Profile of Cardiac Involvement in Children After Exposure to COVID-19.

OBJECTIVE: To evaluate the incidence and pattern of cardiac involvement in children post-COVID (coronavirus disease) infection in a tertiary care referral hospital in India. METHODS: A prospective observational study was conducted including all consecutive children with suspected MIS-C referred to the cardiology services. RESULTS: Of the 111 children with mean (SD) age was 3.5 (3.6) years, 95.4% had cardiac involvement. Abnormalities detected were coronary vasculopathy, pericardial effusion, valvular regurgitation, ventricular dysfunction, diastolic flow reversal in aorta, pulmonary hypertension, bradycardia and intra-cardiac thrombus. The survival rate post treatment was 99%. Early and short-term follow-up data was available in 95% and 70%, respectively. Cardiac parameters improved in majority. CONCLUSION: Cardiac involvement post COVID-19 is often a silent entity and may be missed unless specifically evaluated for. Early echocardiography aided prompt diagnosis, triaging, and treatment, and helps in favorable outcomes.

Human iPSC-derived cerebral organoids model features of Leigh syndrome and reveal abnormal corticogenesis.

Leigh syndrome (LS) is a rare, inherited neurometabolic disorder that presents with bilateral brain lesions caused by defects in the mitochondrial respiratory chain and associated nuclear-encoded proteins. We generated human induced pluripotent stem cells (iPSCs) from three LS patient-derived fibroblast lines. Using whole-exome and mitochondrial sequencing, we identified unreported mutations in pyruvate dehydrogenase (GM0372, PDH; GM13411, MT-ATP6/PDH) and dihydrolipoyl dehydrogenase (GM01503, DLD). These LS patient-derived iPSC lines were viable and capable of differentiating into progenitor populations, but we identified several abnormalities in three-dimensional differentiation models of brain development. LS patient-derived cerebral organoids showed defects in neural epithelial bud generation, size and cortical architecture at 100 days. The double mutant MT-ATP6/PDH line produced organoid neural precursor cells with abnormal mitochondrial morphology, characterized by fragmentation and disorganization, and showed an increased generation of astrocytes. These studies aim to provide a comprehensive phenotypic characterization of available patient-derived cell lines that can be used to study Leigh syndrome.

Reversible neurological and brain MRI changes following COVID-19 vaccination: A case report.

BACKGROUND: Various neurological sequalae have been described following COVID-19 vaccination. Here we describe the first case of untreated post COVID-19 vaccine encephalitis with spontaneous resolution of contrast enhancing hyperintensities on MRI concomitant with clinical improvement. CASE PRESENTATION: A 59-year-old woman presented with a two-day history of unsteady gait, incoordination, visual symptoms, and lethargy. She had received AZD1222 (AstraZeneca) and mRNA-1273 (Moderna) COVID-19 vaccines at 3 months and 12 days, respectively, before presentation. Brain MRI showed no abnormality on the non-enhanced sequences, but numerous enhancing lesions in the cerebral cortex, deep grey matter, brainstem, and cerebellum. Treatment was expectant, the patient improved clinically over 10 days, and repeat MRI showed near complete resolution of the imaging abnormality. CONCLUSIONS: We describe neurological deterioration 12 days after a second dose of COVID-19 vaccine. There was no evidence of edema or demyelinating lesions in the brain on MRI, but there was extensive contrast-enhancement indicating loss of blood-brain barrier (BBB) integrity. This provides a potential in vivo, clinical-imaging correlate of the post-mortem evidence that SARS-CoV-2 spike protein may induce loss of BBB permeability. While this adds to the list of rare adverse neurological reactions to COVID-19 vaccination, the benefits of receiving the vaccine far outweigh these risks.

Surgical treatment options for congenital pseudarthrosis of tibia in children: cross-union versus other options: a systematic review.

