Boston Children's Hospital

Background Tuberous Sclerosis Complex (TSC) is a rare genetic condition caused by mutation to TSC1 or TSC2 genes, with a population prevalence of 1/7000 births. TSC manifests behaviorally with features of autism, epilepsy, and intellectual disability. Resting state electroencephalography (EEG) offers a window into neural oscillatory activity and may serve as an intermediate biomarker between gene expression and behavioral manifestations. Such a biomarker could be useful in clinical trials as an endpoint or predictor of treatment response. However, seizures and antiepileptic medications also affect resting neural oscillatory activity and could undermine the utility of resting state EEG features as biomarkers in neurodevelopmental disorders such as TSC. Methods This paper compares resting state EEG features in a cross-sectional cohort of young children with TSC (n = 49, ages 12–37 months) to 49 age- and sex-matched typically developing controls. Within children with TSC, associations were examined between resting state EEG features, seizure severity composite score, and use of GABA agonists. Results Compared to matched typically developing children, children with TSC showed significantly greater beta power in permutation cluster analyses. Children with TSC also showed significantly greater aperiodic offset (reflecting nonoscillatory neuronal firing) after power spectra were parameterized using SpecParam into aperiodic and periodic components. Within children with TSC, both greater seizure severity and use of GABAergic antiepileptic medication were significantly and independently associated with increased periodic peak beta power. Conclusions The elevated peak beta power observed in children with TSC compared to matched typically developing controls may be driven by both seizures and GABA agonist use. It is recommended to collect seizure and medication data alongside EEG data for clinical trials. These results highlight the challenge of using resting state EEG features as biomarkers in trials with neurodevelopmental disabilities when epilepsy and anti-epileptic medication are common.

Unrecognized clinical deterioration in patients on general hospital wards (also known as failure to rescue) is associated with very high morbidity and mortality around the world. Data surrounding these deteriorations and their outcome is severely underreported in sub-Saharan African, but the scarce data available suggest unacceptably high incidence of cardiopulmonary arrests, many of which are not witnessed. Rapid response programs have been shown to mitigate the risks of failure to rescue in many parts of the world. With commitment and careful planning, similar programs are possible in sub-Saharan Africa as evidenced by recent successful implementation of a rapid response program at a teaching hospital in Lagos, Nigeria. The successful implementation of this program required close attention to necessary system processes and holds as an example for wider implementation in hospitals in other sub-Saharan African countries.

Background Anteroposterior (AP) and lateral radiographs often underestimate displacement in medial epicondyle fractures, further complicating the already debated operative indications. The radiocapitellar (RC) view is an alternative radiograph that allows for the separation of the humeroradial and humeroulnar joints. This study investigates the utility of the RC view in measuring displacement and identifying the need for operative intervention in pediatric medial epicondyle fractures. Methods A retrospective analysis was conducted on pediatric patients who presented to our institution with a medial epicondyle fracture treated operatively from 2015 to 2022 and received initial AP and RC radiographs. Fracture displacement was measured by 3 orthopaedic surgeons using the corresponding point measurement method and inter/intra-rater reliability was computed. A fracture >5 mm was considered to be within the threshold for recommendation of operative treatment. McNemar test was used to assess differences in sensitivity in detecting operative fractures between AP and RC radiographs, with a P -value of < 0.05 considered significant. Results A total of 45 patients met the inclusion criteria. The RC view had significantly higher sensitivity in identifying fractures greater than the operative threshold of 5 mm compared with the AP view (93.3% vs. 68.9%, P =0.0127), and on average, measured 2.5 mm more displacement ( P <0.001) than the corresponding AP view. AP and RC radiographs both measured >5 mm of displacement in 62.2% (28/45) of fractures, with 6.7% (3/45) determined as >5 mm by AP view and ≤5 mm by RC view. 31.1% (14/45) of fractures were measured to be >5 mm by RC view and ≤5 mm by AP view. Conclusion The RC view significantly increases sensitivity in detecting the 5 mm displacement threshold for operative treatment of pediatric medial epicondyle fractures due to improved visualization of fracture displacement. Level of Evidence Level III, diagnostic study.

