Incomplete Functional Recovery Research Articles

A molecular brain atlas reveals cellular shifts during the repair phase of stroke.

Ischemic stroke triggers a cascade of pathological events that affect multiple cell types and often lead to incomplete functional recovery. Despite advances in single-cell technologies, the molecular and cellular responses that contribute to long-term post-stroke impairment remain poorly understood. To gain better insight into the underlying mechanisms, we generated a single-cell transcriptomic atlas from distinct brain regions using a mouse model of permanent focal ischemia at one month post-injury. Our findings reveal cell- and region-specific changes within the stroke-injured and peri-infarct brain tissue. For instance, GABAergic and glutamatergic neurons exhibited upregulated genes in signaling pathways involved in axon guidance and synaptic plasticity, and downregulated pathways associated with aerobic metabolism. Using cell-cell communication analysis, we identified increased strength in predicted interactions within stroke tissue among both neural and non-neural cells via signaling pathways such as those involving collagen, protein tyrosine phosphatase receptor, neuronal growth regulator, laminin, and several cell adhesion molecules. Furthermore, we found a strong correlation between mouse transcriptome responses after stroke and those observed in human nonfatal brain stroke lesions. Common molecular features were linked to inflammatory responses, extracellular matrix organization, and angiogenesis. Our findings provide a detailed resource for advancing our molecular understanding of stroke pathology and for discovering therapeutic targets in the repair phase of stroke recovery.

Exploring the kynurenine pathway in mild traumatic brain injury: A longitudinal study.

A potential source of novel biomarkers for mTBI is the kynurenine pathway (KP), a metabolic pathway of tryptophan (Trp), that is up-regulated by neuroinflammation and stress. Considering that metabolites of the KP (kynurenines) are implicated in various neuropsychiatric diseases, exploration of this pathway could potentially bridge the gap between physiological and psychological factors in the recovery process after mTBI. This study, therefore, set out to characterize the KP after mTBI and to examine associations with long-term outcome. Patients were prospectively recruited at the emergency department (ED), and blood samples were obtained in the acute phase (<24 h; N = 256) and at 1-month follow-up (N = 146). A comparison group of healthy controls (HC; N = 32) was studied at both timepoints. Trp, kynurenines, and interleukin (IL)-6 and IL-10 were quantified in plasma. Clinical outcome was measured at six months post-injury. Trp, xanthurenic acid (XA), and picolinic acid (PA) were significantly reduced in patients with mTBI relative to HC, corrected for age and sex. For Trp (d = -0.57 vs. d = -0.29) and XA (d = -0.98 vs. d = -0.32), larger effects sizes were observed during the acute phase compared to one-month follow-up, while for PA (d = -0.49 vs. d = -0.52) effect sizes remained consistent. Findings for other kynurenines (e.g., kynurenine, kynurenic acid, and quinolinic acid) were non-significant after correction for multiple testing. Within the mTBI group, lower acute Trp levels were significantly related to incomplete functional recovery and higher depression scores at 6 months post-injury. No significant relationships were found for Trp, XA, and PA with IL-6 or IL-10 concentrations. In conclusion, our findings indicate that perturbations of the plasma KP in the hyperacute phase of mTBI and 1 month later are limited to the precursor Trp, and glutamate system modulating kynurenines XA and PA. Correlations between acute reductions of Trp and unfavorable outcomes may suggest a potential substrate for pharmacological intervention.

