Randomized Controlled Trial of the Effect of an Exercise Rehabilitation Program on Symptom Burden in Maintenance Hemodialysis: A Clinical Research Protocol.

Background: People receiving hemodialysis experience high symptom burden that contributes to low functional status and poor health-related quality of life. Management of symptoms is a priority for individuals receiving hemodialysis but limited effective treatments exist. There is emerging evidence that exercise programming can improve several common dialysis-related symptoms. Objective: The primary aim of this study is to evaluate the effect of an exercise rehabilitation program on symptom burden in individuals receiving maintenance hemodialysis. Design: Multicenter, randomized controlled, 1:1 parallel, open label, prospective blinded end point trial. Setting: Three facility-based hemodialysis units in Winnipeg, Manitoba, Canada. Participants: Adults aged 18 years or older with end-stage kidney disease receiving facility-based maintenance hemodialysis for more than 3 months, with at least 1 dialysis-related symptom as indicated by the Dialysis Symptom Index (DSI) severity score >0 (n = 150). Intervention: Supervised 26-week exercise rehabilitation program and 60 minutes of cycling during hemodialysis thrice weekly. Exercise intensity and duration were supervised and individualized by the kinesiologist as per participant baseline physical function with gradual progression over the course of the intervention. Control: Usual hemodialysis care (no exercise program). Measurements: Our primary outcome is change in symptom burden at 12 weeks as measured by the DSI severity score. Secondary outcomes include change in modified DSI severity score (includes 10 symptoms most plausible to improve with exercise), change in DSI severity score at 26 and 52 weeks; time to recover post-hemodialysis; health-related quality of life measured using EuroQol (EQ)-5D-5L; physical activity behavior measured by self-report (Godin-Shepherd questionnaire) and triaxial accelerometry; exercise capacity (shuttle walk test); frailty (Fried); self-efficacy for exercise; and 1-year hospitalization and mortality. Methods: Change in primary outcome will be compared between groups by independent 2-tailed t test or Mann-Whitney U test depending on data distribution and using generalized linear mixed models, with study time point as a random effect and adjusted for baseline DSI score. Similarly, change in secondary outcomes will be compared between groups over time using appropriate parametric and nonparametric statistical tests depending on data type and distribution. Limitations: The COVID-19 pandemic restrictions on clinical research at our institution delayed completion of target recruitment and prevented collection of accelerometry and physical function outcome data for 15 months until restrictions were lifted. Conclusions: The application of an exercise rehabilitation program to improve symptom burden in individuals on hemodialysis may ameliorate common symptoms observed in individuals on hemodialysis and result in improved quality of life and reduced disability and morbidity over the long term. Importantly, this pragmatic study, with a standardized exercise intervention that is adaptable to baseline physical function, addresses an important gap in both clinical care of hemodialysis patients and our current knowledge.