The systematic review aimed to provide a comprehensive update on various surgical treatment options for congenital pseudarthrosis of tibia (CPT) in children and the outcome achieved in terms of union, union time and complications of non-union and refracture. A literature search was performed in PubMed (including Medline) database for broad keywords: 'Congenital pseudarthrosis of tibia and children'. Studies selected included full-text articles on surgical treatments of CPT following: intra-medullary rod (IMR)/Ilizarov/combined IMR with Ilizarov/vascularized fibular graft (VFG) and cross-union. Out of 719 studies, 57(1227 CPT patients/1235 tibias) were included for review. Cross-union group had 100% union rate with no non-unions, least refracture rate (22.5%) and minimal time to primary union (4.5 months). For IMR, Ilizarov, combined IMR with Ilizarov and VFG, the respective results were as follows: primary union rates - 67.7, 84.2, 83.7 and 65.3%; final union - 76.5, 81.5, 92.4 and 87.1%; primary union time - 12.6, 9.3, 5.3 and 9.5 months; non-union rates - 17.0, 13.6, 6.0 and 7.9%; refracture rates - 48.1, 47.7, 33.7 and 34.6%. The success probability was lowest for IMR (35.2%), 44% for Ilizarov, 55.5% for combined IMR with Ilizarov, 42.7% for VFG and highest 77.5% for cross-union group. Outcomes of the more recent cross-union technique fare better than other surgical methods. However, studies on cross-union are few and longer follow-up is lacking. Combined IMR with Ilizarov and VFG have better results compared to IMR or Ilizarov alone.

Unilateral limb orthosis for maintenance of deformity correction following treatment of clubfoot with Ponseti technique: a systematic review.

The systematic review study aimed to investigate the following details in the clubfoot children treated with the Ponseti technique: (1) to review the various designs and prescriptions of unilateral limb orthosis described in literature; (2) to find the outcome following use of this orthosis, especially patient adherence and recurrence; (3) comparison with standard bilateral limb foot abduction orthosis. A literature search was performed for articles published in 'Pubmed (includes Medline indexed journals)' electronic databases for broad key words: 'Clubfoot or CTEV or congenital talipes equinovarus', 'orthosis or brace or splint'. Included were studies that addressed the treatment of idiopathic clubfoot in children up to 2 years of age using the Ponseti technique and use of unilateral limb orthosis for the subsequent maintenance phase. We excluded studies reporting Ponseti technique for nonidiopathic clubfoot, child age older than 2 years at the time of primary treatment, studies where unilateral limb orthosis was used as a tool for primary correction of all or some components of clubfoot and design descriptions of orthosis without practical usage data. Of the 1537 articles from the database, 10 articles were included in the final review. Most studies were retrospective, underpowered and had a short term follow-up. In some series, the use of this orthosis was driven by personal experiences and regional preferences rather than a just scientific explanation. The tested designs were variable and nonstandardized. Being less restrictive, unilateral limb orthosis may have an edge over bilateral limb orthosis in terms of patient adherence. The available comparative studies however showed inferiority of unilateral orthoses when compared to the bilateral limb orthosis in preventing recurrences in clubfoot treatment. There is insufficient evidence to support use of unilateral limb orthosis for maintenance of deformity correction following treatment of clubfoot with the Ponseti technique. Their use was found associated with high recurrence rates.

Long-term outcomes of the Ponseti method for treatment of clubfoot: a systematic review.

