Full Functional Recovery Research Articles

Contrasting resistance and resilience trajectories of zooplankton communities in restored fishless alpine lakes

AbstractCatastrophic state changes often occur in ecosystems as consequences of shifts in the dominant life forms, such as in the case of sportfish introduction into naturally fishless mountain lakes. While the pronounced ecological displacement of native communities by these novel predators (i.e., weak resistance) is well documented, few studies have also examined the dynamics of their recovery rates (i.e., “engineering resilience”) following stressor removal. We addressed this knowledge gap by quantifying the taxonomic and species trait‐based ordination trajectories of crustacean zooplankton communities in stocked alpine lakes, which differed in how they were restored to a natural fishless state over a period of six decades. Resilience and resistance trajectories differed in each lake as the ecological importance of trait‐based species recolonization potential (e.g., asexual vs. sexual reproduction) replaced that of tolerance of size‐selective predation by fish (e.g., body size, pigmentation, motility). As a result, re‐establishment of large‐bodied zooplankton following the elimination of fish restored annual secondary production. In contrast, a more gradual unidirectional ordination trajectory toward smaller zooplankton body size and a decline in total zooplankton biomass occurred in a nearby alpine lake containing a protected native bull trout population. Although recovery trajectories returned via routes that differed from those of earlier resistance trajectories (i.e., hysteresis), we discovered that full taxonomic and functional recovery was realized in all the restored fishless lakes within three decades, regardless of the approach used to achieve ecosystem restoration.

Study on therapeutic management of carpal tunnel syndrome

Carpal tunnel syndrome has long been considered a pathology requiring surgical intervention. Over the years, therapeutic management has become increasingly complex, with improvements observed in patients benefiting from orthopedic, surgical, ergotherapeutic and physiotherapeutic treatments, tailored to individual possibilities. The objective of this case study is to observe whether individualized and adapted kinetic treatment based on specific, non-specific and comprehensive means, succeeds in optimizing the results within the QuickDASH-Score for a 64-year-old patient following surgical intervention for carpal tunnel syndrome. The QuickDASH analyses physical function, pain and other symptoms associated with various types of upper limb musculoskeletal pathologies and disorders. The initial evaluation score was 47 points, with the physiotherapy program carried out over a six-months period. The main objectives included pain, edema, and inflammation control; enhancing joint range of motion within physiological limits in affected areas; preventing muscle-tendon retractions; and fostering independence in daily activities. The final evaluation had 32 points, signifying a 15-point improvement and achievement of the objective, resulting in enhanced quality of life. Physiotherapy in carpal tunnel syndrome is a meticulously applied treatment that alleviates specific symptoms. It's crucial to educate patients on how physiotherapy contributes to full functional recovery, as premature ending can have significant adverse effects on quality of life.

Best Practice of Peritoneal Dialysis-Associated Gram-Negative Peritonitis in Children: Insights From the International Pediatric Peritoneal Dialysis Network Registry

Gram-negative peritonitis (GNP) is associated with significant morbidity in children receiving long-term peritoneal dialysis (PD) and current treatment recommendations are based on limited data. Analysis of 379 GNP episodes in 308 children (median age 6.9 years, interquartile range [IQR]: 3.0-13.6) from 45 centers in 28 countries reported to the International Pediatric Peritoneal Dialysis Network registry between 2011 and2023. Overall, 74% of episodes responded well to empiric therapy and full functional recovery (FFR) was achieved in 82% of cases. Invitro bacterial susceptibility to empiric antibiotics and lack of severe abdominal pain at onset were associated with a good initial response. Risk factors for failure to achieve FFR included severe abdominal pain at onset and at 60 to 72 hours from treatment initiation (odds ratio [OR]: 3.81, 95% confidence interval [CI]: 2.01-7.2 and OR: 3.94, 95% CI: 1.06-14.67, respectively), Pseudomonas spp. etiology (OR: 1.73, 95% CI: 1.71-4.21]) and invitro bacterial resistance to empiric antibiotics (OR: 2.40, 95% CI: 1.21-4.79); the risk was lower with the use of monotherapy as definitive treatment (OR: 0.40, 95% CI: 0.21-0.77). Multivariate analysis showed no benefit of dual antibiotic therapy for treatment of Pseudomonas peritonitis after adjustment for age, presenting symptomatology, 60 to 72-hour treatment response, and treatment duration. Monotherapy with cefazolin in susceptible Enterobacterales peritonitis resulted in a similar FFR rate (91% vs. 93%) as treatment with ceftazidime or cefepime monotherapy. Detailed microbiological assessment, consisting of patient-specific and center-specific antimicrobial susceptibility data, should guide empiric treatment. Treatment "deescalation" with the use of monotherapy and narrow spectrum antibiotics according to susceptibility data is not associated with inferior outcomes and should be advocated in the context of emerging bacterial resistance.