BACKGROUND Accurate assessment of oxygen delivery relative to oxygen demand is crucial in the care of a critically ill patient. The central venous oxygen saturation (Sv o 2 ) enables an estimate of cardiac output yet obtaining these clinical data requires invasive procedures and repeated blood sampling. Interpretation remains subjective and vulnerable to error. Recognition of patient’s evolving clinical status as well as the impact of therapeutic interventions may be delayed. OBJECTIVE The predictive analytics algorithm, inadequate delivery of oxygen (ID o 2 ) index, was developed to noninvasively estimate the probability of a patient’s Sv o 2 to fall below a preselected threshold. DERIVATION COHORT A retrospective multicenter cohort study was conducted using data temporally independent from the design and development phase of the ID o 2 index. VALIDATION COHORT A total of 20,424 Sv o 2 measurements from 3,018 critically ill neonates, infants, and children were retrospectively analyzed. Collected data included vital signs, ventilator data, laboratory data, and demographics. PREDICTION MODEL The ability of the ID o 2 index to predict Sv o 2 below a preselected threshold (30%, 40%, or 50%) was evaluated for discriminatory power, range utilization, and robustness. RESULTS Area under the receiver operating characteristic curve (AUC) was calculated for each index threshold. Datasets with greater amounts of available data had larger AUC scores. This was observed across each configuration. For the majority of thresholds, Sv o 2 values were observed to be significantly lower as the ID o 2 index increased. CONCLUSIONS The ID o 2 index may inform decision-making in pediatric cardiac critical care settings by providing a continuous, noninvasive assessment of oxygen delivery relative to oxygen demand in a specific patient. Leveraging predictive analytics to guide timely patient care, including support for escalation or de-escalation of treatments, may improve care delivery for patients and clinicians.

Erythromelalgia is a rare, chronic pain disorder characterized by the triad of intense burning sensation, warmth, and redness, primarily involving the hands and feet, and usually alleviated by cold and worsened by heat. The objective of this scoping review was to: 1) map the existing literature on erythromelalgia in youth, 2) identify knowledge gaps, and 3) inform directions for future research in pediatric erythromelalgia. One hundred and sixty-seven studies reporting 411 cases of childhood-onset erythromelalgia were identified. Variability was found in reporting of clinical symptoms, the clinical presentations and diagnostic criteria used for classification of erythromelagia, the clinical assessments and investigations performed, and the types of interventions and management plans utilised. While factors to aid early recognition and optimize management have been identified, there are also significant gaps for future research to address. Ongoing efforts to develop a multicenter registry of pediatric erythromelalgia cases, with standardized data collection and reporting, will be beneficial to establish consensus recommendations for the diagnosis and management of pediatric erythromelalgia. Impact This scoping review maps the existing literature on pediatric erythromelalgia. Variability was found in reporting of clinical symptoms, the clinical presentations and diagnostic criteria used for classification of erythromelagia, the clinical assessments and investigations performed, and the types of interventions and management plans utilised. The development of an international registry would immensely benefit multidisciplinary experts involved in the care of pediatric erythromelalgia and those with lived experience.

Background Globally, most children seek emergency care at general rather than specialized pediatric emergency departments. There remains significant variation in the provision of pediatric emergency care, particularly in resource-constrained settings. The objective of this study is to pilot a self-assessment tool to evaluate pediatric emergency care capabilities in low- and middle-income country (LMIC) hospitals on the African Continent. Methods This was a prospective cross-sectional descriptive study using a convenience sample of sub-Saharan African hospitals. The assessment tool was developed by operationalizing the technical contents of existing standards and guidelines from international bodies including the World Health Organization and International Federation of Emergency Medicine. The pilot was conducted at emergency departments located across different regions on the African continent. Descriptive statistics were used to evaluate different domains of pediatric emergency care capabilities including pediatric triage, protocols, staffing, training, equipment, consumables, and medicines. Results Sixteen hospitals with emergency departments completed the assessment tool (participation rate of 76%). The hospitals were in nine different countries across four regions of sub-Saharan Africa. National/academic hospitals comprised 56.3% of the participating hospitals. The majority, 44%, of these hospitals saw pediatric patient volumes of 2,000–4,999 patients per year. Dedicated pediatric triage spaces and resuscitation spaces were available at 37.5% and 56.3%, respectively. Formal pediatric resuscitation guidelines were used at 62.5%. Doctors on the self-assessment teams came from primarily pediatrics and general practitioner training backgrounds (both 68.8%). Basic respiratory and airway support equipment (e.g. oxygen, bag-valve mask devices) were available in all participating hospitals, whereas advanced airway equipment (e.g. pediatric intubation equipment) was available in 37.5% of hospitals. Most medicines from the World Health Organization Essential Medicines list were available at participating hospitals. Conclusions To date, this is the first assessment tool dedicated to the comprehensive evaluation of pediatric emergency care in LMICs. This pilot provides a first approach to evaluate pediatric emergency healthcare capabilities in the hospital setting with future directions to improve the tool based on qualitative feedback.