UNPREDICTABLE IDENTIFICATION OF A TITIN MUTATION IN A YOUNG PATIENT PRESENTING WITH INFLAMMATORY CARDIOMYOPATHY

Abstract Case Presentation A 23 years old patient, affected by type 1 diabetes, presented with fever, dyspnea and bilateral peripheral edemas. In the last week he received antibiotic treatment for a persistent dry cough and sore throat, and became symptomatic for exertional dyspnea from three days. His mother died at the age of 40 for sudden cardiac death. Blood pressure and oxygen saturation were normal: the ECG showed sinus tachycardia with symmetric negative T waves in all precordial leads. High sensitivity troponin T was 0.01 mcg/L (normal value &amp;lt; 0.014 mcg/L). All remaining blood tests were normal, except for CRP that was slightly elevated. His echocardiogram revealed left ventricular (LV) remodelling and dilation, severely reduced LV ejection fraction (LVEF 20%) with global hypokinesia, more pronounced at the level of the anterior wall, interventricular septum and apex and a dilated right ventricle (RV) with reduced systolic function. Cardiac magnetic resonance (CMR) confirmed severe biventricular disfunction (LVEF 19%; RVEF 23%) and showed a small area of subepicardial inferior junctional late gadolinium enhancement (LGE). The patient underwent an endomyocardial biopsy that showed a lymphocytic virus–negative myocarditis. Given his known type 1 diabetes, steroid treatment was not considered and anakinra was started. The patient was discharged after two weeks with a slight amelioration of the LV function (LVEF 27%), on optimal heart failure therapy and anakinra. At six months he was in NYHA class II and CMR showed slight reduction in LV dimensions and improvement of the LV and RV function (LVEF 39%; RVEF 45%), with no changes in the LGE pattern. A genetic test was performed and revealed two titin gene mutations, both categorized as likely pathogenic (TTN c.[11831T&amp;gt;A]; c.[72510_72517delGACAAATG]), responsible for a genetic form of dilated cardiomyopathy. Conclusion The present case suggests that in young patients presenting with clinical or histological diagnosis of myocarditis, genetic testing for cardiomyopathies should be considered especially in presence of a positive family history for sudden death or an incomplete recovery of the LV function at follow–up. Identification of a gene mutation in these patients allows a more tailored risk stratification of the index case and a proper management of the entire family.

Effect of hydrogen-rich saline on melanopsin after acute blue light-induced retinal damage in rats.

Excessive exposure to blue light can cause retinal damage. Hydrogen-rich saline (HRS), one of the hydrogen therapies, has been demonstrated to be effective in eye photodamage, but the effect on the expression of melanopsin in intrinsically photosensitive retinal ganglion cells (ipRGCs) is unknown. In this study, we used a rat model of light-induced retinal injury to observe the expression of melanopsin after HRS treatment and to determine the effect of HRS on retinal ganglion cell protection. Adult SD rats were exposed to blue light (48 h) and treated with HRS for 0, 3, 7, and 14 days. Real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) were performed to find the expression of genes and proteins, respectively. The function of retinal ipRGCs was measured by pattern-evoked electroretinography (pERG). The number and morphological changes of melanopsin-positive ganglion cells in the retina were observed by immunofluorescence (IF). Acute blue light exposure caused a decrease in ipRGC function, decreased expression of melanopsin protein and the melanopsin-positive RGCs, and diminished immunoreactivity in dendrites. However, over time, melanopsin showed a tendency to self-recovery, with an increase in melanopsin protein expression and the number of melanopsin-positive RGCs, with incomplete recovery of function within two weeks. HRS treatment accelerated the recovery process, with a significant increase in melanopsin expression and the number of melanopsin-positive RGCs, and an improvement in the pERG waveform within two weeks.

176 Repetitive Traumatic Brain Injuries Are Associated With Poorer Outcomes at 1-Year and 3-7 Years After Index Injury

INTRODUCTION: Traumatic brain injury (TBI) patients are at risk for subsequent TBIs. Research on the longitudinal impact of repetitive TBI is limited. METHODS: The 18-center TRACK-TBI study enrolled subjects who presented to hospital and received head computed tomography (CT) within 24-hours of TBI between 2014-2018. Subjects were interviewed regarding post-index TBI during follow-up. Data from subjects aged = 17-years with 1-year or 3-7-year outcomes were extracted. Outcome measures included functional (GOSE:Glasgow Outcome Scale-Extended), post-concussive symptoms (PCS) (RPQ:Rivermead Post-Concussion Symptoms Questionnaire), psychological distress (BSI-18:Brief Symptom Inventory-18), depression (PHQ-9:Patient Health Questionnaire-9), post-traumatic stress disorder (PCL-5:PTSD-Checklist for DSM-5), and quality of life (QOL) (QOLIBRI-OS:Quality of Life After Brain Injury-Overall Scale). Multivariable regressions were adjusted for demographic, socioeconomic, and injury severity factors, and for multiple comparisons. Mean-differences (B), relative risks (RR), and 95% confidence intervals [CI] were reported. RESULTS: In 1,572 subjects, 3.2% and 12.2% sustained post-index TBI at 1-year and 3-7-years, respectively; 2.4% sustained multiple post-index TBIs at 3-7-years. Risk factors included psychiatric history, prior TBI, and extracranial injury severity. At 1-year, post-index TBI was independently associated with incomplete recovery (GOSE&lt;8; RR = 1.75 [1.04-2.94]), decreased QOL (QOLIBRI-OS: B = -15.9 [-22.6, -9.1]), and increased severity of PCS, psychological distress, PTSD, and depression (RPQ: B = 8.1 [4.2-11.9], BSI-18: B = 5.3 [2.1-8.6]; PCL-5: B = 7.8 [3.2-12.4]; PHQ-9: B = 3.0 [1.5-4.4]); effects were conserved at reduced magnitudes at 3-7-years. Multiple (=2 vs. 1) post-index TBIs were associated with greater symptom severities across all outcome measures. CONCLUSIONS: Post-index TBI is associated with incomplete functional recovery, increased PCS, psychological distress, PTSD, and depressive symptom severities, and decreased QOL at 1- and 3-7-years post-injury. Sustaining multiple post-index TBIs further increases symptom severity across all outcome domains. Institutional processes and resources for TBI prevention, education, counseling, and follow-up are greatly needed.