PURPOSE: The Ponseti method has revolutionized the clubfoot treatment and has been adopted globally in the past couple of decades. However, most reported results of the Ponseti method are either short or midterm. Studies reporting long-term outcomes of the Ponseti method are limited. The following systematic review aimed to provide a comprehensive overview of the published articles on long-term outcomes of the Ponseti method. MATERIAL AND METHODS: A literature search was performed for articles published in electronic database PubMed (includes Medline) and Cochrane for broad keywords: "Clubfoot"; "Ponseti method/technique"; "long term outcomes/results." Studies selected included full-text articles in English language on children less than one year with primary idiopathic clubfoot treated by the Ponseti method with mean ten year follow-up. Non-idiopathic causes or syndromic clubfoot and case reports/review articles/meta-analyses were excluded. The following parameters were included for analysis: number of patients/clubfeet, male/female, mean age at treatment, mean/range of follow-up, relapses, additional surgery, range of motion, various outcome scores, and radiological variables. RESULTS: Fourteen studies with 774 patients/1122 feet were included. The male:female ratio was 2.4:1. Mean follow-up recorded in studies was 14.5 years. Relapses occurred in 47% patients with additional surgery being required in 79% patients with relapses. Of these, 86% of surgery were extra-articular while 14% were intra-articular. Plantigrade foot was achieved in majority patients with mean ankle dorsiflexion of 11 degrees. The outcome scores were in general good in contrast to radiological angles which were mostly outside normal range with talar flattening/navicular wedging/degenerative osteoarthritis changes occurring in 60%, 76%, and 30%, respectively. CONCLUSIONS: Long-term follow-up of infants with primary idiopathic clubfeet treated by the Ponseti method revealed relatively high relapse and additional surgery rates. Radiologically, the various angles were inconsistent compared to normal ranges and anatomical deformations/degenerative changes were present in treated feet. Moreover, the relapse rates and requirement of additional surgery increased on long-term follow-up. Despite this, majority feet were plantigrade and demonstrated good clinical results as measured by various outcome tools. There should be emphasis on long-term follow-up of children with clubfeet in view of late relapses and secondary late changes.

Relapses in clubfoot treated with Ponseti technique and standard bracing protocol- a systematic analysis.

PURPOSE: The analysis determined the relapses in clubfoot children treated with Ponseti technique and standard bracing protocol and their correlation with overall follow up duration using pooled data from various series. It also tested the prescribed timelines of 5 and 7 years for slow-down/cessation of relapses in clubfoot children. METHODS: A systematic literature search was performed for articles published in "Pubmed (includes Medline indexed journals)" electronic databases using key words: "Clubfoot or CTEV or congenital talipes equinovarus", "Ponseti" for years 1st January 2001 to 15th November 2020. Included were studies that addressed treatment of idiopathic clubfoot using the standard Ponseti technique, followed a well defined brace protocol (maintenance of corrected deformity using a central bar based brace and prescribed duration mentioned), reported a minimum mean follow up of 4 years and having relapse as one of their outcome measure. Studies reporting Ponseti technique for non-idiopathic clubfoot, child's age older than 1 year at the time of primary treatment, clubfoot with previous interventions before Ponseti treatment, where relapse and residual deformities were not identified distinctly in follow up, abstract only publications, letter to the editors, case reports, technique papers and review articles were excluded. The following characteristics of clubfoot patients in the selected articles were included for analysis: Patient numbers/feet treated with Ponseti technique; follow up years (<5; 5-7 and >7 years; overall) and corresponding relapse percentages for patients. RESULTS: There were total 2206 patients in the included 24 studies. Average follow up was 6 years. The average relapse rates for clubfoot patients in the pooled data stood at 30%. The overall relapse rates increased with a longer follow up and the curve befitted a linear regression equation with weak positive correlation (Pearson correlation coefficient = 0.08). The relapse rates in follow up categories of <5 years (26.6 ± 15.6%), 5-7 years (30.8 ± 16.3%) and >7 years (28.4 ± 6.2%) were similar statistically (Analysis of variance, ANOVA). CONCLUSIONS: Approximately 1 in 3 clubfoot patients suffer relapse post Ponseti technique and standard bracing protocol. A weak positive correlation was observed for relapses when correlated with increasing follow up years. The relapses however tend to slow down after initial growth years. There is a need to educate the care receivers regarding the possibility of late relapses despite proper Ponseti treatment and accordingly to keep them under supervised follow up for longer periods.

Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons.

