Identification of Rare EIF3E::RSPO2 Fusion in Recurrent and Aggressive Urachal Adenocarcinoma.

INTRODUCTION: Urachal cancer (UC) is a rare genitourinary malignancy arising from the urachus, an embryonic remnant of the placental allantois. Its diagnosis remains ambiguous with late-stage cancer detection and represents a highly aggressive disease. Due to its rarity, there is no clear consensus on molecular signatures and appropriate clinical management of UC. CASE REPORT: We report a 45-year-old man with recurrent urachal adenocarcinoma (UA) treated with cystectomies, chemotherapy, and radiotherapy. The patient initially presented with hematuria and abdominal pain. Imaging revealed a nodular mass arising from the superior wall of the urinary bladder and extending to the urachus. Biopsy results suggested moderately differentiated UA with muscle layer involvement. The tumor recurred after 20 months, following which, another partial cystectomy was performed. Repeat progression was noted indicating highly aggressive disease. Targeted next-generation sequencing revealed the presence of EIF3E::RSPO2 fusion, along with BRAF and TP53 mutations, and EGFR gene amplification. This is the first case reporting the presence of this fusion in UA. Palliative medication and radiotherapy were administered to manage the disease. CONCLUSION: Current treatment modality of surgery may be effective in the early stages of recurrent UA; however, a standard chemotherapy and radiotherapy regimen is yet to be determined for advanced stages. The detection of the rare EIF3E::RSPO2 fusion warrants further studies on the significance of this variant as a possible therapeutic target for improved clinical management.

COVID-19-associated rhino-orbito-cerebral mucormycosis: a single center prospective study of 264 patients.

PURPOSE: Outbreaks of mucormycosis were reported worldwide throughout the COVID-19 pandemic. We report clinical outcomes of a treatment protocol for COVID-19-associated rhino-orbital-cerebral mucormycosis (ROCM). METHODS: Patients with biopsy-proven mucormycosis and COVID-19 were included. All received intravenous amphotericin B deoxycholate 1 mg/kg and surgical endoscopic sinus debridement (FESS). Those with rhino-orbital or cerebral disease limited to the cavernous sinus were eligible for transcutaneous retrobulbar amphotericin B (TRAMB). Patients were followed with weekly imaging, endoscopic examinations, and serial debridement as necessary. Patients were discharged on oral posaconazole for 6 months. RESULTS: In total, 264 patients were followed for a mean of 2.5 months. On presentation, 163 patients (174 eyes) had eye involvement. Of these, 141 eyes (81.0%) had light perception or worse vision. By the last follow-up, 163 patients (176 eyes) were affected, and of these, 96 eyes (54.5%) had no light perception. Twenty-one patients (8%) died and 3 orbits (0.5%) were exenterated. There was no change in mortality (p = 0.38) or exenteration (p = 0.38) in the 55 patients who received TRAMB compared to patients with rhino-orbital or cerebral disease limited to the cavernous sinus who did not. Asymptomatic COVID-19 was associated with higher mortality than symptomatic COVID-19 (p = 0.025). Uncontrolled diabetes was a risk factor for death (p = 0.022). New diabetes was associated with increased mortality versus pre-existing diabetes (p = 0.005). CONCLUSION: A multidisciplinary approach is crucial to manage COVID-19-ROCM. In our cohort, TRAMB therapy did not increase mortality or exenteration rates. While poor vision on presentation was profound, some vision recovery was noted with treatment. COVID-19 immune dysregulation may predispose patients to ROCM, particularly those with asymptomatic disease.

Searching beyond nevi - A rare case of neurocutaneous ocular syndrome.

Epidermal nevus syndrome is a rare congenital disorder affecting only a few hundred people in the world. It has ophthalmic, dermatological, and neurological manifestations, with varied presentation. Here, we report a case of two-year-old child who presented with epibulbar mass in left eye, pigmented nevi over left side of the body and alopecia over left side of parieto-temporal scalp. Imaging confirmed epibulbar mass and presence of calcification of choroid on ipsilateral side with presence of arachnoid cyst of brain with underlying pachygyria. Neurological examination was normal and dermatologist confirmed presence of verrucous nevi over skin. Excisional biopsy of epibulbar mass revealed a complex choristoma with presence of lacrimal gland tissue. Underlying ocular findings were near normal with normal posterior segment. It is a rare form of epidermal nevus syndrome with near normal ocular findings in the presence of anterior and posterior choristoma, which has not been reported.