ADVANCED TENDON REPAIR STRATEGIES: FROM EVS TO MRNA-BASED APPROACHES

Approximately 30% of general practice consultations for musculoskeletal pain are related to tendon disorders, causing substantial personal suffering and enormous related healthcare costs. Treatments are often prone to long rehabilitation times, incomplete functional recovery, and secondary complications following surgical repair. Overall, due to their hypocellular and hypovascular nature, the regenerative capacity of tendons is very poor and intrinsically a disorganized scar tissue with inferior biomechanical properties forms after injury. Therefore, advanced therapeutic modalities need to be developed to enable functional tissue regeneration within a degenerative environment, moving beyond pure mechanical repair and overcoming the natural biological limits of tendon healing.Our recent studies have focused on developing biologically augmented treatment strategies for tendon injuries, aiming at restoring a physiological microenvironment and boosting endogenous tissue repair. Along these lines, we have demonstrated that the local application of mesenchymal stromal cell-derived small extracellular vesicles (sEVs) has the potential to improve rotator cuff tendon repair by modulating local inflammation and reduce fibrotic scarring. In another approach, we investigated if the local delivery of the tendon ECM protein SPARC, which we previously demonstrated to be essential for tendon maturation and tissue homeostasis, has the potential to enhance tendon healing. Finally, I will present results demonstrating the utility of nanoparticle-delivered, chemically modified mRNAs (cmRNA) to improve tendon repair.

Impact of sepsis on Eastern Cooperative Oncology Group performance status among fully ambulatory patients: a prospective nationwide multicenter cohort.

Investigations of the impact of sepsis on the Eastern Cooperative Oncology Group performance status (ECOG PS) of fully ambulatory patients are scarce. This is a retrospective analysis of prospectively collected nationwide data on septic patients recruited from 19 hospitals of the Korean Sepsis Alliance between August 2019 and December 2020. Adult septic patients with good ECOG PS (i.e., 0 or 1) before sepsis were enrolled in this study. The change in ECOG PS and the prevalence of disability (ECOG PS ≥2) at hospital discharge were recorded. Of the 4,145 septic patients, 1,735 (41.9%) patients who had ECOG PS of 0 or 1 before sepsis and eventually survived to discharge were selected. After treatment for sepsis, the ECOG PS deteriorated in 514 (29.6%) patients; 376 (21.7%) patients had poor ECOG PS (i.e., ≥2) at hospital discharge. The proportion of patients with poor ECOG PS at hospital discharge increased with increases in the initial sequential organ failure assessment (SOFA) score and lactate level. Furthermore, poor ECOG PS at hospital discharge was found in young patients (aged <65 years, 17.4%), those with no history of cancer (18.2%) or with low comorbidities [Charlson comorbidity index (CCI) ≤2; 13.6%], and those without septic shock (19.9%). In multivariable analysis, age, solid cancer, immunocompromised condition, SOFA score, mechanical ventilation, and use of inappropriate empirical antibiotics (odds ratio: 1.786; 95% confidence interval: 1.151-2.771) were significant risk factors for poor ECOG PS. One in five septic patients who were fully ambulatory before sepsis were not functionally independent at hospital discharge. Incomplete functional recovery was also seen in a substantial proportion of younger patients, those with low comorbidities, and those without septic shock. However, the adequacy of empirical antibiotics may improve the functional status in such patients.

A comprehensive description of kidney disease progression after acute kidney injury from a prospective, parallel-group cohort study