Contexte: Les personnes sous hémodialyse éprouvent un grand nombre de symptômes qui contribuent à un faible état fonctionnel et à une mauvaise qualité de vie liée à la santé. La prise en charge des symptômes est une priorité pour les personnes sous hémodialyse, mais les traitements efficaces sont limités. De nouvelles preuves montrent que l'adoption d'un programme d'exercice permettrait d'améliorer plusieurs symptômes courants liés à la dialyse. Objectifs: Le principal objectif de cette étude est d'évaluer l'effet d'un programme de rééducation par l'exercice sur le fardeau des symptômes chez les personnes recevant une hémodialyse d'entretien. Conception: Essai clinique prospectif randomisé-contrôlé, en aveugle, en parallèle 1:1 et ouvert, multicentrique. Cadre: Trois unités d'hémodialyse de Winnipeg, au Manitoba (Canada). Sujets: Des adultes atteints d'insuffisance rénale terminale qui reçoivent des traitements d'hémodialyse d'entretien en centre depuis plus de trois mois et qui présentent au moins un symptôme lié à la dialyse, tel qu'indiqué par un score de gravité de l'indice des symptômes de la dialyse (Dialysis Symptom Index) supérieur à zéro (n = 150). Intervention: Programme supervisé de rééducation par l'exercice d'une durée de 26 semaines et 60 minutes de vélo trois fois par semaine pendant l'hémodialyse. L'intensité et la durée de l'exercice ont été supervisées par un kinésiologue qui les a ensuite personnalisées en fonction de la forme physique initiale du participant en prévoyant une progression graduelle tout au long de l'intervention. Groupe témoin: Soins habituels d'hémodialyse (sans programme d'exercice). Mesures: Notre principal critère de jugement est un changement dans le fardeau lié aux symptômes après 12 semaines, tel que mesuré par le score de gravité de l'indice des symptômes de dialyse (ISD). Les critères d'évaluation secondaires comprennent un changement du score modifié de gravité de l'ISD (portant sur 10 symptômes les plus plausibles de s'améliorer avec l'exercice), la modification du score de gravité de l'ISD après 26 et 52 semaines, le temps de récupération après l'hémodialyse, la qualité de vie liée à la santé mesurée par le questionnaire EQ5D-5L, le comportement lié à l'activité physique mesuré par autoévaluation (questionnaire Godin-Shepherd) et par accéléromètre triaxial, la capacité d'effort (test de marche navette), la fragilité (Fried), le sentiment d'efficacité autodéclaré face à l'exercice, ainsi que les hospitalisations et la mortalité à un an. Méthodologie: Les changements pour le principal critère de jugement seront comparés entre les groupes par un test t bilatéral indépendant ou un test U de Mann-Whitney en fonction de la distribution des données, ainsi qu'à l'aide de modèles linéaires mixtes généralisés avec un point temporel de l'étude comme effet aléatoire et corrigé en fonction du score ISD initial. Les changements dans les résultats secondaires seront comparés entre les groupes au fil du temps à l'aide des tests statistiques paramétriques et non paramétriques appropriés selon le type de données et la distribution. Limites: Les restrictions liées à la pandémie de COVID-19 dans notre établissement ont retardé le recrutement des cibles et empêché pendant 15 mois la collecte de données sur les résultats mesurés par l'accéléromètre et les mesures de la fonction physique, soit jusqu'à ce que les restrictions soient levées. Conclusion: L'adoption d'un programme de rééducation par l'exercice visant à réduire le fardeau lié aux symptômes chez les personnes sous hémodialyse peut améliorer les symptômes courants observés dans cette population et se traduire par une amélioration de la qualité de vie et une réduction de l'invalidité et de la morbidité à long terme. Il convient de noter que cet essai pragmatique, avec son intervention d'exercice standardisée adaptable à la condition physique initiale de la personne, comble une lacune importante dans les soins cliniques des patients sous hémodialyse et dans nos connaissances actuelles.

An International Survey of Peritoneal Dialysis Exercise Practices and Perceptions.

Introduction: Low activity levels and poor physical function are associated with technique failure and mortality in people receiving peritoneal dialysis (PD). Adequate levels of physical function are required to maintain independence for people choosing this predominantly home-based therapy. The objective of this study was to identify the exercise-related perceptions and practices of PD clinicians globally. Methods: We conducted a cross-sectional survey of PD clinicians from English-, Thai-, Spanish-, and Portuguese-speaking PD-prevalent countries exploring clinicians' perceptions and practices of swimming, activity following PD catheter insertion, lifting, and falls prevention. This study was convened by the International Society of Peritoneal Dialysis and Global Renal Exercise Network between July and December 2021. Results: Of 100 of the highest PD-prevalent countries, 85 responded and were represented in the findings. A total of 1125 PD clinicians (448 nephrologists, 558 nephrology nurses, 59 dietitians, and 56 others) responded from 61% high-income, 32% upper middle-income and 7% lower middle-income countries. The majority (n = 1054, 94%) agreed that structured exercise programs would be beneficial for people receiving PD. Most respondents believed people on PD could perform more exercise (n = 907, 81%) and that abdominal strengthening exercises could be safely performed (n = 661, 59%). Compared to clinicians in high-income countries, clinicians from lower middle-income status (odds ratio [OR], 5.57; 1.64 to 18.9) are more likely to promote participation in physical activity. Conclusion: Clinicians know the importance of physical activity in people receiving PD. Exercise counseling and structured exercise plans could be included in the standard care of people receiving PD to maintain independence.