Hypokalemia- Induced Rhabdomyolysis – Case Report and Literature Review

Abstract Nowadays, rhabdomyolysis is a common cause of acute kidney injury and it is associated with severe, sometimes life-threatening hyperkalemia. We report the case of a patient with profuse diarrheic syndrome caused by Crohn's disease who developed hypokalemia-induced rhabdomyolysis and multifactorial anuric acute kidney injury. Prompt diagnosis and treatment of Crohn's disease, along with electrolyte replacement and dialysis were followed by full recovery of renal function and correction of hypokalemia. We also review literature data regarding the rare cases presenting with rhabdomyolysis secondary to hypokalemia.

Preparation of bilayer tissue-engineered polyurethane/poly-L-lactic acid nerve conduits and their in vitro characterization for use in peripheral nerve regeneration

BackgroundDue to loss of peripheral nerve structure and/or function resulting from trauma, accidents, and other causes, peripheral nerve injuries continue to be a major clinical problem. These injuries can cause partial or total loss of sensory, motor, and autonomic capabilities as well as neuropathic pain. PNI affects between 13 and 23 out of every 100,000 people annually in developed countries. Regeneration of damaged nerves and restoration of function after peripheral nerve injury remain significant therapeutic challenges. Although autologous nerve graft transplantation is a viable therapy option in several clinical conditions, donor site morbidity and a lack of donor tissue often hinder full functional recovery. Biomimetic conduits used in tissue engineering to encourage and direct peripheral nerve regeneration by providing a suitable microenvironment for nerve ingrowth are only one example of the cutting-edge methods made possible by this field. Many innate extracellular matrix (ECM) structures of different tissues can be successfully mimicked by nanofibrous scaffolds. Nanofibrous scaffolds can closely mimic the surface structure and morphology of native ECMs of many tissues.MethodsIn this study, we have produced bilayer nanofibrous nerve conduit based on poly-lactic acid/polyurethane/multiwall carbon nanotube (PLA/PU/MWCNT), for application as composite scaffolds for static nerve tissue engineering. The contact angle was indicated to show the hydrophilicity properties of electrospun nanofibers. The SEM images were analyzed to determine the fiber’s diameters, scaffold morphology, and endometrial stem cell adhesion. Moreover, MTT assay and DAPI staining were used to show the viability and proliferation of endometrial stem cells.ResultsThe constructed bilayer PLA/PU/MWCNT scaffolds demonstrated the capacity to support cell attachment, and the vitality of samples was assessed using SEM, MTT assay, and DAPI staining technique.ConclusionsAccording to an in vitro study, electrospun bilayer PLA/PU/MWCNT scaffolds can encourage the adhesion and proliferation of human endometrial stem cells (hEnSCs) and create the ideal environment for increasing cell survival.

Right ventricular cardiomyocyte expansion accompanies cardiac regeneration in newborn mice after large left ventricular infarcts.

Cauterization of the root of the left coronary artery (LCA) in the neonatal heart on postnatal day 1 (P1) resulted in large, reproducible lesions of the left ventricle (LV), and an attendant marked adaptive response in the right ventricle (RV). The response of both chambers to LV myocardial infarction involved enhanced cardiomyocyte (CM) division and binucleation, as well as LV revascularization, leading to restored heart function within 7 days post surgery (7 dps). By contrast, infarction of P3 mice resulted in cardiac scarring without a significant regenerative and adaptive response of the LV and the RV, leading to subsequent heart failure and death within 7 dps. The prominent RV myocyte expansion in P1 mice involved an acute increase in pulmonary arterial pressure and a unique gene regulatory response, leading to an increase in RV mass and preserved heart function. Thus, distinct adaptive mechanisms in the RV, such as CM proliferation and RV expansion, enable marked cardiac regeneration of the infarcted LV at P1 and full functional recovery.

