragmatic weakness.

Inhibition of cell surface MHC class II expression by Salmonella.

Peptide presentation by MHC molecules is an essential component of the adaptive immune response. To persist in a host, many pathogens have evolved strategies that interfere with MHC antigen-presentation. We show that in human cells harboring intracellular Salmonella, MHC class II cell surface expression was substantially reduced. The effect was specific for MHC class II as expression of additional surface receptors remained unchanged. We investigated the underlying mechanism and showed that class II biosynthesis and peptide loading were unaffected by the presence of Salmonella; however, infection led to an intracellular accumulation of mature molecules. The intracellular class II colocalized with lysosome-associated membrane protein-1 and HLA-DM but not with the Salmonella-containing vacuole. Using Salmonella mutants defective in different components and effectors of the Salmonella pathogenicity island-2 type-III secretion system, we traced the effect on class II to the sifA locus. SifA has been shown to be involved in recruiting membrane for the Salmonella-containing vacuoles. Our data suggest an additional role for SifA in interfering with MHC class II antigen-presentation.