Orbital tooth - not always a teratoma : a case report.

A 7-year-old girl presented with a painless firm to cystic mass in the infero-temporal quadrant of her right orbit since birth. The mass had recurred with a cutaneous sinus after initial surgery. Right eye vision was affected by mass induced astigmatism. The anterior and posterior segments were normal. Magnetic Resonance Imaging of the orbit suggested a mature teratoma within the orbital bone. Mass excision showed a fully developed molar tooth within a cyst associated with a cutaneous sinus. Histopathological examination reported odontogenic choriostoma. We report this unique case of orbital odontogenic choristoma in an unusual location, associated with a cutaneous sinus, emphasizing the need for complete excision to prevent recurrence.

Bone Structure and Turnover Status in Postmenopausal Women with Atypical Femur Fracture After Prolonged Bisphosphonate Therapy.

Atypical femur fracture (AFF), a serious complication of long-term bisphosphonate therapy, is usually preceded by an incomplete fracture appearing on the lateral femur. AFF is most likely the result of severely suppressed bone turnover (SSBT). However, the differences in bone structure and turnover between patients with incomplete and complete AFF remain unknown. We examined trans-iliac bone biopsies from 12 white postmenopausal women with AFF (incomplete = 5; complete = 7) on BP therapy of >5 years and 43 healthy white premenopausal women. Histomorphometric measurements were performed separately in cancellous, intracortical and endosteal envelopes. Of the 43 histomorphometric measurements on 3 difference bone surfaces (cancellous, intracortical and endosteal), only 2 bone resorption variables (Oc.S/BS and Oc.S/NOS) on the endosteal surface were significantly lower in patients with complete AFF than those with incomplete AFF. Compared to healthy premenopausal women, the trabecular bone volume, thickness and number were all significantly lower in patients with AFF. The dynamic bone formation variables in patients with AFF were significantly reduced on all bone surfaces. The likelihood of a biopsy with no tetracycline labeling was significantly higher in AFF patients than in healthy premenopausal women. Based on these results, we conclude that there are no significant differences in bone turnover between patients with incomplete and complete AFF, suggesting that the suppression of bone turnover had already existed in the femur with incomplete AFF. Compared to healthy premenopausal women, bone turnover is similarly suppressed in patients with either type of AFF.

Metacognitive knowledge about self-control.

Good self-control is highly valuable, but the processes that promote it are not fully understood. This review emphasizes that self-control is "inherently metacognitive" (p. 204, Duckworth et al., 2014) and describes the potential benefits of metacognitive knowledge for self-control. In line with research on metacognition in academic goal pursuit, we elaborate how three distinct types of metacognitive knowledge may aid self-control: strategy knowledge (for example, a repertoire of self-regulatory strategies), task knowledge (for example, understanding self-control demands), and person knowledge (for example, awareness of one's self-control strengths and weaknesses). Additionally, we identify research gaps and suggest that future studies should investigate the development and updating of metacognitive knowledge about self-control and how metacognitive knowledge can prevent individuals from justifying indulgence.

Abnormal Development of the Corpus Callosum in Autism Spectrum Disorder: An MRI Study.