Improving Mental Health Outcomes in Patients with Major Depressive Disorder in the Gulf States: A Review of the Role of Electronic Enablers in Monitoring Residual Symptoms.

Up to 75% of individuals with major depressive disorder (MDD) may have residual symptoms such as amotivation or anhedonia, which prevent full functional recovery and are associated with relapse. Globally and in the Gulf region, primary care physicians (PCPs) have an important role in alleviating stigma and in identifying and monitoring the residual symptoms of depression, as PCPs are the preliminary interface between patients and specialists in the collaborative care model. Therefore, mental healthcare upskilling programmes for PCPs are needed, as are basic instruments to evaluate residual symptoms swiftly and accurately in primary care. Currently, few if any electronic enablers have been designed to specifically monitor residual symptoms in patients with MDD. The objectives of this review are to highlight how accurate evaluation of residual symptoms with an easy-to-use electronic enabler in primary care may improve functional recovery and overall mental health outcomes, and how such an enabler may guide pharmacotherapy selection and positively impact the patient journey. Here, we show the potential advantages of electronic enablers in primary care, which include the possibility for a deeper "dive" into the patient journey and facilitation of treatment optimisation. At the policy and practice levels, electronic enablers endorsed by government agencies and local psychiatric associations may receive greater PCP attention and backing, improve patient involvement in shared clinical decision-making, and help to reduce the general stigma around mental health disorders. In the Gulf region, an easy-to-use electronic enabler in primary care, incorporating aspects of the Hamilton Depression Rating Scale to monitor amotivation, and aspects of the Montgomery-Åsberg Depression Rating Scale to monitor anhedonia, could markedly improve the patient journey from residual symptoms through to full functional recovery in individuals with MDD.

Effects of local and systemic treatment with human natural killer-1 mimetic peptide (HNK-1) after ventral root avulsion and reimplantation in mice.

Spinal ventral root injuries generate significant motoneuron degeneration, which hinders full functional recovery. The poor prognosis of functional recovery can be attributed to the use or combination of different therapeutic approaches. Several molecules have been screened as potential treatments in combination with surgical reimplantation of the avulsed roots, the gold standard approach for such injuries. Among the studied molecules, human natural killer-1 (HNK-1) stands out as it is related to the stimulation of motor axon outgrowth. Therefore, we aimed to comparatively investigate the effects of local administration of an HNK-1 mimetic peptide (mp-HNK-1) and systemic treatment with ursolic acid (UA), another HNK-1 mimetic, after ventral root avulsion and reimplantation with heterologous fibrin biopolymer (HFB). Female mice of the isogenic strain C57BL/6JUnib were divided into five experimental groups: Avulsion, Reimplantation, mp-HNK-1 (in situ), and UA (systemic treatment). Mice were evaluated 2 and 12 weeks after surgery. Functional assessment was performed every four days using the Catwalk platform. Neuronal survival was analyzed by cytochemistry, and glial reactions and synaptic coverage were evaluated by immunofluorescence. Treatment with UA elicited long-term neuroprotection, accompanied by a decrease in microglial reactions, and reactive astrogliosis. The neuroprotective effects of UA were preceded by increased glutamatergic and GABAergic inputs in the ventral spinal cord two weeks after injury. However, a single application of mp-HNK-1 had no significant effects. Functional analysis showed that UA treatment led to an improvement in motor and sensory recovery. Overall, the results indicate that UA is neuroprotective, acting on glial cells and synaptic maintenance, and the combination of these findings led to a better functional recovery.

Live Imaging Analysis of Axonal Regeneration in Human iPSC-Derived Motor Neurons Using a Microfluidic System.

Axonal damage is a common feature of traumatic injury and neurodegenerative disease. The capacity for axons to regenerate and to recover functionality after injury is a phenomenon that is seen readily in the peripheral nervous system, especially in rodent models, but human axonal regeneration is limited and does not lead to full functional recovery. Here we describe a system where dynamics of human axonal outgrowth and regeneration can be evaluated via live imaging of human-induced pluripotent stem cell (hiPSC)-derived neurons cultured in microfluidic systems, in which cell bodies are isolated from their axons. This system could aid in studying axonal outgrowth dynamics and could be useful for testing potential drugs that encourage regeneration and repair of the nervous system.