Solute carrier family 6 member 1 (SLC6A1) is abundantly expressed in the developing brain even before the CNS is formed. Its encoded GABA transporter 1 (GAT-1) is responsible for the reuptake of GABA into presynaptic neurons and glia, thereby modulating neurotransmission. GAT-1 is expressed globally in the brain, in both astrocytes and neurons. The GABA uptake function of GAT-1 in neurons cannot be compensated for by other GABA transporters, while the function in glia can be partially replaced by GABA transporter 3. Recently, many variants in SLC6A1 have been associated with a spectrum of epilepsy syndromes and neurodevelopmental disorders, including myoclonic atonic epilepsy, childhood absence epilepsy, autism, and intellectual disability, but the pathomechanisms associated with these phenotypes remain unclear. The presence of GAT-1 in both neurons and astrocytes further obscures the role of abnormal GAT-1 in the heterogeneous disease phenotype manifestations. Here we examine the impact on transporter trafficking and function of 22 SLC6A1 variants identified in patients with a broad spectrum of phenotypes. We also evaluate changes in protein expression and subcellular localization of the variant GAT-1 in various cell types, including neurons and astrocytes derived from human patient induced pluripotent stem cells. We found that a partial or complete loss-of-function represents a common disease mechanism, although the extent of GABA uptake reduction is variable. The reduced GABA uptake appears to be due to reduced cell surface expression of the variant transporter caused by variant protein misfolding, endoplasmic reticulum retention, and subsequent degradation. Although the extent of reduction of the total protein, surface protein, and the GABA uptake level of the variant transporters is variable, the loss of GABA uptake function and endoplasmic reticulum retention is consistent across induced pluripotent stem cell-derived cell types, including astrocytes and neurons, for the surveyed variants. Interestingly, we did not find a clear correlation of GABA uptake function and the disease phenotypes, such as myoclonic atonic epilepsy versus developmental delay, in this study. Together, our study suggests that impaired transporter protein trafficking and surface expression are the major disease-associated mechanisms associated with pathogenic SLC6A1 variants. Our results resemble findings from pathogenic variants in other genes affecting the GABA pathway, such as GABAA receptors. This study provides critical insight into therapeutic developments for SLC6A1 variant-mediated disorders and implicates that boosting transporter function by either genetic or pharmacological approaches would be beneficial.

Pathogenesis and management of Brugada syndrome in schizophrenia: A scoping review.

CONTEXT: Excess cardiovascular morbidity and an increased prevalence of sudden cardiac death (SCD) contributes to premature mortality in schizophrenia. Brugada syndrome (BrS) is an important but underrecognized cause of SCD. It is more commonly seen in schizophrenia than in general population controls. METHODS: We conducted a scoping review to describe the pathogenesis of BrS in schizophrenia and to identify the psychotropic medications that increase the risk of unmasking BrS and associated ventricular arrhythmias resulting in SCD. FINDINGS: Schizophrenia and BrS share similar calcium channel abnormalities, which may result in aberrant myocardial conductivity. It remains uncertain if there is a genetic pre-disposition for BrS in a subset of patients with schizophrenia. However, the unmasking of Brugada ECG patterns with the use of certain antipsychotics and antidepressants increases the risk of precipitating SCD, independent of QT prolongation. CONCLUSIONS AND FUTURE DIRECTIONS: Specific cardiology assessment and interventions may be required for the congenital or unmasked Brugada ECG pattern in schizophrenia. The current long-term standard of care for BrS is an implantable cardioverter defibrillator (ICD), but post-implantation psychological effects must be considered. Careful use of antipsychotic and other psychotropic medications is necessary to minimize proarrhythmic effects due to impact on cardiac sodium and calcium ion channels. When prescribing such drugs to patients with schizophrenia, clinicians should be mindful of the potentially fatal unmasking of Brugada ECG patterns and how to manage it. We present recommendations for psychiatrists managing this patient population.

Remodeling of mitochondrial morphology and function: an emerging hallmark of cellular reprogramming.