Purified regenerating retinal neurons reveal regulatory role of DNA methylation-mediated Na+/K+-ATPase in murine axon regeneration.

While embryonic mammalian central nervous system (CNS) axons readily grow and differentiate, only a minority of fully differentiated mature CNS neurons are able to regenerate injured axons, leading to stunted functional recovery after injury and disease. To delineate DNA methylation changes specifically associated with axon regeneration, we used a Fluorescent-Activated Cell Sorting (FACS)-based methodology in a rat optic nerve transection model to segregate the injured retinal ganglion cells (RGCs) into regenerating and non-regenerating cell populations. Whole-genome DNA methylation profiling of these purified neurons revealed genes and pathways linked to mammalian RGC regeneration. Moreover, whole-methylome sequencing of purified uninjured adult and embryonic RGCs identified embryonic molecular profiles reactivated after injury in mature neurons, and others that correlate specifically with embryonic or adult axon growth, but not both. The results highlight the contribution to both embryonic growth and adult axon regeneration of subunits encoding the Na+/K+-ATPase. In turn, both biochemical and genetic inhibition of the Na+/K+-ATPase pump significantly reduced RGC axon regeneration. These data provide critical molecular insights into mammalian CNS axon regeneration, pinpoint the Na+/K+-ATPase as a key regulator of regeneration of injured mature CNS axons, and suggest that successful regeneration requires, in part, reactivation of embryonic signals.

Predictive Modeling of New-Onset Postoperative Diplopia Following Orbital Decompression for Thyroid Eye Disease.

PURPOSE: To identify risk factors for the development of new-onset, postoperative diplopia following orbital decompression surgery based on patient demographics, clinical exam characteristics, radiographic parameters, and surgical techniques. METHODS: We conducted a multi-center retrospective chart review of patients who underwent orbital decompression for thyroid eye disease (TED). Patient demographics, including age, gender, smoking history, preoperative exophthalmometry, clinical activity score (CAS), use of peribulbar and/or systemic steroids, and type of orbital decompression were reviewed. Postoperative diplopia was determined at a minimum of 3 months postoperatively and before any further surgeries. Cross-sectional area ratios of each extraocular muscle to orbit and total fat to orbit were calculated from coronal imaging in a standard fashion. All measurements were carried out using PACS imaging software. Multivariable logistic regression modeling was performed using Stata 14.2 (StataCorp, College Station, TX). RESULTS: A total of 331 patients without preoperative diplopia were identified. At 3 months postoperatively, 249 patients had no diplopia whereas 82 patients developed diplopia. The average postoperative follow-up was 22 months (range 3-156) months. Significant preoperative clinical risk factors for postoperative diplopia included older age at surgery, proptosis, use of peribulbar or systemic steroids, elevated clinical activity score, and presence of preoperative compressive optic neuropathy. Imaging findings of enlarged cross-sectional areas of each rectus muscle to the overall orbital area also conferred a significant risk of postoperative diplopia. Regarding surgical factors, postoperative diplopia was more common among those undergoing medial wall decompression, bilateral orbital surgery, and balanced decompression, whereas endoscopic medial wall decompression was found to be relatively protective. CONCLUSIONS: This study identifies risk factors associated with the development of diplopia following orbital decompression using multivariable data. This study demonstrates that several characteristics including age, clinical activity score, the cross-sectional muscle to orbit ratios, in addition to the type of orbital decompression surgery, are predictive factors for the development of new-onset postoperative diplopia.

Physical activity and exercise in peritoneal dialysis: International Society for Peritoneal Dialysis and the Global Renal Exercise Network practice recommendations.

Life participation requiring physical activity and physical function is a key patient-reported outcome for people receiving peritoneal dialysis (PD). Clinician guidance is required from multidisciplinary sources regarding exercise and activity advice to address the specific needs of this group. From August 2020 through to June 2021, the Global Renal Exercise Network and the International Society for Peritoneal Dialysis reviewed the published literature and international clinical experience to develop a set of clinical practice points. A set of questions relevant to physical activity and exercise were developed from the perspective of a person receiving PD and were the basis for the practice point development. The GRADE framework was used to evaluate the quality of evidence and to guide clinical practice points. The review of the literature found sparse quality evidence, and thus the clinical practice points are generally based on the expert consensus of people receiving PD, PD exercise expert clinicians and experienced PD exercise researchers. Clinical practice points address timing of exercise and activity (post-catheter insertion, peritoneal space empty or full), the uptake of specific activities (work, sex, swimming, core exercise), potential adverse outcomes related to activity and exercise (exit site care, perspiration, cardiovascular compromise, fatigue, intra-abdominal pressure), the effect of exercise and activity on conditions of interest (mental health, obesity, frailty, low fitness) and exercise nutrition.