Cognitive, Mental Health, Functional, and Quality of Life Outcomes 1 Year After Spontaneous Subarachnoid Hemorrhage: A Prospective Observational Study

BackgroundPatients with spontaneous subarachnoid hemorrhage (SAH) frequently encounter cognitive dysfunction and mental health issues with negative effects on health-related quality of life (HR-QoL). Here, we aimed to describe the prevalence of cognitive deficits, mental health problems, and HR-QoL impairments 1 year after SAH.MethodsIn this prospective observational study, 177 patients with SAH admitted to our neurointensive care unit over a time span of ten years followed the invitation for an in-person 1-year follow-up, including a standardized neuropsychological test battery. Mental health issues (anxiety and depression) and HR-QoL were evaluated using questionnaires (Hospital Anxiety and Depression Scale; 36-item Short Form questionnaire). Functional outcome was assessed with the modified Rankin Scale (mRS) score.ResultsPatients were 54 years of age (interquartile range 47–62 years) and presented with a median Hunt and Hess score of 2 (interquartile range 1–3) at admission. Most patients (93%) achieved good functional 1-year outcomes (mRS score 0–2). Seventy-one percent of patients had deficits in at least one cognitive domain, with memory deficits being the most prevalent (51%), followed by deficits in executive functions (36%), visuoconstruction (34%), and attention (21%). Even patients with perimesencephalic SAH (18%) or with full functional recovery (mRS score = 0, 46%) had a comparable prevalence of cognitive deficits (61% and 60%, respectively). Symptoms of depression and anxiety were reported by 16% and 33% of patients, respectively. HR-QoL was impaired in 37% (55 of 147). Patients with cognitive deficits (p = 0.001) or mental health issues (p < 0.001) more frequently reported impaired HR-QoL.ConclusionsMost patients with SAH have cognitive deficits and mental health issues 1 year after SAH. These deficits impair patients’ quality of life.

Which Factors Are Associated with Distal Pancreatectomy Outcomes' Optimization with the Application of an Enhanced Recovery After Surgery Program?

Background: Distal pancreatectomy (DP) represents the best therapeutic option for patients with body-tail pancreatic neoplasms (PNs). The enhanced recovery after surgery protocol is widely used for treating patients with PN to speed up postoperative recovery. This study aims to describe our institute's experience in the application of fast recovery protocol in a cohort of patients treated with DP, identifying predictors facilitating a decrease in the length of hospital stay. Patient and Methods: Were retrospectively enrolled 60 consecutive cases of DP performed from January 2016 to June 2022 in patients treated with enhanced recovery protocol, 25% of them were treated with spleen preserving procedure. Single-variable logistic regression models were used to evaluate the potential association between patient characteristics and the probability of postoperative complications. Standard linear regression models were used for length of stay, number of postoperative days (PODs) from surgery to full bowel function recovery, and PODs to the interruption of intravenous analgesia administration. Results: Thirty-four (57%) patients underwent open surgery and 26 (43%) laparoscopic surgery. Patients who underwent laparoscopic surgery and spleen-preserving procedures experienced a lower complication rate (P = .037), shorter length of stay, and time of analgesic requirements. With single-variable logistic regression models patients treated with laparoscopic surgery had statistically significant higher recovery times in terms of nasogastric tube removal (P = .004) and early enteral nutrition (P = .001). Conclusion: Continual refinement with enhanced recovery protocol for treating PN patients based on perioperative counseling and surgical decision-making is crucial to reduce patient morbidity and time for recovery.