Acute kidney injury (AKI) is associated with adverse long-term outcomes, but many studies are retrospective, focused on specific patient groups or lack adequate comparators. The ARID (AKI Risk in Derby) Study was a five-year prospective parallel-group cohort study to examine this. Hospitalized cohorts with and without exposure to AKI were matched 1:1 for age, baseline kidney function, and diabetes. Estimated glomerular filtration rate (eGFR) and the urinary albumin:creatinine ratio (uACR) were measured at three-months, one-, three- and five-years. Outcomes included kidney disease progression, heart failure episodes and mortality. In 866 matched individuals, kidney disease progression at five years was found to be significantly increased in 30% of the exposed group versus 7% of those non-exposed (adjusted odds ratio 2.49 [95% confidence interval 1.43 to 4.36]). In the AKI group, this was largely characterized by incomplete recovery of kidney function by three months. Further episodes of AKI during follow-up were significantly more common in the exposed group (odds ratio 2.71 [1.94 to 3.77]) and had an additive effect on risk of kidney disease progression. Mortality and heart failure episodes were more frequent in the exposed group, but the association with AKI was no longer significant when models were adjusted for three-month eGFR and uACR. In a general hospitalized population, kidney disease progression after five years was common and strongly associated with AKI. Thus, the time course of changes and the attenuation of associations with adverse outcomes after adjustment for three-month eGFR and uACR suggest non-recovery of kidney function is an important assessment in post-AKI care and a potential future target for intervention. STUDY REGISTRATION: ISRCTN25405995.

Focal Muscle Vibration (fMV) for Post-Stroke Motor Recovery: Multisite Neuroplasticity Induction, Timing of Intervention, Clinical Approaches, and Prospects from a Narrative Review

Despite newly available therapies for acute stroke and innovative prevention strategies, stroke remains the third leading cause of disability-adjusted life-years (DALYs) lost worldwide, mostly because more than half of stroke survivors aged 65 and over exhibit an incomplete functional recovery of the paretic limb. Given that a repeated sensory input is one of the most effective modulators of cortical motor and somatosensory structures, focal muscle vibration (fMV) is gaining growing interest as a safe, well-tolerated, and non-invasive brain stimulation technique to promote motor recovery after stroke with a long-lasting and clinically relevant improvement in strength, step symmetry, gait, and kinematics parameters. In this narrative review, we first summarize the structural (neural plasticity) and functional changes (network relearning) triggered by the stroke lesion and carried out at a brain and spinal cord level in an attempt to recover from the loss of function. Then, we will focus on the fMV’s plasticity-based mechanisms reporting evidence of a possible concurrently acting multisite plasticity induced by fMV. Finally, to understand what the most effective fMV rehabilitation protocol could be, we will report the most recent evidence regarding the different clinical approaches and timing of the fMV treatment, the related open issues, and prospects.

Acellular collagen-glycosaminoglycan matrix promotes functional recovery in a rat model of volumetric muscle loss.

Aim: Volumetric muscle loss (VML) is a composite loss of skeletal muscle, which heals with fibrosis, minimal muscle regeneration, and incomplete functional recovery. This study investigated whether collagen-glycosaminoglycan scaffolds (CGS) improve functional recovery following VML. Methods: 15Sprague-Dawley rats underwent either sham injury or bilateral tibialis anterior (TA) VML injury, with or without CGS implantation. Results: In rats with VML injuries treated with CGS, the TA exhibited greater in vivo tetanic forces and in situ twitch and tetanic dorsiflexion forces compared with those in the non-CGS group at 4- and 6-weeks following injury, respectively. Histologically, the VML with CGS group demonstrated reduced fibrosis and increased muscle regeneration. Conclusion: Taken together, CGS implantation has potential augment muscle recovery following VML.

#6722 A RARE CASE OF ACUTE KIDNEY INJURY IN A PATIENT GRANULOMATOSIS WITH POLYANGIITIS, MONOCLONAL GAMMOPATHY WITH RENAL SIGNIFICANCE AND AMYLOIDOSIS