Correction to: Ancestral Folate Promotes Neuronal Regeneration in Serial Generations of Progeny.

The original version of this article unfortunately contained error in Figure 4a to where some of the text was overlapping.

Ancestral Folate Promotes Neuronal Regeneration in Serial Generations of Progeny.

Folate supplementation in F0 mating rodents increases regeneration of injured spinal axons in vivo in 4 or more generations of progeny (F1-F4) in the absence of interval folate administration to the progeny. Transmission of the enhanced regeneration phenotype to untreated progeny parallels axonal growth in neuron culture after in vivo folate administration to the F0 ancestors alone, in correlation with differential patterns of genomic DNA methylation and RNA transcription in treated lineages. Enhanced axonal regeneration phenotypes are observed with diverse folate preparations and routes of administration, in outbred and inbred rodent strains, and in two rodent genera comprising rats and mice, and are reversed in F4-F5 progeny by pretreatment with DNA demethylating agents prior to phenotyping. Uniform transmission of the enhanced regeneration phenotype to progeny together with differential patterns of DNA methylation and RNA expression is consistent with a non-Mendelian mechanism. The capacity of an essential nutritional co-factor to induce a beneficial transgenerational phenotype in untreated offspring carries broad implications for the diagnosis, prevention, and treatment of inborn and acquired disorders.

Ultrasonic Aspiration for Debulking Infiltrative Masses of the Orbit.

PURPOSE: To demonstrate the utility of an ultrasonic aspirator (Sonopet, Stryker Corporation; Kalamazoo, MI) for debulking firm, soft tissue masses of the orbit. METHODS: Case series. The ultrasonic aspirator was used to debulk firm, soft tissue masses in 3 cases. The initial patient had a large orbitofacial mass extending to the inferior and lateral orbital apex secondary to IgG4 disease. The second patient had a lacrimal sac adenocarcinoma extending to the medial orbital apex. The third patient had a large orbital mass extending to the apex secondary to granulomatosis with polyangiitis. RESULTS: The ultrasonic aspirator facilitated debulking of infiltrative firm soft tissue masses of the orbit. The device's ability to emulsify, irrigate, and aspirate, along with its small footprint, facilitated precise sculpting and debulking to an extent which would have been difficult otherwise due to location. CONCLUSIONS: The ultrasonic aspirator allows precise sculpting of infiltrative firm soft tissue masses in the orbit and is particularly useful in cases with challenging anatomical access.

Nitrous Oxide Impairs Axon Regeneration after Nervous System Injury in Male Rats.

BACKGROUND: Nitrous oxide can induce neurotoxicity. The authors hypothesized that exposure to nitrous oxide impairs axonal regeneration and functional recovery after central nervous system injury. METHODS: The consequences of single and serial in vivo nitrous oxide exposures on axon regeneration in four experimental male rat models of nervous system injury were measured: in vitro axon regeneration in cell culture after in vivo nitrous oxide administration, in vivo axon regeneration after sharp spinal cord injury, in vivo axon regeneration after sharp optic nerve injury, and in vivo functional recovery after blunt contusion spinal cord injury. RESULTS: In vitro axon regeneration 48 h after a single in vivo 70% N2O exposure is less than half that in the absence of nitrous oxide (mean ± SD, 478 ± 275 um; n = 48) versus 210 ± 152 um (n = 48; P < 0.0001). A single exposure to 80% N2O inhibits the beneficial effects of folic acid on in vivo axonal regeneration after sharp spinal cord injury (13.4 ± 7.1% regenerating neurons [n = 12] vs. 0.6 ± 0.7% regenerating neurons [n = 4], P = 0.004). Serial 80% N2O administration reverses the benefit of folic acid on in vivo retinal ganglion cell axon regeneration after sharp optic nerve injury (1277 ± 180 regenerating retinal ganglion cells [n = 7] vs. 895 ± 164 regenerating retinal ganglion cells [n = 7], P = 0.005). Serial 80% N2O exposures reverses the benefit of folic acid on in vivo functional recovery after blunt spinal cord contusion (estimate for fixed effects ± standard error of the estimate: folic acid 5.60 ± 0.54 [n = 9] vs. folic acid + 80% N2O 5.19 ± 0.62 [n = 7], P < 0.0001). CONCLUSIONS: These data indicate that nitrous oxide can impair the ability of central nervous system neurons to regenerate axons after sharp and blunt trauma.