Upgradation of aircrew with minor musculoskeletal injuries in the operational bases: Need for a relook

Objectives: Musculoskeletal injuries (MSKI) have been one of the most common contributors to disabilities among aircrew. The existing policy mandates all cases of MSKI in aircrew of the Indian Air Force, including minor injuries such as a sprain of small joints and phalangeal fractures to be evaluated at the Institute of Aerospace Medicine (IAM), majority of which do not warrant a complete Human Engineering (HE) assessment. Hence, a need was felt to decentralize evaluation and empower other boarding centers/operational bases with local aerospace medicine specialists to carry out the evaluation. Material and Method: A retrospective analysis was carried out of a total of 930 cases of MSKI among serving aircrew who reported to IAM between Jan 2016 and Oct 2020. Results: About 27.68% of cases were of lower limb injuries and 16.52% of cases were of upper limb injuries. About 36.77% of cases of upper limb and 52.71% of cases of lower limb injuries were treated surgically while 63.23% upper limb and 47.29% lower limb injuries were managed conservatively. Full functional recovery within 12 weeks was seen in a significant number of conservatively treated distal upper and lower limb injuries not involving joints. Conclusion: HE assessment of MSKI at IAM is comprehensive including exposure to simulated aeromedical stressors. However, certain minor musculoskeletal disabilities did not require full HE evaluation and simulator facilities of IAM. Sending aircrew with such minor disabilities from field units to IAM amounts to an administrative obligation that can be avoided by empowering other medical boarding centers and local operational bases which have aerospace medicine specialists. This paper discusses the procedure of conduct and facilitation of aeromedical evaluation of aircrew in the non-flying medical category with certain minor MSKI in the field.

Adipo-glial signaling mediates metabolic adaptation in peripheral nerve regeneration

The peripheral nervous system harbors a remarkable potential to regenerate after acute nerve trauma. Full functional recovery, however, is rare and critically depends on peripheral nerve Schwann cells that orchestrate breakdown and resynthesis of myelin and, at the same time, support axonal regrowth. How Schwann cells meet the high metabolic demand required for nerve repair remains poorly understood. We here report that nerve injury induces adipocyte to glial signaling and identify the adipokine leptin as an upstream regulator of glial metabolic adaptation in regeneration. Signal integration by leptin receptors in Schwann cells ensures efficient peripheral nerve repair by adjusting injury-specific catabolic processes in regenerating nerves, including myelin autophagy and mitochondrial respiration. Our findings propose a model according to which acute nerve injury triggers a therapeutically targetable intercellular crosstalk that modulates glial metabolism to provide sufficient energy for successful nerve repair.

A new model of axon degeneration in the mouse optic nerve using repeat intraocular pressure challenge

We characterize a new experimental model for inducing retinal ganglion cell (RGC) dysfunction and degeneration in mice. C57BL/6J mice were subjected to two acute periods of intraocular pressure (IOP) elevation (50 mmHg for 30 min) by cannulation of the anterior chamber. We used full-field electroretinography and visual evoked potentials (VEPs) to measure subsequent changes in retina and optic nerve function, and histochemical techniques to assess RGC survival and optic nerve structure. In 12 month old mice, a single IOP challenge caused loss and subsequent recovery of RGC function over the following 28 days with minimal cell death and no observed axonal damage. A second identical IOP challenge resulted in persistent RGC dysfunction and significant (36%) loss of RGC somas. This was accompanied by a 16.7% delay in the latency and a 27.6% decrease in the amplitude of the VEP. Severe axonal damage was seen histologically with enlargement of axons, myelin disruption, reduced axon density, and the presence of glial scarring. In contrast, younger 3 month old mice when exposed to a single or repeat IOP challenge showed quicker RGC functional recovery after a single challenge and full functional recovery after a repeat challenge with no detectable optic nerve dysfunction. These data demonstrate a highly reproducible and minimally invasive method for inducing RGC degeneration and axonal damage in mice. Resilience of the optic nerve to damage is highly dependent on animal age. The time-defined nature of functional versus structural loss seen in this model stands to facilitate investigation of neuroglial responses in the retina after IOP injury and the associated evaluation of neuroprotective treatment strategies. Further, the model may be used to investigate the impact of aging and the cellular switch between neurorecovery and neurodegeneration.

Cell Therapy by Mesenchymal Stromal Cells Versus Myoblasts in a Pig Model of Urinary Incontinence.

