Sequence-specific dynamic DNA bending explains mitochondrial TFAM's dual role in DNA packaging and transcription initiation.

Mitochondrial transcription factor A (TFAM) employs DNA bending to package mitochondrial DNA (mtDNA) into nucleoids and recruit mitochondrial RNA polymerase (POLRMT) at specific promoter sites, light strand promoter (LSP) and heavy strand promoter (HSP). Herein, we characterize the conformational dynamics of TFAM on promoter and non-promoter sequences using single-molecule fluorescence resonance energy transfer (smFRET) and single-molecule protein-induced fluorescence enhancement (smPIFE) methods. The DNA-TFAM complexes dynamically transition between partially and fully bent DNA conformational states. The bending/unbending transition rates and bending stability are DNA sequence-dependent-LSP forms the most stable fully bent complex and the non-specific sequence the least, which correlates with the lifetimes and affinities of TFAM with these DNA sequences. By quantifying the dynamic nature of the DNA-TFAM complexes, our study provides insights into how TFAM acts as a multifunctional protein through the DNA bending states to achieve sequence specificity and fidelity in mitochondrial transcription while performing mtDNA packaging.

Stem Cell-Derived Exosomes: An Advanced Horizon to Cancer Regenerative Medicine.

Cancer research has made significant progress in recent years, and extracellular vesicles (EVs) based cancer investigation reveals several facts about cancer. Exosomes are a subpopulation of EVs. In the present decade, exosomes is mostly highlighted for cancer theranostic research. Tumor cell derived exosomes (TEXs) promote cancer but there are multiple sources of exosomes that can be used as cancer therapeutic agents (plant exosomes, stem cell-derived exosomes, modified or synthetic exosomes). Stem cells based regenerative medicine faces numerous challenges, such as promote tumor development, cellular reprogramming etc., and therefore addressing these complications becomes essential. Stem cell-derived exosomes serves as an answer to these problems and offers a better solution. Global research indicates that stem cell-derived exosomes also play a dual role in the cellular system by either inhibiting or promoting cancer. Modified exosomes which are genetically engineered exosomes or surface modified exosomes to increase the efficacy of the therapeutic properties can also be considered to target the above concerns. However, the difficulties associated with the exosomes include variations in exosomes heterogenity, isolation protocols, large scale production, etc., and these have to be managed effectively. In this review, we explore exosomes biogenesis, multiple stem cell-derived exosome sources, drug delivery, modified stem cells exosomes, clinical trial of stem cells exosomes, and the related challenges in this domain and future orientation. This article may encourage researchers to explore stem cell-derived exosomes and develop an effective and affordable cancer therapeutic solution.

Prediction and prevention of preterm birth: Quality assessment and systematic review of clinical practice guidelines using the AGREE II framework.

BACKGROUND: Prediction of pregnancies at risk of preterm birth (PTB) may allow targeted prevention strategies. OBJECTIVES: To assess quality of clinical practice guidelines (CPGs) and identify areas of agreement and contention in prediction and prevention of spontaneous PTB. SEARCH STRATEGY: We searched for CPGs regarding PTB prediction and prevention in asymptomatic singleton pregnancies without language restriction in January 2024. SELECTION CRITERIA: CPGs included were published between July 2017 and December 2023 and contained statements intended to direct clinical practice. DATA COLLECTION AND ANALYSIS: CPG quality was assessed using the AGREE-II tool. Recommendations were extracted and grouped under domains of prediction and prevention, in general populations and high-risk groups. MAIN RESULTS: We included 37 CPGs from 20 organizations; all were of moderate or high quality overall. There was consensus in prediction of PTB by identification of risk factors and cervical length screening in high-risk pregnancies and prevention of PTB by universal screening and treatment for asymptomatic bacteriuria, screening and treatment for BV in high-risk pregnancies, and use of preventative progesterone and cerclage. Areas of contention or limited consensus were the role of PTB clinics, universal cervical length measurement, biomarkers and cervical pessaries. CONCLUSIONS: This review identified strengths and limitations of current PTB CPGs, and areas for future research.