Orbital Septum Fibrosis in Congenital Ptosis Correlates With Eyelid Function: A Clinicopathologic Study.

PURPOSE: Congenital ptosis can threaten visual function and is usually treated with surgical correction. This study tests the hypothesis that congenital ptosis involves not only the levator muscle but also the orbital septum, which may tether the eyelid in the primary position. METHODS: A retrospective chart review was performed on 30 patients (41 eyelids) with congenital ptosis who underwent surgical correction that included partial septum excision. Histologic analysis was performed by a masked pediatric pathologist, with grading of septal tissue disorganization and fibrosis based on standard histologic criteria. An independent comparison of histologic grading with clinical ptosis measures was then performed. RESULTS: Fifteen eyelids demonstrated significant septal fibrosis, 19 were mild, and 7 were not fibrotic. Thirty-six eyelids demonstrated histologic disorganization. Mildly fibrotic eyelids were found to have reduced preoperative levator function than those that were not fibrotic (2.84 ± 1.92 vs. 9.57 ± 4.76 mm; p < 0.0001). Samples that demonstrated significant fibrosis were also found to have reduced preoperative levator function (4.67 ± 2.12 vs. 9.57 ± 4.76 mm; p = 0.0007). Histologically disorganized samples were also found to have a lower preoperative levator function (9.50 ± 6.04 vs. 3.99 ± 2.49; p = 0.0052). CONCLUSIONS: Orbital septae in patients with congenital ptosis demonstrate histologic disorganization and fibrosis. When decreased levator function is observed clinically, septal fibrosis and/or disorganization is likely present. These observations suggest that debulking the fibrotic septum during congenital ptosis surgery may improve outcomes by releasing the eyelid from its congenitally tethered position, improving eyelid elasticity.

An Aesthetic Orbicularis Oculi Myectomy Technique for Blepharospasm: Use of Topical 5-Fluorouracil and Fibrin Sealant.

PURPOSE: To describe a modified technique of orbicularis oculi myectomy for refractory blepharospasm. This technique includes removal of orbicularis muscle, reformation of the eyelid crease and pretarsal platform using fibrin sealant (Tisseel), and topical 5-fluorouracil to reduce scar formation and improve aesthetic outcome. METHODS: Retrospective chart review of 7 patients who underwent bilateral orbicularis oculi myectomy with our technique from 2013 to 2016. Outcome measures were postoperative botulinum toxin dose, frequency, duration between treatments, the amount of lagophthalmos, severity of dry eye, and patient satisfaction with aesthetic and functional outcome. RESULTS: Patients who underwent the aesthetic myectomy technique had significantly decreased botulinum toxin use with relief of symptoms postoperatively. Only 1 of 7 patients experienced mild dry eye symptoms postoperatively, managed with artificial tears. All patients were satisfied with the aesthetic and functional outcome. CONCLUSIONS: The aesthetic myectomy technique provides effective treatment for blepharospasm with good functional and aesthetic outcome.

Effects of intradialytic cycling compared with pedometry on physical function in chronic outpatient hemodialysis: a prospective randomized trial.