The leading cause of stress urinary incontinence (SUI) in women is the urethral sphincter muscle deficiency caused by mechanical stress during pregnancy and vaginal delivery. In men, prostate cancer surgery and injury of local nerves and muscles are associated with incontinence. Current treatment often fails to satisfy the patient's needs. Cell therapy may improve the situation. We therefore investigated the regeneration potential of cells in ameliorating sphincter muscle deficiency and UI in a large animal model. Urethral sphincter deficiency was induced surgically in gilts by electrocautery and balloon dilatation. Adipose tissue-derived stromal cells (ADSCs) and myoblasts from Musculus semitendinosus were isolated from male littermates, expanded, characterized in depth for expression of marker genes and in vitro differentiation, and labeled. The cells were injected into the deficient sphincter complex of the incontinent female littermates. Incontinent gilts receiving no cell therapy served as controls. Sphincter deficiency and functional regeneration were recorded by monitoring the urethral wall pressure during follow-up by two independent methods. Cells injected were detected in vivo during follow-up by transurethral fluorimetry, ex vivo by fluorescence imaging, and in cryosections of tissues targeted by immunofluorescence and by polymerase chain reaction of the sex-determining region Y (SRY) gene. Partial spontaneous regeneration of sphincter muscle function was recorded in control gilts, but the sphincter function remained significantly below levels measured before induction of incontinence (67.03% ± 14.00%, n = 6, p < 0.05). Injection of myoblasts yielded an improved sphincter regeneration within 5 weeks of follow-up but did not reach significance compared to control gilts (81.54% ± 25.40%, n = 5). A significant and full recovery of the urethral sphincter function was observed upon injection of ADSCs within 5 weeks of follow-up (100.4% ± 23.13%, n = 6, p < 0.05). Injection of stromal cells provoked slightly stronger infiltration of CD45pos leukocytes compared to myoblasts injections and controls. The data of this exploratory study indicate that ADSCs inherit a significant potential to regenerate the function of the urethral sphincter muscle.

Adjunctive hyperbaric oxygen therapy for spinal cord ischemia after complex aortic repair

ObjectiveSpinal cord ischemia (SCI) with paraplegia or paraparesis is a devastating complication of complex aortic repair (CAR). Treatment includes cerebrospinal fluid drainage, maintenance of hemoglobin concentration (>10 g/L), and elevating mean arterial blood pressure. Animal and human case series have reported improvements in SCI outcomes with hyperbaric oxygen therapy (HBOT). We reviewed our center’s experience with HBOT as a rescue treatment for spinal cord ischemia post-CAR in addition to standard treatment. MethodsA retrospective review of the University Health Network’s Hyperbaric Medicine Unit treatment database identified HBOT sessions for patients with SCI post-CAR between January 2013 and June 2021. Mean estimates of overall motor function scores were determined for postoperative, pre-HBOT, post-HBOT (within 4 hours of the final HBOT session), and at the final assessment (last available in-hospital evaluation) using a linear mixed model. A subgroup analysis compared the mean estimates of overall motor function scores between improvement and non-improvement groups at given timepoints. Improvement of motor function was defined as either a ≥2 point increase in overall muscle function score in patients with paraparesis or an upward change in motor deficit categorization (para/monoplegia, paraparesis, and no deficit). Subgroup analysis was performed by stratifying by improvement or non-improvement of motor function from pre-HBOT to final evaluation. ResultsThirty patients were treated for SCI. Pre-HBOT, the motor deficit categorization was 10 paraplegia, three monoplegia, 16 paraparesis, and one unable to assess. At the final assessment, 14 patients demonstrated variable degrees of motor function improvement; eight patients demonstrated full motor function recovery. Seven of the 10 patients with paraplegia remained paraplegic despite HBOT. The estimated mean of overall muscle function score for pre-HBOT was 16.6 ± 2.9 (95% confidence interval [CI], 10.9-22.3) and for final assessment was 23.4 ± 2.9 (95% CI, 17.7-29.1). The estimated mean difference between pre-HBOT and final assessment overall muscle function score was 6.7 ± 3.1 (95% CI, 0.6-16.1). The estimated mean difference of the overall muscle function score between pre-HBOT and final assessment for the improved group was 16.6 ± 3.5 (95% CI, 7.5-25.7) vs −4.9 ± 4.2 (95% CI, −16.0 to 6.2) for the non-improved group. ConclusionsHBOT, in addition to standard treatment, may potentially improve recovery in spinal cord function following SCI post-CAR. However, the potential benefits of HBOT are not equally distributed among subgroups.