Development and Validation of an Outpatient Clinical Predictive Score for the Diagnosis of Duchenne Muscular Dystrophy/Becker Muscular Dystrophy in Children Aged 2-18 Years.

Introduction: There is no bedside clinical examination-based prediction score for Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) in children with neuromuscular diseases (NMDs) presenting with proximal limb-girdle weakness. Methods: We compared the details of 200 cases of lower motor neuron type of weakness and had some proximal limb-girdle muscle weakness and divided them into 2 groups: with/without a confirmed diagnosis of DMD/BMD. We determined the predictive factors associated with a diagnosis of DMD/BMD using multivariate binary logistic regression. We assessed our proposed prognostic model using both discrimination and calibration and subsequently used the bootstrap method to successfully validate the model internally. Results: A total of 121 patients had DMD/BMD and the rest of the patients had other diagnoses. Male gender, presence of Gower's sign, valley sign, toe walking, calf pseudohypertrophy, and tongue hypertrophy were independent predictors for a confirmed diagnosis of DMD/BMD and included in the final CVT2MG score (Calf pseudohypertrophy, Valley sign, Toe walking, Tongue hypertrophy, Male gender, and Gower's sign). The final model showed good discrimination (AUC = 87.4% [95% CI: 80.5-92.3%, P < 0.001]) and calibration (P = 0.57). A score of 6 or above appeared to be the best cutoff for discriminating between the DMD/BMD group and the rest of the group with both sensitivity and specificity of 98%. The interrater reliability was almost perfect between two pediatric neurologists and strong between a pediatric neurologist and a pediatric neurology trainee resident (k = 0.91 and 0.87). Conclusion: The CVT2MG score has good sensitivity and specificity in predicting a confirmed diagnosis of DMD/BMD in subsequent tests.

Sensory processing abilities and their impact on disease severity in children with attention-deficit hyperactivity disorder.

Objectives: Although several studies have shown sensory processing abnormalities in pediatric subjects with attention-deficit hyperactivity disorder (ADHD), there is significant heterogeneity among their results. Materials and Methods: This study was performed to compare the sensory processing abilities of children and adolescents with and without ADHD aged 6-15 years and to correlate the sensory processing problems in these patients, with the symptom profile and severity of ADHD. While child sensory profile-2 (SP-2) was used to assess, the sensory processing abilities of ADHD patients, revised Connor's parent rating scale revised, Malin's intelligence scale for Indian children, grade level assessment device, and child behavior checklist were used to assess ADHD symptom severity, intelligence, learning, and behavioral problems, respectively. Results: A total of 66 ADHD patients enrolled (60 boys), 22 (28%), 7 (9%), and 49 (63%) cases were the ADHD-hyperactive-impulsive (ADHD-HI), ADHD-inattentive, and ADHD-combined (ADHD-C) types, respectively, and 33 typically developing controls. The ADHD patients had a significantly low raw score on most of the factors, sections, and response patterns of SP-2 (P < 0.05), but only four and one ADHD patients had auditory and visual processing scores outside the normal clinical range. There was a trend toward higher scores in the children with ADHD-C and ADHD-HI subtypes. There was a moderate negative correlation between hyperactivity/impulsivity T-score and auditory processing scores in the SP (P < 0.05, r = -0.43). We observed a negative correlation, although weak, between visual processing scores and hyperactivity/impulsivity and a positive correlation between the severity of conduct disorder-related problems, oppositional defiant problems, anxiety problems, and auditory as well as tactile processing scores (P < 0.05). In the quadrant score summary, the scores for all four types, that is, sensory sensitivity, low registration, sensation avoiding, and sensation seeking, were significantly more in the ADHD group, as compared to healthy controls. Conclusion: Sensory processing abilities in ADHD children differ from that of typically developing children when objectively assessed, although most of the ADHD children had scores in the clinically normal range. The sensory processing profile also has an impact on the severity and comorbidity profile of ADHD patients.

A physiologically-based pharmacokinetic model for tuberculosis drug disposition at extrapulmonary sites.