BACKGROUND: Altered size in the corpus callosum (CC) has been reported in individuals with autism spectrum disorder (ASD), but few studies have investigated younger children. Moreover, knowledge about the age-related changes in CC size in individuals with ASD is limited. OBJECTIVES: Our objective was to investigate the age-related size of the CC and compare them with age-matched healthy controls between the ages of 2 and 18 years. METHODS: Structural-weighted images were acquired in 97 male patients diagnosed with ASD; published data were used for the control group. The CC was segmented into 7 distinct subregions (rostrum, genu, rostral body, anterior midbody, posterior midbody, isthmus, and splenium) as per Witelson's technique using ITK-SNAP software. We calculated both the total length and volume of the CC as well as the length and height of its 7 subregions. The length of the CC measures was studied as both continuous and categorical forms. For the continuous form, Pearson's correlation was used, while categorical forms were based on age ranges reflecting brain expansion during early postnatal years. Differences in CC measures between adjacent age groups in individuals with ASD were assessed using a Student t-test. Mean and standard deviation scores were compared between ASD and control groups using the Welch t-test. RESULTS: Age showed a moderate positive association with the total length of the CC (r = 0.43; Padj = 0.003) among individuals with ASD. Among the subregions, a positive association was observed only in the anterior midbody of the CC (r = 0.41; Padj = 0.01). No association was found between the age and the height of individual subregions or with the total volume of the CC. In comparison with healthy controls, individuals with ASD exhibited shorter lengths and heights of the genu and splenium of the CC across wide age ranges. CONCLUSION: Overall, our results highlight a distinct abnormal developmental trajectory of CC in ASD, particularly in the genu and splenium structures, potentially reflecting underlying pathophysiological mechanisms that warrant further investigation.

Landscape of Clinically Relevant Genomic Alterations in the Indian Non-small Cell Lung Cancer Patients.

BACKGROUND: The genomic landscape of non-small cell lung cancer (NSCLC) in the Indian patients remains underexplored. We revealed distinctive genomic alterations of Indian NSCLC patients, thereby providing vital molecular insights for implementation of precision therapies. METHODS: We analyzed the genomic profiles of 325 lung adenocarcinoma and 81 lung squamous carcinoma samples from Indian patients using targeted sequencing of 50 cancer related genes. Correlations between genomic alterations and clinical characteristics were computed using statistical analyses. Additionally, we identified distinct features of Indian NSCLC genomes by comparison across different ethnicities. RESULTS: Our genomic analysis revealed several noticeable features of Indian NSCLC patients. Alterations in EGFR (45.8%), TP53 (27.4%), ALK (11.4%) and KRAS (10.2%) were predominant in adenocarcinoma, with 68% eligible for targeted therapies. Squamous carcinoma exhibited prevalent alterations in TP53 (40.7%), PIK3CA (17.3%), and CDKN2A (8.6%). We observed higher frequency of EGFR alterations (18.5%) in lung squamous carcinoma patients, significantly distinct from other ethnicities reported till date. Beyond established correlations, we observed 60% of PD-L1 negative squamous patients harbored TP53 alterations, suggesting intriguing therapeutic implications. CONCLUSIONS: Our data revealed unique genomic variations of adenocarcinoma and squamous carcinoma patients, with significant indications for precision medicine and clinical practice of lung cancers. The study emphasizes the importance of clinical utility of NGS for routine diagnostics.

Group medicare wellness visits: A pilot exploration of an approach to wellness and preventive medicine for older adults.

Introduction: The Medicare annual wellness visit was designed to address health risks and encourage evidence-based preventive care in aging. However, it can be challenging for providers to dedicate time for comprehensive attention to wellness during these visits. Our project implements a group setting for Medicare wellness visits (GMWV) as an efficient method for delivering high value preventive care. Methods: Three hundred patients from two primary care ambulatory clinics in Detroit, MI in need of their annual Medicare visit were invited to participate in the pilot GMWV. Fifty-eight patients agreed and completed their GMWV. The visit included collection of vitals, vision screening, and risk assessment during check-in, followed by educational wellness presentations led by an interdisciplinary team of six healthcare professionals. Patients completed a post visit-satisfaction survey and researchers calculated rates of completion of health maintenance gaps (HMG), i.e. immunizations and cancer screenings, among participants. Results: The average age of participants (N female = 48) was 74 years old. Thirty-four participants had more than one HMG at baseline. On average, 8 % of immunization gaps and 12 % of screening gaps were completed at or within one-year post GMWV. Participant feedback reported that 82 % of patients felt that they learned something new from the presentation and 81 % of patients felt satisfied with the amount of time they spent with their physician. Discussion: GMWV is a feasible approach to promoting wellness and healthy aging that patients find satisfying although, additional study is needed to compare the effectiveness of this model to standard care.

Frontal osteomyelitis post-COVID-19 associated mucormycosis.