Phase Ib/2 Study of Oral Decitabine/Cedazuridine (ASTX727) and Venetoclax in Combination with the Targeted Mutant IDH1 Inhibitor Ivosidenib or the Targeted Mutant IDH2 Inhibitor Enasidenib: 2023 Update

Background Isocitrate Dehydrogenase (IDH) 1 or 2 mutations occur in ~20% of acute myeloid leukemia (AML). Both venetoclax (VEN)-based and targeted IDH-inhibitor (IDHi) therapies are effective treatment options for IDH mutated AML in combination with hypomethylating agents (HMA). ASTX727 is an oral, fixed dose (35 mg/100 mg) combination of decitabine and cedazuridine with bioequivalency to IV decitabine. Herein we report interim results including completion of the Phase 1b portion of the first all-oral triplet regimen of ASTX727 (day 1-5) + VEN (day 1-14) in combination with a targeted mutant IDH1i ivosidenib (IVO) or IDH2i enasidenib (ENA), for IDH mutated AML. Methods Eligible patients (pts) were &amp;gt; 18 years old with newly diagnosed (ND) AML not eligible for intensive chemotherapy, or relapsed/refractory (R/R) IDH1 or IDH2 mutated AML. Prior VEN, HMA, and/or IDHi use was not exclusionary in the R/R cohort. The primary objectives were to determine safety and the recommended phase 2 dose (RP2D) of ASTX727 and VEN with IVO (Arm A) or ENA (Arm B) [Phase 1b], and to determine the composite remission rate (CRc; CRh+CRi+CR) for both arms [Phase 2]. Results A total of 51 pts (1b: 26 pts, 2: 25 pts) have been enrolled. The phase 1b portion is completed and the RP2D is established at VEN 600mg in combination with IVO (due to the CYP3A4 inducing effects of ivosidenib requiring a higher dose of VEN to maintain therapeutic concentrations), and VEN 400mg in combination with ENA. There are currently 50 evaluable pts (Arm A: 20, Arm B: 30); median follow up is 11.0 months (mos) for ND pts and 14.6 mos for R/R pts. Median age at enrollment was 72 years (41 - 86). 48% (n=24) pts had ND-AML (A: 10, B: 14) and 52% (n = 26) with R/R AML (A: 10, B: 16). ELN 2022 classification was intermediate or adverse in 87% of ND-AML and 92% of the R/R AML cohorts. Median variant allele frequency in ND pts was 22% (7-38, IDH1) and 36% (4-49, IDH2) and was 29% (8-45, IDH1) and 37% (2-48, IDH2) in the R/R arms. Patients with R/R-AML received a median of 2 lines of prior therapy, including 20 pts having received prior VEN and 7 receiving prior IDH-inhibitor. The composite remission rate (CRc), defined as CR + CRh + CRi, was 96% (n=23) in ND-AML and 46% (n=12) with R/R disease (Table 1). Of pts who received prior VEN, 30% (n=6) achieved a CRc (3 CR, 2 CRi, 1CRh) and in those with prior IDHi exposure, 71% (n=5) achieved a CRc (4 CR, 1 CRh)(Table 2). Measurable residual disease (MRD) negative CRc by flow cytometry was achieved as best response in 91% of the responding ND pts (35% IDH1 and 56% IDH2) and 67% (42% IDH1 and 25% IDH2) of R/R pts. Duration of response (DOR) was not reached (NR) for ND pts and 16.1 mos in R/R pts. Event free survival (EFS) was NR and 5.9 mos (2.76 - NA), respectively. Overall survival (OS) was NR for ND and 10.4 mos (4.7 - NA) for R/R AML. The most common non-hematologic grade 3/4 AEs included indirect hyperbilirubinemia (n=3, 6%) all in enasidenib-treated pts, and two pts (4%) had grade 3 mucositis, one which was attributed to prior cytoreductive therapy. AEs of special interest regardless of grade included differentiation syndrome in 10% (n=5, A:3; B:2), all successfully managed with corticosteroids and diuresis. 4% (n=2) had TLS which was medically managed, one pt required CRRT briefly with full recovery of renal function. 19 pts remain on study, 8 transitioned to SCT in response, and 5 pts (4 ND, 1 R/R) withdrew from the study, including 4 in CRc response, after 2 (n=2), 5 (n=1) and 8 (n=1) cycles of protocol therapy. Conclusions Triplet therapy with ASTX727 + VEN + IDH1/2 inhibition appears safe and preliminarily effective for IDH mutated AML, with high rates of MRD-negative CRc particularly in ND pts and in R/R pts not having received prior VEN or IDHi. AEs were anticipated and tolerable. Enrollment is ongoing.