Tuberculosis (TB) is a leading cause of mortality attributed to an infectious agent. TB primarily targets the lungs, but in about 16% cases can affect other organs as well, giving rise to extrapulmonary TB (EPTB). However, an optimal regimen for EPTB treatment is not defined. Although the recommended treatment for most forms of EPTB is the same as pulmonary TB, the pharmacokinetics of EPTB therapy are not as well studied. To address this gap, we formulate a whole-body physiologically-based pharmacokinetic (PBPK) model for EPTB that for the first time includes the ability to simulate drug concentrations in the pleura and lymph node, the most commonly affected sites of EPTB. Using this model, we estimate the time-dependent concentrations, at potential EPTB infection sites, of the following four first-line anti-TB drugs: rifampicin, ethambutol, isoniazid, and pyrazinamide. We use reported plasma concentration kinetics data to estimate model parameters for each drug and validate our model using reported concentration data not used for model formulation or parameter estimation. Model predictions match the validation data, and reported pharmacokinetic parameters (maximum plasma concentration, time to reach maximum concentration) for the drugs. The model also predicts ethambutol, isoniazid, and pyrazinamide concentrations in the pleura that match reported experimental values from an independent study. For each drug, the predicted drug concentrations at EPTB sites are compared with their critical concentration. Simulations suggest that although rifampicin and isoniazid concentrations are greater than critical concentration values at most EPTB sites, the concentrations of ethambutol and pyrazinamide are lower than their critical concentrations at most EPTB sites.

Analysis of spatio-temporal propagation of occipito-frontal spikes in childhood epilepsies by 3D sequential voltage mapping and dipole localization.

OBJECTIVE: We sought to study the spatio-temporal propagation of occipito-frontal spikes in childhood epilepsies by voltage mapping and dipole localization and identify types of occipito-frontal spikes based on onset, propagation, and stability of their dipoles. METHODS: Sleep EEG data of children, aged 1-14 years, with a minimum 1 h of recording from June 2018 to June 2021, were analyzed to identify occipito-frontal spikes. In total, 150 successive occipito-frontal spikes were manually selected from each EEG and using a source localization software were averaged using automated pattern matching with a threshold of 80%, and sequential 3D voltage maps of averaged spike were analyzed. Stability quotient (SQ) was calculated as the total number of averages/150. Stable dipole was defined as SQ ≥ .8. Dipole analysis was performed with principal component analysis using an age-appropriate template head model. RESULTS: Ten children with occipito-frontal spikes were identified; five with self-limited epilepsy with autonomic seizures (SeLEAS) and five with non-SeLEAS epilepsies. Three types of occipito-frontal spikes were identified: (1) narrow occipito-frontal spikes with stable dipoles seen in all five children with SeLEAS which were "apparently" synchronous and bilateral clone-like with an occipito-frontal interval of 10-30 ms and a homogeneous propagation pattern from a unilateral medial parieto-occipital region to an ipsilateral mesial frontal region; (2) wide occipito-frontal spikes with stable dipoles seen in one child with non-SeLEAS and developmental and/or epileptic encephalopathy with spike-wave activation in sleep (D/EE-SWAS) with an occipito-frontal interval of 45 ms, caused by focal spike propagation from a deeper temporal focus to ipsilateral peri-rolandic cortex; and (3) wide occipito-frontal spikes with unstable dipoles seen in four children with non-SeLEAS lesional epilepsies with an occipito-frontal latency of >50 ms and heterogeneous propagation patterns with poor intra-individual dipole stability. SIGNIFICANCE: We successfully identified different types of occipito-frontal spikes in childhood epilepsies. Although the term "occipito-frontal" is used to describe these spikes on the 10-20 EEG system, true propagation from occipital to frontal regions is not necessary. It is possible to differentiate idiopathic from symptomatic cases by analyzing the stability quotient and the occipito-frontal interval of occipito-frontal spikes.

Nutritional vitamin B12 deficiency-associated Infantile epileptic spasms syndrome: Clinico-neurophysiological presentation, response to treatment, and neurodevelopmental outcome.