Abstract Introduction Anti - neutrophil cytoplasmic antibody /ANCA/- associated vasculitis is a small vessel vasculitis. It is a rare, autoimmune, inflammatory disease, with undetermined etiology, including granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis. It could lead to pauci - immune necrotizing and crescentic glomerulonephritis and rapidly progressive glomerulonephritis. Monoclonal gammopathy of renal significance /MGRS/ is a plasma cell or B-cell disorder that could lead to renal impairment due to production of monoclonal protein, which do not meet the criteria for myeloma multiplex. There is a significant higher risk in progression to end stage renal disease/ESRD/ in groups with renal vasculitis and concomitant disease due to nonrenal factors. Clinical case We present a rare clinical case of a patient with combination of ANCA -vasculitis, MGRS and amyloidosis. A 60 year-old male patient with deteriorated renal function was presented to the clinic. Chronic congestive heart failure, arterial hypertension, situs inversus, anemic syndrome, hepatosplenomegaly were reported as concomitant diseases. Due to progressive worsening of renal function emergency hemodialysis treatment was initiated through temporary vascular access. Against the background of several chronic diseases, which could lead to chronic kidney failure, the echographic image of the kidneys stands out. Both kidneys are enlarged, with increased echogenicity of the parenchyma as in a diffuse renal process. The performed immunological tests confirm the diagnosis of granulomatosis with polyangiitis /formerly called Wegener's/, PR3-105,7. The results for the screened viral infections was negative. An episode of severe pulmonary edema was registered in the context of obstruction of the hemodialysis catheter due to coagulation disorders. The renal biopsy supports the diagnosis of vasculitis, crescentic glomerulonephritis - in advanced stage of development, probably a morphological manifestation of secondary nephropathy. An interesting finding is the presence of amyloidosis /AL/. The immunofixation blood test identify monoclonal IgG kappa type component. A sternal puncture, SPECT/CT was performed and diagnosis of multiple myeloma was excluded. Pathogenic treatment with corticosteroids and cyclophosphamide was initiated. In addition a short-term change in vision is observed in the context of the underlying disease. A consultation with ophthalmologist and neurologist was held, confirming cerebral arteritis. At this stage the recovery of renal function is incomplete. High flux membrane were used during dialysis treatment to reduce large and middle sized molecules. In addition, for the treatment of light chain amyloidisis, bortezomib was considered. Conclusion This clinical case emphasizes on the need to precisely clarify the cause that led to acute kidney injury. A thorough search for the underlying disease causing the deterioration of kidney function is critical for the renal outcome. The reasons for incomplete recovery of renal function during active treatment of vasculitis should be sought in underlying diseases-arterial hypertension, chronic heart failure, amyloidosis. Discussion Younger patients with lower eGFR at the onset of ANCA-associated vasculitis and no concomitant disease show significant improvement in renal function by the end of the first year regardless the need of dialysis treatment. Patients with severe accompanying disease have slow and insufficient improvement in renal function due to the prevalence of higher percentage of globally sclerotic glomeruli. Considering the severe prognosis of ANCA-associated vasculitis it is crucial to start early treatment. The state of the renal function at the first year of pathogenic treatment along with the pathological findings of the renal biopsy could be a predictors for the renal function course.

A passive ankle dorsiflexion testing system to assess mechanobiological and structural response to cyclic loading in rat Achilles tendon

Tendinopathy is thought to be caused by repeated overload of the tendon with insufficient recovery time, leading to an inadequate healing response and incomplete recovery of preinjury material strength and function. The etiology of tendinopathy induced by mechanical load is being explored with a variety of mechanical load scenarios in small animals. This study establishes a testing system that applies passive ankle dorsiflexion to a rat hindlimb, estimates the force applied to the tendon during cyclic loading and enables the assessment of subsequent structural and biological changes. We demonstrated that the system had no drift in the applied angle, and the registered maximum angle and torque inputs and outputs were consistent between tests. We showed that cyclic loading decreased hysteresis and loading and unloading moduli with increasing cycles applied to the tendon. Histology showed gross changes to tendon structure. This work establishes a system for passively loading the rat Achilles tendon in-vivo in a physiological manner, facilitating future studies that will explore how mechanics, structure, and biology are altered by mechanical repetitive loading.

Poor nutritional status is associated with incomplete functional recovery in elderly patients with mild traumatic brain injury.

The geriatric nutritional risk index (GNRI) is a simple index for evaluating the nutrition status of elderly patients. Many investigations have demonstrated that this index is associated with the prognosis of several diseases. This study aims to identify the relationship between the GNRI and recovery in elderly mild traumatic brain injury (mTBI) patients. A total of 228 mTBI patients older than 65 years were included in this study. mTBI was defined as an injury to the brain with a loss of consciousness of 30 min or less, a duration of posttraumatic amnesia of <24 h, and an admission Glasgow Coma Scale (GCS) score of 13-15. The Glasgow Outcome Scale Extended (GOSE), an outcome scale assessing functional independence, work, social activities, and personal relationships, was applied to assess the recovery of the patients. The clinical outcome was divided into complete recovery (GOSE = 8) and incomplete recovery (GOSE ≤ 7) at 6 months after the injury. Multivariate logistic regression was applied to evaluate the association between the GNRI and recovery of elderly mTBI patients, with adjustment for age, sex, hypertension, diabetes, and other important factors. The receiver operating curve (ROC) analysis demonstrated that the cutoff value of GNRI was 97.85, and the area under the curve (AUC) was 0.860. Compared to the patients with a high GNRI, the patients with a low GNRI were older, had a higher prevalence of anemia, acute subdural hematoma, and subarachnoid hemorrhage, had a higher age-adjusted Charlson Comorbidity Index value, and had lower levels of albumin, lymphocytes, and hemoglobin. Multivariable analysis showed that high GNRI was associated with a lower risk of 6-month incomplete recovery (OR, 0.770, 95% CI: 0.709-0.837, p < 0.001). The GNRI has utility as part of the objective risk assessment of incomplete 6-month functional recovery in elderly patients with mTBI.