Pathogenic variants in HMGCR were recently linked to a limb‐girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin‐associated myopathy (SAM) and autoimmune anti‐HMGCR myopathy, are not inherited in a Mendelian pattern. Statins inhibit HMGCR activity to generate their cholesterol‐lowering effects and are known to cause multiple types of adverse effects on skeletal muscle, while the antibodies associated with anti‐HMGCR myopathy specifically target this enzyme. The mechanism linking pathogenic variants in HMGCR with skeletal muscle dysfunction is unclear. We knocked down Hmgcr in mouse skeletal myoblasts, knocked down hmgcr in Drosophila, and expressed three pathogenic HMGCR variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in Hmgcr knockdown mouse myoblasts. Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle‐specific knockdown of hmgcr in Drosophila led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not. These results suggest that the three HMGCR‐related muscle diseases share disease mechanisms related to skeletal muscle development.

There is a growing interest in using diffusion MRI to study the white matter tracts and structural connectivity of the fetal brain. Recent progress in data acquisition and processing suggests that this imaging modality has a unique role in elucidating the normal and abnormal patterns of neurodevelopment in utero. However, there have been no efforts to quantify the prevalence of crossing tracts and bottleneck regions, important issues that have been investigated for adult brains. In this work, we determined the brain regions with crossing tracts and bottlenecks between 23 and 36 gestational weeks. We performed probabilistic tractography on 62 fetal brain scans and extracted a set of 51 distinct white matter tracts, which we grouped into 10 major tract bundle groups. We analyzed the results to determine the patterns of tract crossings and bottlenecks. Our results showed that 20%–25% of the white matter voxels included two or three crossing tracts. Bottlenecks were more prevalent. Between 75% and 80% of the voxels were characterized as bottlenecks, with more than 40% of the voxels involving four or more tracts. These results highlight the relevance of these regions to key developmental processes, specifically, the dispersion of projection fibers, the protracted growth of commissural pathways, and the emergence of association tracts that contribute to the formation of complex intersection regions. These developmental interactions lead to a high prevalence of crossing fibers and bottleneck areas, reflecting the intricate organization required for establishing structural and functional connectivity. Additionally, our results highlight the challenge of fetal brain tractography and structural connectivity assessment and call for innovative image acquisition and analysis methods to mitigate these problems.

Spatial molecular profiling has provided biomedical researchers valuable opportunities to better understand the relationship between cellular localization and tissue function. Effectively modeling multimodal spatial omics data is crucial for understanding tissue complexity and underlying biology. Furthermore, improvements in spatial resolution have led to the advent of technologies that can generate spatial molecular data with subcellular resolution, requiring the development of computationally efficient methods that can handle the resulting large-scale datasets. MISO (MultI-modal Spatial Omics) is a versatile algorithm for feature extraction and clustering, capable of integrating multiple modalities from diverse spatial omics experiments with high spatial resolution. Its effectiveness is demonstrated across various datasets, encompassing gene expression, protein expression, epigenetics, metabolomics and tissue histology modalities. MISO outperforms existing methods in identifying biologically relevant spatial domains, representing a substantial advancement in multimodal spatial omics analysis. Moreover, MISO’s computational efficiency ensures its scalability to handle large-scale datasets generated by subcellular resolution spatial omics technologies.

Background Pediatric respiratory syncytial virus (RSV)-related acute lower respiratory tract infection (LRTI) commonly requires hospitalization. The Clinical Progression Scale Pediatrics (CPS-Ped) measures level of respiratory support and degree of hypoxia across a range of disease severity, but it has not been applied in infants hospitalized with severe RSV-LRTI. Methods We analyzed data from a prospective surveillance registry of infants hospitalized for RSV-related complications across 39 U.S. PICUs from October through December 2022. We assigned CPS-Ped (0=discharged home at respiratory baseline to 8=death) at admission, days 2-7,10, and 14. We identified predictors of clinical improvement (CPS-Ped≤2 or 3-point decrease) by day 7 using multivariable log-binomial regression models and estimated the sample size (80% power) to detect 15% between-group clinical improvement with CPS-Ped versus hospital length of stay (LOS). Results Of 585 hospitalized infants, 138 (23.6%) received invasive mechanical ventilation (IMV). Of the 49 (8.4%) infants whose CPS-Ped score worsened by 2 points after admission, one died. Failure to clinically improve by day 7 occurred in 205 (35%) infants and was associated with age <3 months, prematurity, underlying respiratory condition, and IMV in the first 24 hours in the multivariable analysis. The estimated sample size per arm required for detecting a 15% clinical improvement in a potential study was 584 using CPS-Ped clinical improvement versus 2,031 for hospital LOS. Conclusions CPS-Ped can be used to capture a range of disease severity and track clinical improvement in infants who develop RSV-related critical illness and could be useful for evaluating therapeutic interventions for RSV.