INTRODUCTION: Nutritional vitamin B12 deficiency has been shown to cause Infantile epileptic spasms syndrome (IESS) in infants in anecdotal studies. METHODS: In this retrospective cohort study, we intended to study the clinical presentation, neurophysiological, laboratory abnormalities, treatment, and neurodevelopmental outcome at 6-months in infants presenting with IESS secondary to nutritional vitamin B12 deficiency (NVBD) and to compare these variables from the rest of the infants with IESS without vitamin B12 deficiency. We included only spasm-free cases or those who showed at least a 50% reduction in spasm frequency on D7 after starting oral/parenteral vitamin B12. We used well-validated measurement tools like the Developmental Assessment Scale for Indian Infants (DASII), Child Feeding Index (CFI), Burden of amplitudes and epileptiform discharges (BASED) score, countable Hypsarrhythmia paroxysm index (cHPI), durational Hypsarrhythmia paroxysm index (dHPI), and Early childhood epilepsy severity scale (E-CHESS) score for documenting these variables. RESULTS: Data from 162 infants with IESS (21 caused by NVBD) were included in our study. The NVBD group had more patients residing in the rural region, with lower socioeconomic status, vegetarian mothers and poor complementary feeding index (p<0.001 for all). The NVBD group also had less number of patients requiring antiseizure medications (ASMs) and hormonal therapy(p<0.001), remained seizure free at six months (p=0.008), lower number of clusters per day (p=0.02) and the number of spasms per clusters at presentation (p=0.03), lower BASED score (p=0.03) and cHPI, dHPI at presentation (p<0.001). All of them remained spasm-free, with normal electroencephalogram at 6-months. Development quotient at baseline, at 6-months, and improvement in development quotient between these two-time points were more in the vitamin B12 deficiency group (p<0.001). All of them had clinical features of pre-ITS (infantile tremor syndrome) or ITS and it was found to be the only independent predictor of NVBD in infants with IESS. Mothers of all these infants had low serum vitamin B12 levels (<200 pg/ml). CONCLUSIONS: Nutritional vitamin B12 deficiency may cause IESS in infants. Hence, vitamin B12 deficiency needs to be ruled out in patients with IESS without any definite etiology.

Efficacy of a pre-specified timeline-based treatment protocol in children with acute repetitive seizures or seizure clusters.

Objectives: Acute repetitive seizures (ARSs) are one of the few commonly encountered neurological emergencies in children. There is a need for an appropriate timeline-based treatment protocol, which will be shown to be safe and efficacious in a clinical study. Materials and Methods: This was a retrospective chart review to determine the efficacy of a pre-specified treatment protocol for the management of ARSs in children aged 1-18 years. The treatment protocol was specifically applied in children with a diagnosis of epilepsy and not critically ill, who met the criteria for ARSs, with the exemption of new onset of ARSs. The first tier of treatment protocol focused on intravenous lorazepam, optimization of dose of existing anti-seizure medications (ASMs), and control of triggers like acute febrile illness, while second-tier focused on adding one or two additional ASMs, commonly used in cases with seizure clusters or status epilepticus. Results: We included the first 100 consecutive patients (7.6 ± 3.2 years, 63% boys). Our treatment protocol was successful in 89 patients (58 and 31 required first-tier and second-tier treatment). The absence of pre-existing drug-resistant epilepsy and the presence of acute febrile illness as a triggering factor (P = 0.02 and 0.03) were associated with the success of the first tier of the treatment protocol. Excessive sedation (n = 29), incoordination (n = 14), transient gait instability (n = 11), and excessive irritability (n = 5) were the most common adverse effects observed during the initial 1 week. Conclusion: This pre-specified treatment protocol is safe and efficacious in controlling ARSs in cases with established epilepsy who are not critically sick. External validation from other parts of the world/centers and a more diverse epilepsy population are required before generalizing the protocol into clinical practice.

Prevalence, nature, and severity of the psychiatric comorbidities and their impact on quality of life in adolescents with Juvenile myoclonic epilepsy.