Research in the stem cell field has traditionally focused on understanding key transcriptional factors that provide pluripotent cell identity. However, much less is known about other critical non-transcriptional signaling networks that govern stem cell identity. Although we continue to gain critical insights into the mechanisms underlying mitochondrial morphology and function during cellular reprogramming - the process of reverting the fate of a differentiated cell into a stem cell, many uncertainties remain. Recent studies suggest an emerging landscape in which mitochondrial morphology and function have an active role in maintaining and regulating changes in cell identity. In this review, we will focus on these emerging concepts as crucial modulators of cellular reprogramming. Recognition of the widespread applicability of these concepts will increase our understanding of the mitochondrial mechanisms involved in cell identity, cell fate and disease.

Anthropometric measurements in Ponseti treated clubfeet.

INTRODUCTION: We measured the foot dimensions in the Ponseti treated idiopathic clubfeet to compare differences in foot sizes, if any. PATIENT AND METHODS: The foot length and width in unaffected, unilateral and bilateral clubfeet were measured and analysed statistically. RESULTS: Average follow up was 22.2 months. Bilateral feet were similar in size. The unilateral affected feet matched in size with contralateral unaffected feet. The size difference between bilateral and unilateral affected feet was not significant. The bilateral feet were significantly smaller than age matched unaffected feet [in length 0.8 cm (6.1%); p = 0.03 and in width 0.2 cm, (3.7%); p = 0.03]. The unilateral foot was comparable with contralateral unaffected foot both during and post bracing. CONCLUSIONS: Post Ponseti treatment, inter bilateral, unilateral affected versus unaffected, bilateral versus unilateral affected feet matched in size. The overall clubfeet size especially those with bilateral disease were significantly shorter than unaffected side. The Ponseti managed unilateral foot size was comparable with unaffected foot during the bracing duration and size comparability was maintained even after bracing protocol of 3 years was over.

Tuberculosis of the Elbow Region in Pediatric Age Group - Experiences from a Single Centre.

BACKGROUND: Clinical series of tuberculosis of elbow region in children are few. The purpose of our study was to retrospectively review the presentation, healing response and functional results of 30 children. METHODS: The pretreatment disease presentation was studied from patient's case records. Serial radiographs of the patients were studied to see remineralization and healing of radiological lesions. For elbow's functional evaluation, pain, range of motion and recurrence were observed at final follow up. RESULTS: The mean patient age was 8.2 years. The mean duration of symptoms before presentation was 47 days. A discharging sinus was present in 6 patients. Multifocal presentation was found in 7 patients. The lesion was most commonly localized in proximal ulna or lower humerus. The classical 'ice cream scoop' appearance of proximal ulnar metaphysis was noted in 5 elbows. Most elbows were in Martini stage 2 (70%) at the time of presentation. All patients were treated non-operatively. Average follow up after completion of antitubercular therapy was 18.97 months. The resolution of regional osteopenia, sclerosis of lytic lesions, reappearance of bony trabeculae and decrease in size of cavities was the usual sequence of radiological healing. End average elbow flexion arc deteriorated with increasing Martini stage. 'Ice cream scoop lesions' resulted in a worse functional outcome with formation of an irregular proximal ulnar articular surface. CONCLUSIONS: Restriction of elbow range of motion, early discharging sinus formation and radiological 'ice cream scoop' appearance indicated a tubercular pathology. Late presentation with advanced disease, total joint involvement, and 'ice cream scoop appearance' resulted in decreased elbow flexion arc.

Modulation of cognitive cerebello-cerebral functional connectivity by lateral cerebellar continuous theta burst stimulation.