BACKGROUND: Individuals on hemodialysis have low physical function and activity levels. Clinical trials have shown improvements in these parameters with exercise programming. Pedometers have not been extensively evaluated in individuals on hemodialysis. This randomized clinical trial compared the effects of intradialytic cycling versus a pedometer program on physical function, physical activity and quality of life. METHODS: Sixty patients were randomly assigned to two study groups. The ergometer group cycled during each hemodialysis session for 24 weeks. Pedometer participants followed a home-based walking program for 24 weeks. The primary outcome was aerobic capacity [VO2peak and 6-minute walk (6MW) test]. Secondary outcomes included lower extremity strength [sit-to-stand (SS) test], flexibility [sit-and-reach (SR) test], physical activity (accelerometer) and health-related quality of life. Measurements were collected at baseline and at 12 and 24 weeks. RESULTS: At 12 and 24 weeks, there was no significant change in the VO2peak or 6MW test between or within study groups. SS testing in the ergometer group improved from 10.2 (SD 3.4) to 11.4 (SD 2.5) cycles from baseline to 24 weeks (P < 0.005). Similarly, in the pedometer group, SS cycles improved from 10.1 (SD 3.3) to 12.2 (SD 3.5) (P < 0.005). The SR test also significantly improved over time in both the study groups. No significant changes were noted for other secondary outcomes. CONCLUSIONS: Both intradialytic cycling and pedometer programming improved aspects of physical function. Neither intervention had a significant effect on aerobic capacity. No significant differences in any outcomes were identified between interventions groups.

Modified full-thickness anterior blepharotomy for upper eyelid retraction in children.

Graded full-thickness anterior blepharotomy has been used to treat eyelid retraction in adult patients with thyroid eye disease. We report 2 children diagnosed with upper eyelid retraction who underwent a modified full-thickness anterior blepharotomy. In both cases, symptoms resolved and cosmetically acceptable outcomes were achieved.

Genetic and environmental influences on total plasma homocysteine and its role in coronary artery disease risk.

BACKGROUND: Elevated levels of total plasma homocysteine are a risk factor for atherosclerotic disease. AIMS: The rationale behind this study is to explore the correlation between degree and site of coronary lesion and hyperhomocysteinemia in Lebanese CAD patients and assess environmental and genetic factors for elevated levels of total plasma homocysteine. METHODS: A total of 2644 patients were analyzed for traditional CAD risk factors. Logistic regression was performed to determine the association of hyperhomocysteinemia with degree and site of coronary lesions controlling for risk factors. Environmental and genetic factors for hyperhomocysteinemia were analyzed by logistic regression using a candidate gene approach. RESULTS: Traditional risk factors were correlated with stenosis. Hyperhomocysteinemia associated with increased risk of overall stenosis, and risk of mild and severe occlusion in major arteries. Hyperhomocysteinemia and hypertension were highly correlated suggesting that hyperhomocysteinemia acts as a hypertensive agent leading to CAD. Diuretics and genetic polymorphisms in MTHFR and SLCO1B1 were associated with hyperhomocysteinemia. CONCLUSIONS: Hyperhomocysteinemia is a medical indicator of specific vessel stenosis in the Lebanese population. Hypertension is a major link between hyperhomocysteinemia and CAD occurrence. Genetic polymorphisms and diuretics' intake explain partly elevated homocysteine levels. This study has important implications in CAD risk prediction.

Modafinil facilitates performance on a delayed nonmatching to position swim task in rats.

Modafinil is a wake-promoting drug approved by the FDA for the treatment of narcolepsy. Recent evidence suggests that modafinil may improve learning and memory processes. To further evaluate possible cognitive properties associated with modafinil, male Sprague-Dawley rats were tested in a delayed nonmatching to position (DNMTP) task. A modified water maze allowed animals to make one of two choices for the location of the escape platform. Each trial consisted of two swims. On the information swim (IS), only one choice was open to the animal for escape. One minute later, a choice swim (CS) presented the animal with two choices with the escape platform in the opposite position. There were 10 trials per day for 10 days. Rats received 0, 30, 55, or 100 mg/kg ip of modafinil 30 min prior to testing. Locomotor activity was also assessed. Animals that received 55 and 100 mg/kg made significantly more correct choices, indicating that higher doses of modafinil learned the task faster than did controls. While animals that received 100 mg/kg did exhibit an enhancement of locomotor activity, this effect did not result in more efficient goal-directed behavior. The evidence is consistent with previous research showing that modafinil facilitates cognitive processes.