INTRODUCTION: Adults with Juvenile myoclonic epilepsy (JME) are at increased risk for psychiatric comorbidities, personality traits, and abnormality in executive function. But studies on adolescents and their impact on quality of life are scarce in the literature. MATERIALS AND METHODS: This cross-sectional study was performed between August 2019 and October 2022 to compare the prevalence of psychiatric comorbidities in adolescents with JME and age and gender-matched healthy controls. After completing DSM-5 Structured Clinical Interview (SCID-5) initially in all patients, we measured the severity of individual psychiatric problems like anxiety, depression, and somatic symptoms by using an appropriate psychometric scale. We also measured both groups' intelligence quotient (IQ), executive function, and quality of life. RESULTS: One hundred patients with JME (14.3 ± 2.5 years, 48 boys) and 100 controls were enrolled. Psychiatric disorders were observed in 46% of JME and 6% of controls (p < 0.01). Psychiatric comorbidities noted in the patients with JME were: somatic symptom and related disorders(n = 14), anxiety (n = 13), adjustment disorders (n = 12), depression (n = 11), oppositional defiant disorder (n = 6), conduct disorder (n = 5), anorexia nervosa (n = 3), narcissistic (n = 3), histrionic (n = 1), substance-related disorder (n = 1), borderline (n = 2) and antisocial personality disorder (n = 2). The prevalence of depressive disorders, anxiety disorders, adjustment disorders, somatic symptoms, related disorders, and any personality disorder was significantly more in the JME group (p < 0.01 for all). Female gender, higher Epilepsy Stigma Scale score, and lower Epilepsy Outcome Expectancy Scale were significantly associated with depressive disorders (p = 0.04, 0.03, 0.03 respectively). Similarly, for anxiety, only female gender and lower Epilepsy Outcome Expectancy Scale were significant associated factors (p = 0.03, 0.02 respectively). CONCLUSIONS: Psychiatric disorders like anxiety, depression, and personality disorders are more frequent in adolescents with JME than in controls.

Cost-effectiveness of adrenocorticotropic hormone injection and oral prednisolone in patients with West syndrome: A comparative analysis.

Objectives: This study aims to compare the cost-effectiveness of oral prednisolone and adrenocorticotropic hormone injection in West syndrome patients, the two most common hormonal therapies used for this condition. Materials and Methods: In this prospective and observational study, we documented sociodemographic, epilepsy, and development-related variables at baseline and up to 6 months after starting hormonal therapy, in all consecutive eligible patients of WS between August 2019 and June 2021, apart from the direct medical and non-medical costs and indirect health-care costs. We selected cost per quality-adjusted life-year (QALY) gained, per one patient with spasm freedom, one positive responder (>50% reduction in spasms), one relapse-free patient, and one patient with development gain. We determined whether incremental cost-effectiveness ratio for these parameters crossed the threshold value in base-case analysis and alternate scenario analysis. Results: Out of 52 patients screened, 38 and 13 patients enrolled in ACTH and prednisolone group. On D28, 76% and 71% achieved spasm cessation (P = 0.78) and the total cost of treatment was INR 19783 and 8956 (P = 0.01), in ACTH and prednisolone group respectively. For all pre-specified parameters, the cost/effectiveness ratios including cost/QALY gain were higher in ACTH group and the corresponding ICER values for all these parameters crossed the threshold cost value of INR 148,777 in base-case analysis and also in alternative scenario analysis. Conclusion: Treatment with oral prednisolone is more cost-effective as compared to ACTH injection for children with WS.

Prevalence, severity, and predictors of malnutrition in Indian children with cerebral palsy and their impact on health-related quality of life.