MP60-13 VIRAL TRANSDUCTION EFFICACY OF PERIPHERAL NEURONS INNERVATING THE EXTERNAL URETHRAL SPHINCTER BY LOCAL INJECTION OF ADENO-ASSOCIATED VIRUS VECTORS

You have accessJournal of UrologyCME1 Apr 2023MP60-13 VIRAL TRANSDUCTION EFFICACY OF PERIPHERAL NEURONS INNERVATING THE EXTERNAL URETHRAL SPHINCTER BY LOCAL INJECTION OF ADENO-ASSOCIATED VIRUS VECTORS Firoj Alom, Richard Johnson, and Aaron Mickle Firoj AlomFiroj Alom More articles by this author , Richard JohnsonRichard Johnson More articles by this author , and Aaron MickleAaron Mickle More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003318.13AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Incomplete functional recovery of the lower urinary tract, including the external urethral sphincter (EUS), frequently occurs in spinal cord injury patients. Electrical neuromodulation of the lower urinary tract remains an attractive therapeutic target, but it has yet to be fully deployed clinically. The wide distribution of sensory and motor axons in the pudendal nerve innervating targets in the lower urinary tract but also other targets in other pelvic structures significantly limits the development of electrical neuromodulation strategies. We can address this limitation by using optogenetic techniques to modulate the lower urinary tract using light stimulation. First, we need to determine the viral vectors' efficiency and potential promoters to transduce the specific neuronal populations through local injection into regions of the lower urinary tract. In this study, we investigated the transduction efficiency of adeno-associated virus serotypes in the peripheral regions by local injection into the external urethral sphincter. METHODS: We injected different AAV vector serotypes along with a neural tracer into the external sphincter of rats. After five weeks, we evaluated the viral transduction efficiency of these AAV serotypes. RESULTS: We observed variable transduction of multiple peripheral neuron populations and showed different efficacies of neuronal transduction by these viruses compared with labeling with a neural tracer. We also found that this level of expression by local injection is also relevant for optogenetic-mediated modulation of the EUS function. CONCLUSIONS: Our preliminary results indicate that by using adeno-associated viruses, it is possible to transduce the neurons controlling the EUS by local injection. We think these studies will potentially help improve the viral targeting of neurons controlling lower urinary tract function. Source of Funding: This research was supported by the NIH NIBIB Trailblazer award (R21 EB031249) and in part by the Urology Care Foundation Research Scholar Award Program and Indian American Urological Association Sakti Das, MD Award © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e848 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Firoj Alom More articles by this author Richard Johnson More articles by this author Aaron Mickle More articles by this author Expand All Advertisement PDF downloadLoading ...

Post-Pulmonary Embolism Impairment Six Months after Acute Pulmonary Embolism: A Prospective Registry.

Little evidence is available on post-pulmonary embolism impairment (PPEI), a recently defined complication of pulmonary embolism (PE) encompassing dysfunctional clinical and imaging parameters. In the present study, we sought to evaluate its frequency with a focus on the main components. In this prospective registry, we included patients with a confirmed diagnosis of acute PE and focused on those with initial right ventricular (RV) dysfunction. Their baseline, pre-discharge, and 6month follow-up clinical and imaging characteristics were recorded. The main study outcomes were incomplete RV functional recovery, exercise capacity limitations (based on the 6minute walk test), and their combination, which defines PPEI, within six months of acute PE. Of 170 consecutive patients with a confirmed diagnosis of acute PE, 123 accepted to participate in the follow-up study, of whom 87 had initial RV dysfunction. The 6month rates of incomplete RV functional recovery, signs of an intermediate-to-high echocardiographic probability of PH, and exercise limitations were observed in 58.6, 32.1, and 45.9%, respectively. A total of 22 (25.2%; 95% CI 15.5-34.4%) patients had PPEI. The RV/LV ratio and the fractional area change on discharge after acute PE were more often impaired among patients with incomplete RV recovery, exercise limitations, and a high probability of PH at 6months. In contrast, an initial impaired RV diastolic function indices appeared to characterize patients with a limited exercise capacity at 6months. PPEI affects one fourth of patients surviving acute PE with half of them presenting with RV dysfunction or exercise limitations.

Effect of silicone oil on retinal microcirculation after vitrectomy for rhegmatogenous retinal detachment evaluated by OCT angiography: a literature review.