Rhino-orbito-cerebral mucormycosis (ROCM) is the most commonly noted form of mucormycosis, which is the most common secondary fungal infection following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Osteomyelitis is one of the rare sequelae of ROCM, frontal osteomyelitis being the rarest. We present four patients of coronavirus disease 2019 (COVID-19)-associated mucormycosis, who presented with frontal bone osteomyelitis after being treated for ROCM surgically and medically. This is the first case series highlighting this complication in post-COVID-19 mucormycosis patients and needs utmost attention as it can be life-threatening and can cause extreme facial disfiguration. All four patients are alive with salvage of the affected globe and vision being preserved in one patient. If identified early, disfiguration of face and intracranial extension can be avoided.

Antimicrobial activity of commercially available essential oils against Streptococcus mutans.

INTRODUCTION: Many essential oils have been advocated for use in complementary medicine for bacterial and fungal infections. However, few of the many claims of therapeutic efficacy have been validated adequately by either in vitro testing or in vivo clinical trials. OBJECTIVE: To study the antibacterial activity of nine commercially available essential oils against Streptococcus mutans in vitro and to compare the antibacterial activity between each material. METHODOLOGY: Nine pure essential oils; wintergreen oil, lime oil, cinnamon oil, spearmint oil, peppermint oil, lemongrass oil, cedarwood oil, clove oil and eucalyptus oil were selected for the study. Streptococcus mutans was inoculated at 37ºC and seeded on blood agar medium. Agar well diffusion assay was used to measure antibacterial activity. Zone of inhibition was measured around the filter paper in millimeters with vernier caliper. RESULTS: Cinnamon oil showed highest activity against Streptococcus mutans followed by lemongrass oil and cedarwood oil. Wintergreen oil, lime oil, peppermint oil and spearmint oil showed no antibacterial activity. CONCLUSION: Cinnamon oil, lemongrass oil, cedarwood oil, clove oil and eucalyptus oil exhibit antibacterial property against S. mutans. CLINICAL SIGNIFICANCE: The use of these essential oils against S. mutans can be a viable alternative to other antibacterial agents as these are an effective module used in the control of both bacteria and yeasts responsible for oral infections.

Population pharmacokinetic/pharmacodynamic assessment of imipenem/cilastatin/relebactam in patients with hospital-acquired/ventilator-associated bacterial pneumonia.

In the phase III RESTORE-IMI 2 study (ClinicalTrials.gov: NCT02493764), the combination antibacterial agent imipenem/cilastatin/relebactam (IMI/REL) demonstrated noninferiority to piperacillin/tazobactam for the end points of all-cause mortality at day 28 and favorable clinical response at the early follow-up visit in adult participants with gram-negative hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP). Existing population pharmacokinetic models for imipenem (IPM) and REL were updated using data from patients with HABP/VABP from RESTORE-IMI 2. Creatinine clearance (CrCl), body weight, infection type, and ventilation status were significant covariates in the updated model. The following simulations were performed to calculate the pharmacokinetic/pharmacodynamic joint probability of target attainment among patients with HABP/VABP and varying degrees of renal function: augmented renal clearance (CrCl ≥150 ml/min), normal renal function (CrCl ≥90 to <150 ml/min), renal impairment (mild, CrCl ≥60 to <90 ml/min; moderate, CrCl ≥30 to <60 ml/min; or severe, CrCl ≥15 to <30 ml/min), and end-stage renal disease (CrCl <15 ml/min). At the recommended IMI/REL dosing regimens across renal categories, greater than 90% of patients in all renal function groups were predicted to achieve joint pharmacokinetic/pharmacodynamic targets at a minimum inhibitory concentration breakpoint of ≤2 µg/ml, regardless of ventilation status. This modeling and simulation analysis supports use of the recommended IMI/REL dosing regimens, adjusted based on renal function, in patients with HABP/VABP.

Phase 1 clinical trial for intravenous administration of mesenchymal stem cells derived from umbilical cord and placenta in patients with moderate COVID-19 virus pneumonia: results of stage 1 of the study.