Although several studies have shown that undernutrition is frequent in children with cerebral palsy (CP), studies determining predictors of undernutrition and its impact on health-related quality of life (HRQoL) are scarce. This study aimed to assess the prevalence, severity, and predictors of malnutrition in children with CP and its impact on quality of life. This prospective study was performed between August 2019 and December 2021 in children with a clinical diagnosis of CP aged 2-18 years. We also intended to determine the socio-demographic and clinical predictors of undernutrition in these children and its impact on HRQoL, measured by the cerebral palsy quality of life (CPQoL)-Primary Caregiver reported version. Out of 569 (5.4 ± 2.8 years of age, 74% boys) children with CP, 71%, 44%, and 72% children were underweight, wasted, and stunted respectively, whereas 22%, 11%, and 21% were severely underweight, wasted and stunted respectively. Lower socioeconomic status, higher Gross Motor Function Classification System, and Manual Ability Classification System level were found to be significantly associated with the severity of stunting and underweight (p < 0.05), but not with wasting. CPQoL score in children with CP aged > 4 years was lower in patients with severe wasting, stunting, and underweight, as compared to their rest of the counterparts when adjusted for socio-demographic and other clinical variables (p < 0.05).  Conclusion: Chronic undernutrition is more common than severe acute malnutrition in children with CP. The severity of undernutrition is an important predictor of impaired HRQoL in children with CP. What is Known: • Several studies have shown that undernutrition is frequent in children with cerebral palsy; however, studies determining predictors of undernutrition and its impact on health-related quality of life are scarce. What is New: • Our study identifies that lower socioeconomic status, higher Gross Motor Function Classification System, and Manual Ability Classification System level are significantly associated with the severity of stunting and being underweight. • Chronic undernutrition is more common than severe acute malnutrition in children with cerebral palsy. Its severity is an important predictor of impaired health-related quality of life in children with cerebral palsy.

Behavioral problems in infants and young children with spinal muscular atrophy and their siblings: A cross-sectional study.

INTRODUCTION: Older children and adults with spinal muscular atrophy (SMA) have been shown to have more anxiety, depression, and other behavioral problems in a few studies. But no similar studies have been performed in infants and young children with SMA. METHOD: Behavioral co-morbidities of young children with SMA were compared with healthy and children with chronic non-neurological illness control group. Infant Behavior Questionnaire-Revised (IBQ-R) and parent-report version of chid behavior checklist (CBCL) were used for infants and preschool-age children respectively. RESULTS: A total of 35 SMA children (age at symptom onset-5.9 ± 2.8 months, at enrolment-21.4 ± 7.1 months, 65% boys, 11, 19 and 5 were SMA 1, 2 and 3 respectively) and 24 siblings (38.6 ± 11.2 months, 71% boys) were enrolled. We also enrolled 15 children with nephrotic syndrome as age and gender matched control to SMA children in age-group 2-5 years (27.7 ± 9.1 months, 67% boys). In infants with SMA, the scale scores of IBQ-R were significantly higher for distress to limitation, fear, sadness, and falling reactivity/rate of recovery from distress (p = 0.005; 0.03; 0.001, and 0.04) and lower for soothability as compared to healthy control group (p = 0.04). Similarly, for the three dimensions of temperament computed from these 13 domains, the mean scale score for surgency/extraversion was lower and negative affectivity was higher (p = 0.04 and 0.03), in infants with SMA as compared to healthy controls. For preschool age group, the internalizing problem scores (p = 0.009 and 0.03) and stress problem scores (p = 0.002 and 0.04) were higher in the SMA group, as compared to both the healthy control group and diseased control group. While assessing the syndrome scale scores, the score was higher for emotionally reactive (p = 0.0002 and 0.01) and anxious domains (p < 0.0001 and p = 0.0002) compared to both healthy and diseased control groups. CONCLUSION: Infants and young children with SMA suffer from increased internalizing problems like anxiety, depression and probably their healthy siblings are also at increased levels of stress, depicted by increased somatic complaints.

The use of virtual reality in the rehabilitation of aphasia: a systematic review.

PURPOSE: This systematic review explored how virtual reality (VR) has been used to rehabilitate aphasia. MATERIALS AND METHODS: Empirical studies were included where VR was used to target language, well-being, or quality of life in adults with acquired language impairment. Degenerative communication disabilities were excluded. Seven health databases were searched in October 2021. Risk of Bias was assessed using published checklists and completeness of intervention reporting evaluated. Narrative synthesis described forms of VR, rationales given, outcome measures, communication functions targeted, characteristics of interventions, and outcomes achieved within the framework of impairment, activity, and participation. RESULTS: Fourteen studies, involving 229 participants, met the criteria. The studies employed four forms of VR with various rationales given. Interventions used published and novel protocols. Primary outcomes targeted language impairment (12/14), activity (1/14), and well-being (1/14) and achieved positive outcomes in impairment and activity. All studies were exploratory. Risk of bias was high. Findings are discussed in the context of gains achieved by VR in other health contexts and the multi-user gaming literature. CONCLUSIONS: Uses of VR in aphasia rehabilitation described in the literature are limited. Most applications target the remediation of language impairments. Opportunities to address activity, participation, and wider aspects of well-being are rare.IMPLICATIONS FOR REHABILITATIONResearch documenting the use of virtual reality (VR) to rehabilitate aphasia is limited and exploratory, so does not yet offer clear guidance for clinicians.Many of the identified studies have used known published protocols (e.g., naming therapy or scripts therapy) delivered through the novel VR format and focus on language impairment outcomes.VR offers clinicians a unique opportunity to address communication activity and participation through the use of multi-user virtual worlds, but this has only been explored by only two research teams.