Silicone oil (SO) has been widely used as intravitreal tamponade agent for rhegmatogenous retinal detachment (RRD) and has been occasionally associated with incomplete retinal structural and functional recovery. The use of Optical Coherence Tomography Angiography (OCT-A) has recently attracted significant attention for detailed analysis of retinal capillary plexus and blood flow changes as predicting factors for postoperative outcomes. A detailed literature search was performed in PubMed database until October 2022. The following keywords were used: rhegmatogenous retinal detachment, silicone oil, optical coherence tomography angiography, macular microvasculature, peripapillary capillary plexus, vessel density, and foveal avascular zone. We identified and reviewed 19 studies referring to microcirculation alterations of the retinal capillary plexus as seen on OCT-A in eyes treated by vitrectomy with intravitreal SO for RRD. A comprehensive update revealed variability of microcirculation characteristics of the retinal capillary plexus including the macular and the peripapillary capillaries. Further studies are warranted to clarify the OCT-A values in an attempt to identify the potential effect of SO on retinal tissue in clinical practice. A review of the existing literature sheds light on the effect of SO on retinal capillary plexus and the potential impact on functional outcomes after vitrectomy for RRD. This article discusses important aspects of key publications on the topic, highlights the importance to identify distinct alterations of the microvasculature status, and proposes the need for further future research in this field.

Novel Therapeutic Approaches Enhance PGC1-alpha to Reduce Oxidant Stress-Inflammatory Signaling and Improve Functional Recovery in Hibernating Myocardium.

Ischemic heart disease affects millions of people around the world. Current treatment options, including coronary artery bypass grafting, do not result in full functional recovery, highlighting the need for novel adjunctive therapeutic approaches. Hibernation describes the myocardial response to prolonged ischemia and involves a set of complex cytoprotective metabolic and functional adaptations. PGC1-alpha, a key regulator of mitochondrial energy metabolism and inhibitor of oxidant-stress-inflammatory signaling, is known to be downregulated in hibernating myocardium. PGC1-alpha is a critical component of cellular stress responses and links cellular metabolism with inflammation in the ischemic heart. While beneficial in the acute setting, a chronic state of hibernation can be associated with self-perpetuating oxidant stress-inflammatory signaling which leads to tissue injury. It is likely that incomplete functional recovery following revascularization of chronically ischemic myocardium is due to persistence of metabolic changes as well as prooxidant and proinflammatory signaling. Enhancement of PGC1-alpha signaling has been proposed as a possible way to improve functional recovery in patients with ischemic heart disease. Adjunctive mesenchymal stem cell therapy has been shown to induce PGC1-alpha signaling in hibernating myocardium and could help improve clinical outcomes for patients undergoing bypass surgery.

Local application of a transcutaneous carbon dioxide paste prevents excessive scarring and promotes muscle regeneration in a bupivacaine-induced rat model of muscle injury.

In postoperative patients with head and neck cancer, scar tissue formation may interfere with the healing process, resulting in incomplete functional recovery and a reduced quality of life. Percutaneous application of carbon dioxide (CO2 ) has been reported to improve hypoxia, stimulate angiogenesis, and promote fracture repair and muscle damage. However, gaseous CO2 cannot be applied to the head and neck regions. Previously, we developed a paste that holds non-gaseous CO2 in a carrier and can be administered transdermally. Here, we investigated whether this paste could prevent excessive scarring and promote muscle regeneration using a bupivacaine-induced rat model of muscle injury. Forty-eight Sprague Dawley rats were randomly assigned to either a control group or a CO2 group. Both groups underwent surgery to induce muscle injury, but the control group received no treatment, whereas the CO2 group received the CO2 paste daily after surgery. Then, samples of the experimental sites were taken on days 3, 7, 14, and 21 post-surgery to examine the following: (1) inflammatory (interleukin [IL]-1β, IL-6), and transforming growth factor (TGF)-β and myogenic (MyoD and myogenin) gene expression by polymerase chain reaction, (2) muscle regeneration with haematoxylin and eosin staining, and (3) MyoD and myogenin protein expression using immunohistochemical staining. Rats in the CO2 group showed higher MyoD and myogenin expression and lower IL-1β, IL-6, and TGF-β expression than the control rats. In addition, treated rats showed evidence of accelerated muscle regeneration. Our study demonstrated that the CO2 paste prevents excessive scarring and accelerates muscle regeneration. This action may be exerted through the induction of an artificial Bohr effect, which leads to the upregulation of MyoD and myogenin, and the downregulation of IL-1β, IL-6, and TGF-β. The paste is inexpensive and non-invasive. Thus, it may be the treatment of choice for patients with muscle damage.