OBJECTIVE: Mesenchymal stem cells can serve as a therapeutic option for COVID-19. Their immunomodulatory and anti-inflammatory properties can regulate the exaggerated inflammatory response and promote recovery of lung damage. METHOD: Phase-1, single-centre open-label, prospective clinical trial was conducted to evaluate the safety and efficacy of intravenous administration of mesenchymal stem cells derived from umbilical cord and placenta in moderate COVID-19. The study was done in 2 stages with total 20 patients. Herein, the results of stage 1 including first 10 patients receiving 100 million cells on day 1 and 4 with a follow up of 6 months have been discussed. RESULTS: No adverse events were recorded immediately after the administration of MSCs or on follow up. There was no deterioration observed in clinical, laboratory and radiological parameters. All symptoms of the study group resolved within 10 days. Levels of inflammatory biomarkers such as NLR, CRP, IL6, ferritin and D-dimer improved in all patients after intervention along with improved oxygenation demonstrated by improvement in the SpO2/FiO2 ratio and PaO2/FiO2 ratio. None of the patients progressed to severe stage. 9 out of 10 patients were discharged within 9 days of their admission. Improvements were noted in chest x-ray and chest CT scan scores at day 7 in most patients. No post-covid fibrosis was observed on chest CT 28 days after intervention and Chest X ray after 6 months of the intervention. CONCLUSION: Administration of 100 million mesenchymal stem cells in combination with standard treatment was found to be safe and resulted in prevention of the cytokine storm, halting of the disease progression and acceleration of recovery in moderate COVID-19. This clinical trial has been registered with the Clinical Trial Registry- India (CTRI) as CTRI/2020/08/027043. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=43175.

Analytical Methods for Determination of Apremilast from Bulk, Dosage Form and Biological Fluids: A Critical Review.

Apremilast is an anti-inflammatory agent. It has been a flourishing molecule in the field of dermatology. In the year 2014, Apremilast got its approval for treatment of psoriatic arthritis. Presently it is known to treat a number of other conditions, including atopic dermatitis and plaque psoriasis. Apremilast a phthalimide derivative, is non-hygroscopic in nature. It is practically insoluble in water. Apremilast acts by inhibiting the activity of phosphodiesterase 4 (PDE4), an intracellular enzyme. Analytical method plays a key role to understand the physio-chemical properties of a drug molecule. Because of poor solubility and low permeability, analytical method development and formulation becomes challenging. Till date, there are no standard test methods available to analyze Apremilast. So, a critical review of the analytical techniques of Apremilast was carried out. The literature search was done by screening the papers reporting analytical techniques of Apremilast from year 2014 to 2019. Methodologies particularly UV spectroscopy, HPTLC, HPLC, X-ray diffraction, NMR, LC-MS were collected and reviewed. Interminable efforts are made by the researchers to develop simple, accurate, robust and cost-effective methods of analysis. In pharmaceutical research, this information will aid in the development of new delivery systems. The review will prove beneficial and advantageous pre-formulation studies and will guide the formulation development.

A pilot study for treatment of COVID-19 patients in moderate stage using intravenous administration of ozonized saline as an adjuvant treatment-registered clinical trial.

OBJECTIVE: Ozone therapy has tremendous therapeutic potential owing to its antiviral, anti-inflammatory and antioxidant properties, and potential to improve oxygenation. A pilot clinical trial was conducted to evaluate the safety and efficacy ofintravenous ozonised saline treatment in patients with moderate COVID-19 pneumonia. PATIENTS AND METHODS: 10 patients were administered 200 ml freshly prepared ozonised saline intravenously over 1 h once a day for 8 days along with standard medical treatment. Clinical symptoms were monitored everyday and laboratory biomarkers, radiological findings at 1,3,6,10 days. Telephonic follow up was done for all after discharge till Day 14. 7 out of 10 patients required oxygen supplementation at recruitment. RESULTS: There was severe adverse event recorded in the study group.All patients improved from moderate to mild category in average 8 days and were discharged in average 9.7 days. None deteriorated to severe stage. All clinical symptoms resolved within 6 days and oxygen supplementation requirement reduced to none within 4.1 days. There wasstatistically significant reduction inCRP (p = 0.003), D-Dimer (p = 0.049), IL6 (p = 0.002)and statistically significant improvement (p = 0.001) in SpO2/FiO2 ratio. Change in LDH was borderline statistically not significant (p = 0.058).All patients showed significant resolution of bilateral interstitial infiltrates at the end of 10 days. CONCLUSION: Resolved clinical symptoms, improved oxygenation, clearance of infiltrates on Chest X-ray and improvement in biomarkers in a short period with non-progression of the disease showed that IV ozonised saline therapy was safe and effective to prevent disease progression in COVID-19, making it an effective novel therapeutic tool.