Validity and prognostic utility of clinical assessment scale for autoimmune encephalitis (CASE) score in children with autoimmune encephalitis.

INTRODUCTION: The clinical assessment scale for autoimmune encephalitis (CASE) is a recently developed and validated scale to rate the severity of autoimmune encephalitis (AE) in adults. But it is yet to be validated in pediatric AE cases. METHODS: In a prospective observational study, we determined the validity and prognostic utility of CASE in the pediatric population with a diagnosis of probable or definite AE. We also determined clinical, neuroimaging, or laboratory-based prognostic factors for favorable clinical outcomes at 3 months after presentation. We used weighted kappa statistics and the intra-class correlation coefficient of individual item scores and total scores for determining inter-observer and intra-observer reliability respectively. RESULTS: We enrolled a total of 54 patients (28 girls, probable [45%] or definite [55%] AE). Functional status score (FSS), CASE score, and other scores showed significant improvement at the time of discharge and 3-months, as compared to baseline (p < 0.0001). The intra-observer and interobserver reliability of the total scores was excellent (k = 0.94 and 0.95 respectively). CASE was also found to have good internal consistency (Cronbach-α = 0.83). The corrected item-total correlations of all items were >0.40. The correlation between the total CASE score and FSS score at admission, at discharge, and at 3 months was strong (r = 0.90, 0.92, and 0.94, p < 0.001). In multivariate analysis, only seropositivity or definite AE and CASE score at baseline was found to be significant predictive factors for functional status at 3 months (p = 0.03, 0.01). CONCLUSION: CASE score can be used for monitoring the severity of pediatric AE patients. It also has prognostic usefulness for predicting functional independence on follow-up.

Voice Related Coping in Professional Voice Users-A Systematic Review.

OBJECTIVES: This systematic review explored coping with voice problems in professional voice users. The objectives were to: 1) evaluate how voice-related coping is assessed in professional voice users 2) investigate how they cope with voice problems, and 3) identify factors associated with voice-related coping. DESIGN: Systematic review. METHODS: A systematic literature search of ten electronic databases using both EBSCOhost and OVID online platforms was conducted following the Preferred Reporting Items for Systematic Reviews (PRISMA) guidelines. Only peer-reviewed articles which assessed coping in the context of voice problems in professional voice users were included. Methodological quality was assessed using Johanna-Briggs Institute Critical Appraisal checklists. Data analysis was conducted using narrative synthesis. RESULTS: Following deduplication, abstract and full-text screening, seven articles were included in the review. All participants (n=2484) were teachers; no other professional voice users were covered. 98% of the cases studied were females. The tools used to assess voice-related coping were Utrecht Coping List (UCL) and Voice Disability Coping Questionnaire (VDCQ). Studies which used UCL reported a passive coping pattern in teachers with high vocal handicap whereas VDCQ showed increased use of social support. Factors associated with coping were not examined by any of the studies. CONCLUSION: Seeking social support was highlighted as a frequently used coping strategy across studies and measures. Teachers with high vocal handicap used a passive coping pattern and active coping styles were not significantly used. Current evidence does not sufficiently specify factors affecting coping in professional voice users. More research on voice-related coping involving all professional voice users is warranted to identify associated factors and further ascertain its influence on vocal health.

Development and Validation of a Prognostic Model and Bedside Score for the Neurological Outcome in Children with Tuberculous Meningitis.