Network connectivity measured with resting state functional magnetic resonance imaging (rsfMRI) has revealed the contribution of distinct cerebellar lobules to an array of brain wide networks sub-serving motor and cognitive processes. As distinct cerebellar lobules form relatively accessible nodes of different brain networks, this raises the possibility for site-specific modulation of network connectivity using non-invasive brain stimulation techniques such as transcranial magnetic stimulation (TMS). Continuous theta burst transcranial magnetic stimulation (cTBS) induces long-lasting inhibition of cortical areas. Although previous studies have shown that cTBS of the lateral cerebellum modulates motor cortical excitability and improves symptoms in several movement disorders, the effect on cognitive domains has not been examined. We explored the immediate effects of cTBS in a sham-controlled study on the strength of intrinsic functional connectivity between cerebellar and cortical motor and cognitive regions in 12 participants. Lateral cerebellar cTBS significantly decreased functional connectivity with frontal and parietal cognitive regions, while connectivity with motor regions remained unaltered. Sham stimulation had no effect on either motor or cognitive connectivity. These results show that inhibitory cerebellar stimulation reduces intrinsic functional connectivity between different cortical areas, in keeping with the known connectivity pattern of the cerebellum. The results highlight the plasticity of cerebello-cerebral networks and indicate for the first time that this functional connectivity can be downregulated using an inhibitory neurostimulation paradigm. This may shed light on the pathophysiology of network dysfunction and is a potential treatment for cognitive and movement disorders.

Biophysical regulation of mouse embryonic stem cell fate and genomic integrity by feeder derived matrices.

For maintaining pluripotency, mouse embryonic stem cells (mESCs) are typically grown on mitotically inactivated mouse embryonic fibroblasts (MEFs). While the role of MEF conditioned media (MEFCM) and leukemia inhibitory factor (LIF) in regulating mESC pluripotency has led to culturing of mESCs on LIF/MEFCM supplemented gelatin-coated substrates, the role of physical interactions between MEFs and mESCs in regulating mESC pluripotency remains to be fully understood. Here, we address this question by characterizing the physicochemical properties of MEF derived matrices (MEFDMs), and probing their role in regulating mESC fate. We show that MEFDM composition and stiffness-dictated by MEF contractility-regulates mESC pluripotency by modulating mESC contractility through integrin-mediated mechanoadaptation. While baseline mESC pluripotency is maintained at early time points, activation of mESC contractility by LPA leads to drop in pluripotency levels. In contrast, addition of blebbistatin and LIF independently increases pluripotency by suppressing mechanoadaptation, highlighting the role of mechanoadaptation in regulating pluripotency and illustrating the role of LIF as a mechano-inhibitor in mESCs. Long-term culture of mESCs on MEFDMs under LIF-free conditions triggers loss of pluripotency, and induces ligand-dependent expression of the osteogenic transcription factor Runx2. Maintenance of genomic integrity (euploidy) on MEFDMs but not on gelatin-coated substrates, combined with the ability of MEFDMs in supporting LIF-free expansion and differentiation of mESCs, illustrates the suitability of MEFDMs for clinical and regenerative medicine applications.

Modulation of cerebello-cerebral resting state networks by site-specific stimulation.

Converging evidence from neuroimaging and neuromodulation literature suggests that the cerebellum plays a broad role in motor as well as cognitive processes through its participation in resting-state networks. A recent study by Halko et al. (J Neurosci 34: 12049-12056, 2014) demonstrates, for the first time, the ability to modulate functional connectivity of some of these distinct resting-state networks using site-specific repetitive transcranial magnetic stimulation (rTMS) of the cerebellum. In this Neuro Forum, we discuss and critically analyze this study, emphasizing important findings, potential therapeutic relevance, and areas worthy of further inquiry.

Effortful versus automatic emotional processing in schizophrenia: Insights from a face-vignette task.

Adaptive emotional responding relies on dual automatic and effortful processing streams. Dual-stream models of schizophrenia (SCZ) posit a selective deficit in neural circuits that govern goal-directed, effortful processes versus reactive, automatic processes. This imbalance suggests that when patients are confronted with competing automatic and effortful emotional response cues, they will exhibit diminished effortful responding and intact, possibly elevated, automatic responding compared to controls. This prediction was evaluated using a modified version of the face-vignette task (FVT). Participants viewed emotional faces (automatic response cue) paired with vignettes (effortful response cue) that signalled a different emotion category and were instructed to discriminate the manifest emotion. Patients made less vignette and more face responses than controls. However, the relationship between group and FVT responding was moderated by IQ and reading comprehension ability. These results replicate and extend previous research and provide tentative support for abnormal conflict resolution between automatic and effortful emotional processing predicted by dual-stream models of SCZ.