Multiple Cellular Therapies Along with Neurorehabilitation in Spastic Diplegic Cerebral Palsy: A Case Report.

Cerebral palsy (CP) is a chronic childhood disorder that is characterized by a group of motor and cognitive impairments, resulting in abnormal movement patterns, loss of motor control, incoordination, and unbalanced posture. It can also have an impact on fine motor skills, gross motor skills, and oral motor functioning. Currently, the treatment of CP is palliative and does not cure the disease pathology. Hence, there is a need for an intervention that might be able to alter the core pathology. Autologous bone marrow mononuclear cells (BMMNC) transplantation is one of the novel treatment strategies in recent years. In this study, we presented the case of a 4-year-old male child with spastic diplegic CP who underwent two intrathecal transplantations at interval of seven months with autologous BMMNC along with neurorehabilitation program. During an overall 16-month follow-up, significant improvements were observed in motor control, coordination, balance, sitting tolerance, and memory. The abnormal 'W' sitting posture and scissoring gait pattern of the patient resolved. Started sitting with good head, trunk, and pelvic alignment and attained regular gait pattern; the patient started to walk independently without support as well. On objective scale, Gross Motor Functional Measure score improved from 60.67 to 81.78. The patient's Gross Motor Functional Classification System grade improved from Level 3 to Level 2, and Functional Independent Measure score improved from 97 to 99. A comparative positron emission tomography-computed tomography (PET CT) brain scan was performed before and seven months after the first intervention, which revealed improvement in the metabolism of the anterior cingulate lobe, parietal cortex, medial temporal cortex, thalamus, basal ganglia, and cerebellum. No adverse events were recorded throughout the study. Thus, multiple cellular therapies, along with neurorehabilitation, might be a novel safe, feasible option to enhance recovery in CP.

Cell transplantation as a novel therapeutic strategy for autism spectrum disorders: a clinical study.

BACKGROUND: Autism spectrum disorders [ASD] is a lifelong disability mainly affecting the development, communication, social interaction and behavior of an individual. Cell transplantation is emerging as a potential therapeutic strategy for ASD. Our previously published proof of concept study showed beneficial effects of cell transplantation in ASD. This study shows effect of cell transplantation in a larger sample size of ASD patients. METHODS: 254 patients diagnosed with ASD on DSM V criteria were enrolled in this open label non-randomized study. The intervention included intrathecal transplantation of autologous bone marrow mononuclear cells and neurorehabilitation. On mean follow up of 7.50 months, percentage analysis was performed on all symptomatic changes. Changes in outcome measures, Indian Scale for Assessment of Autism [ISAA] and Childhood Autism Rating Scale [CARS], were analyzed statistically using Wilcoxon Signed-Rank Test. Comparative analysis of Positron Emission Tomography [PET CT] scan brain, performed before and 6 months after intervention, was done in 86 patients to monitor the outcome at cellular level. Change in the standardized uptake values was statistically evaluated using T-Test [P≤0.05]. RESULTS: Improvements were observed in eye contact, attention and concentration, hyperactivity, sitting tolerance, social interaction, stereotypical behavior, aggressiveness, communication, speech, command following and self-stimulatory behavior. Statistically significant improvement was observed in scores of ISAA and CARS after intervention. A significantly better outcome of the intervention was found in patients at younger age and with shorter duration of disease [<5 years from time of diagnosis]. 86 patients who underwent a repeat PET CT scan showed improved brain metabolism after intervention in areas which correlated to the symptomatic changes. No major procedure related adverse events were recorded. However, 5 patients, with history of seizure and abnormal EEG, had an episode of seizure which was managed using medications. Outcome of intervention in these patients was not affected by seizures as improvements were observed in them. CONCLUSION: The results of this study indicate that autologous bone marrow mononuclear cells in combination with neurorehabilitation are a safe and effective treatment modality for ASD. It improves the quality of life of patients and helps them to integrate in mainstream lifestyle.

Autologous bone marrow mononuclear cell transplantation in patients with chronic traumatic brain injury- a clinical study.