Only a few studies have explored prognostic factors for tuberculous meningitis (TBM) in children, and an easily applicable bedside prognostic score for TBM has not been developed yet. We compared the sociodemographic, clinical, radiological, and cerebrospinal fluid parameters in the cohort of 94 TBM cases aged 1 to 18 years, with at least 6 months of completed follow-up and determined the prognostic factors associated with poor functional outcome. We assessed our proposed prognostic model using both discrimination and calibration and subsequently used the bootstrap method to validate the model internally. We finally derived an easily applicable bedside prognostic score by rounding off the regression coefficients to the nearest integers. A total of 39 (41%) and 55 (59%) patients had poor and good functional outcomes, respectively, at the end of 6 months (12 died, 13%). In multivariate analysis, a high baseline Pediatric Cerebral Performance Category (PCPC) score, brain infarction in neuroimaging, tonic motor posturing, younger age, and stage III TBM were independent predictors of poor functional outcomes. The final model showed good discrimination (area under the curve = 88.2%, P < 0.001) and good calibration (Hosmer-Lemeshow test, P = 0.53). Bootstrapping also confirmed the internal validity of this model. The PITAS (PCPC score [P], brain infarction in neuroimaging [I], tonic motor posturing [T], age [A], and stage of TBM [S]) score developed from this model has a score ranging from 0 to 12, with a higher score predicting a higher risk of poor functional outcome. The PITAS score performed better than medical research council staging alone in predicting poor functional outcomes (area under the curve = 87.1% versus 82.3%). Our study's PITAS score, developed and internally validated, has good sensitivity and specificity in predicting poor functional outcomes in pediatric TBM cases at 6 months.

Performance of a pediatric adaptation of the RITE2 and APE2 scores in children with autoimmune epilepsy: P-RITE2 and P-APE2 scores.

INTRODUCTION: In adult patients with epilepsy, predictive models have been developed and validated for anticipating a favorable response to immunotherapy. However, no such model has been evaluated in children. METHODS: This retrospective cohort study intended to assess the performance of a pediatric adaptation of the Response to Immunotherapy in Epilepsy (RITE2) score: P-RITE2 score and Antibody Prevalence in Epilepsy (APE2) score: P-APE2 score in patients aged 1-18 years. We included data of those patients who had epilepsy duration of not more than 12 months, no other known etiology (e.g., genetic, metabolic, neoplastic, or structural causes), and tested for neural-specific antibody in cerebrospinal fluid or serum for P-APE2 score and only those who received immunotherapy for P-RITE2 score. We added cognitive dysfunction, speech dysfunction, sleep disturbance, and movement disorder to the original scores to increase specificity for pediatric autoimmune epilepsy. We assumed at least a 50% reduction in seizure frequency at 6 months as a favorable response to immunotherapy. Cut-offs were chosen for both scores to maximize true positives and minimize false negatives using ROC curves. RESULTS: We included data from a total of 237 patients with epilepsy (10.4 ± 2.5 years, 129 boys, 54%), out of which, 25 (10.5%, 13 girls, 52%) tested positive for autoantibodies. The median P-APE2 score in the subgroup with and without antibody positivity were 7 (IQR: 5-11) and 2 (IQR: 1-5), respectively (p<0.0001). ROC analysis of the P-APE2 score determined an AUC of 0.96. The sensitivity and specificity values of the P-APE2 score ≥6 were 94% and 92%, respectively. A total of 162 patients (10.3 ± 2.5 years, 88 boys, 54%) received immunotherapy, out of which, 101 had a favorable response at 6 months. The median P-RITE2 score in the subgroup with and without favorable response following a trial of immunotherapy were 10 (IQR: 6-17) and 3 (IQR: 1-6), respectively (p<0.0001). ROC analysis of the P-RITE2 score determined an AUC of 0.96. The sensitivity and specificity values of P-RITE2 score ≥8 were 95% and 93%, respectively. The AUC of both these ROCs was significantly higher than the AUC of ROCs for original scores in our cohort. CONCLUSION: The P-RITE2 and P-APE2 scores can be used to predict the response to immunotherapy and predict autoantibody positivity in children with epilepsy with/without encephalopathy or cognitive dysfunction.