Yüzme Egzersizinin Siyatik Sinir Hasarı Sonrasında Elektrofizyolojik Parametreler Üzerindeki İyileştirici Etkisi

The sciatic nerve damage can cause symptoms such as loss of muscle strength and pain as a result of trauma to the nerve due to pressure, stretching or cutting, as well as lifelong disability. Despite the increasing knowledge about sciatic nerve regeneration mechanisms, full functional recovery is still insufficient. It is well known that exercise improves overall health. The current study aimed to reveal the therapeutic effects of swimming exercises using electrophysiological methods in rats with experimental sciatic nerve injury. Eighteen male Wistar Albino rats were used in this study. The subjects were randomly divided into three groups (n=6): 1-Control (C), 2-Intact Exercise (IntE), 3-Operated Exercise (OpE) groups. Sciatic nerve injury was performed by inducing experimental damage to the left hind extremity sciatic nerve of rats. Swimming exercise was applied for 45 minutes a day, five days a week (25°C) for four weeks. The level of regeneration was evaluated by taking motor function test-sciatic function index and EMG recording performed at the beginning of the experiment (day 0), after nerve damage (day 3), and at the end of the experiment (day 35). It was determined that sciatic function index, amplitude of motor and sensory nerves, peak-peak amplitude, percentage of compound muscle action potential, motor and sensory nerve conduction velocities, which decreased after sciatic nerve injury, increased with swimming exercise (p

Guillain-Barré Syndrome Following Spinal Fusion Surgery in an Elderly Patient: A Case Report

Guillain–Barré syndrome (GBS) is a rare immune-mediated polyneuropathy that rapidly leads to symmetric, ascending progressive weakness. Although GBS is typically associated with various infectious diseases, such as upper respiratory infections or gastroenteritis, it has also been reported following spine surgery. In this report, the authors present a case of GBS in an elderly patient after spinal fusion surgery and emphasize the importance of evaluating new-onset weakness in such cases. A 79-year-old man with diabetes mellitus and hypertension presented with weakness of the lower extremities and neurogenic claudication with chronic radicular pain. Magnetic resonance imaging revealed anterolisthesis at the L4-L5 level and disc protrusions with central and lateral recess spinal stenosis at L3-L4-L5. Following surgery, the patient complained of weakness and paresthesia in both upper extremities, prompting further investigation. An electrophysiologic study confirmed demyelinating neuropathy and cerebrospinal fluid (CSF) analysis showed elevated viral immunoglobulin levels and albumin-cytological dissociation despite negative bacterial and antiganglioside antibody tests. The patient received intravenous immunoglobulin infusion treatment and showed significant improvement, with full motor function recovery in all extremities after 6 weeks. The authors emphasize the importance of considering GBS in patients experiencing deteriorating neurological symptoms after spine surgery and suggest that electrophysiologic studies and CSF analysis are needed for an accurate diagnosis. Additionally, this report highlights the need for increased vigilance regarding the rapid onset of GBS symptoms in elderly patients following spinal surgery.

High-resolution MR neurography follow-up of SARS-CoV-2 vaccination-associated neuralgic amyotrophy.

Little is known about the value of high-resolution follow-up imaging in patients with neuralgic amyotrophy (NA) and the question of the best treatment algorithm remains unclear. Three patients (one female, two male) with the clinical presentation of SARS-CoV-2-vaccination-associated NA underwent initial magnetic resonance neurography (MRN) imaging and follow-up examinations. All patients showed a marked clinical improvement, independent of treatment, including an almost full recovery of motor function over the course of 8-12 months which was accurately mirrored by imaging findings on MRN. MRN imaging is a valuable tool for monitoring the further clinical course of patients suffering from vaccination-associated NA.