BACKGROUND: Chronic Traumatic Brain Injury (TBI) is one of the common causes of longterm disability worldwide. Cell transplantation has gained attention as a prospective therapeutic option for neurotraumatic disorders like TBI. The postulated mechanism of cell transplantation which includes angiogenesis, axonal regeneration, neurogenesis and synaptic remodeling, may tackle the pathology of chronic TBI and improve overall functioning. METHODS: To study the effects of cell transplantation, 50 patients with chronic TBI were enrolled in an open label non-randomized study. The intervention included intrathecal transplantation of autologous bone marrow mononuclear cells and neurorehabilitation. Mean follow up duration was 22 months. Fifteen patients underwent second dose of cell transplantation, 6 months after their first intervention. Percentage analysis was performed to analyze the symptomatic improvements in the patients. Functional independence measure (FIM) was used as an outcome measure to evaluate the functional changes in the patients. Statistical tests were applied on the pre-intervention and post-intervention scores for determining the significance. Comparative Positron Emission Tomography- computed tomography (PET CT) scans were performed in 10 patients to monitor the effect of intervention on brain function. Factors such as age, multiple doses, time since injury and severity of injury were also analyzed to determine their effect on the outcome of cell transplantation. Adverse events were monitored throughout the follow up period. RESULTS: Overall 92% patients showed improvements in symptoms such as sitting and standing balance, voluntary control, memory, oromotor skills lower limb activities, ambulation, trunk & upper limb activity, speech, posture, communication, psychological status, cognition, attention and concentration, muscle tone, coordination, activities of daily living. A statistically significant (at p ≤ 0.05 with p-value 0) improvement was observed in the scores of FIM after intervention on the Wilcoxon signed rank test. Better outcome of the intervention was found in patients with mild TBI, age less than 18 years and time since injury less than 5 years. Ten patients who underwent a repeat PET CT scan brain showed improved brain metabolism in areas which correlated to the symptomatic changes. Two patients had an episode of seizures which was managed with medication. They both had an abnormal EEG before the intervention and 1 of them had previous history and was on antiepileptics. No other major adverse events were recorded. CONCLUSION: This study demonstrates the safety and efficacy of cell transplantation in chronic TBI on long term follow up. Early intervention in younger age group of patients with mild TBI showed the best outcome in this study. In combination with neurorehabilitation, cell transplantation can enhance functional recovery and improve quality of life of patients with chronic TBI. PET CT scan brain should be explored as a monitoring tool to study the efficacy of intervention.

Intrathecal transplantation of autologous bone marrow mononuclear cells in patients with sub-acute and chronic spinal cord injury: An open-label study.

OBJECTIVE: The objective of the study was to analyze the effect of intrathecal transplantation of autologous bone marrow-derived mononuclear cells (BMMNCs) in functional recovery of spinal cord injury (SCI) patients along with neurorehabilitation and to evaluate various factors influencing the outcome of cellular therapy. METHODS: We conducted an open-label study including 180 sub-acute and chronic SCI patients. All patients received intrathecal autologous BMMNCs along with neurorehabilitation. 80-100 mL of bone marrow was aspirated and BMMNCs were obtained using density gradient separation. An average of 1.06 × 108 cells with 97% viability was administered through lumbar puncture immediately. After transplantation, all patients underwent neurorehabilitation. Patients were followed up after an average of 9 ± 7 months. They were assessed for functional symptomatic changes and the outcome measures used were functional independence measure (FIM) and walking index for SCI (WISCI). RESULTS: Patients showed symptomatic improvement in sitting/standing balance, bed mobility, trunk stability, upper limb function, mobility, sensation, bowel/bladder functions, and activities of daily living with no serious adverse events. Scores on FIM and WISCI showed statistically significant improvement. On subgroup analysis, it was found that early intervention and more than one dose of BMMNCs demonstrate a better functional outcome. Younger patients demonstrated better improvements in functional independence. Both cervical and dorsolumbar levels of injury show significant improvements in motor and sensory deficits. CONCLUSIONS: Autologous BMMNC transplantation with neurorehabilitation is safe, effective, enhances functional recovery, and improves the quality of life of SCI patients in sub-acute and chronic stage.