The impact of different exercise protocols on rat soleus muscle reinnervation and recovery following peripheral nerve lesion and regeneration.

Background: Incomplete functional recovery following traumatic peripheral nerve injury is common, mainly because not all axons successfully regenerate and reinnervate target muscles. Exercise can improve functional outcomes increasing the terminal sprouting during the muscle reinnervation. However, exercise is not a panacea per se. Indeed, the type of exercise adopted dramatically impacts the outcomes of rehabilitation therapy. To gain insight into the therapeutic effects of different exercise regimens on reinnervation following traumatic nerve lesion, we evaluated the impact of different clinically transferable exercise protocols (EPs) on metabolic and functional muscle recovery following nerve crush. Methods: The reinnervation of soleus muscle in adult nerve-crushed rats was studied following 6 days of different patterns (continuous or intermittent) and intensities (slow, mid, and fast) of treadmill running EPs. The effects of EPs on muscle fiber multiple innervation, contractile properties, metabolic adaptations, atrophy, and autophagy were assessed using functional and biochemical approaches. Results: Results showed that an intermittent mid-intensity treadmill EP improves soleus muscle reinnervation, whereas a slow continuous running EP worsens the functional outcome. However, the mid-intensity intermittent EP neither enhanced the critical mediators of exercise-induced metabolic adaptations, namely, PGC-1α, nor improved muscle atrophy. Conversely, the autophagy-related marker LC3 increased exclusively in the mid-intensity intermittent EP group. Conclusion: Our results demonstrated that an EP characterized by a mid-intensity intermittent activity enhances the functional muscle recovery upon a nerve crush, thus representing a promising clinically transferable exercise paradigm to improve recovery in humans following peripheral nerve injuries.

336.3: Clinical Utility of Donor-Derived Cell-Free DNA During the Period of Recovery of Renal Function After Kidney Transplantation

Background: The transplant of kidneys with high KDPI, and the incidence and duration of delayed graft function (DGF) are risk factors associated with incomplete recovery of kidney function (IRF). In both situations, kidney biopsies are essential to exclude the diagnosis of acute rejection (AR). Purpose: This study evaluates the clinical utility of monitoring donor-derived cell-free DNA (dd-cfDNA), a biomarker of kidney injury, in recipients of high Kidney Donor Profile Index (KDPI) transplants during the period of kidney function recovery. Methods: This is a single center, prospective, cohort study in recipients of high KDPI kidneys who developed delayed graft function (DGF), defined as the need for dialysis within the first week after transplantation. All patients received a single 3 mg/kg anti-thymocyte globulin dose, tacrolimus, mycophenolate, and prednisone. Blood samples were obtained at 14 (D14) and 30 (D30) days to measure the percentage (%) of dd-cfDNA. The dd-cfDNA > 1% is associated with increased probability for acute rejection (AR). Results: This preliminary analysis includes data from 69 patients. The median KDPI was 73% [IQR 47-87] and the mean cold ischemia time was 27± 7 hours. The incidence of DGF was 89.8% with a median duration of 6 (IQR 2 – 9) days. At D14 the median GFR was 12 ml/min/1.73 m2 (IQR 6-21) and the median dd-cfDNA levels were 0.43% (IQR 0.02-0.78), with 19 patients (28%) showing dd-cfDNA >1%. Surveillance biopsies during DGF were performed in 42 (61%) patients showing one T-cell mediated rejection IA (dd-cfDNA of 0.41%) and 4 borderline changes (dd-cfDNA 0.82%, 0.85%, 0.98%, 1.90%). Using dd-cfDNA >1% to guide the indication of the surveillance biopsy, we would have avoided 22 (52%) biopsies but missed 1 (2%) patient with AR. At D30, the median GFR was 36 ml/min/1.73 m2 (IQR 28-48) and the median dd-cfDNA levels were 0.40% (IQR 0.01-0.66), with 12 patients (19%) showing dd-cfDNA >1%. Surveillance biopsies performed in 21 (30.43%) patients with incomplete recovery of kidney function showed 4 borderline changes (dd-cfDNA 0.17%, 0.66%, 0.67%, and 2.80%). Using dd-cfDNA >1% to guide the indication of the surveillance biopsy, we would have avoided 12 (57%) biopsies without missing any AR episodes. Overall, 5 (7%) patients showed dd-cfDNA >1% at D14 and D30, but none of them showed biopsy confirmed AR. Conclusions: This preliminary analysis suggests that monitoring dd-cfDNA may assist clinical decision during the period of DGF and in kidney transplant recipients with incomplete recovery of graft function.