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Peripheral Neuropathy as an Early Marker in Newborn-Screened Krabbe Disease: The Value of Pre-Confirmatory Neurophysiological Testing
No full textINTRODUCTION: Krabbe disease, or globoid cell leukodystrophy, is a rare autosomal recessive neurodegenerative disorder characterized by deficient activity of the lysosomal enzyme galactosylceramidase (GALC). This deficiency leads to the toxic accumulation of psychosine, resulting in progressive demyelination and neuronal death. The clinical manifestations of Krabbe disease progress through different stages, starting with irritability, stiffness, and feeding difficulties, followed by myoclonic-like jerks in the upper and lower extremities, hypertonicity, and eventually severe hypotonia and lack of movement. METHODS: This case report features two newborn screening patients with (NBS)-positive Krabbe disease who underwent electrodiagnostic (EDX) testing and hematopoietic stem cell transplantation (HSCT) soon after birth. RESULTS: The EDX results indicated severe sensory-motor polyneuropathy of mixed demyelinating and axonal types. Biochemical analyses confirmed significantly reduced GALC enzyme activity and elevated psychosine levels in both cases. Genetic testing identified pathogenic variants, including compound heterozygous deletions and mutations within the GALC gene. At 6-month follow-up post-HSCT, one patient showed age-appropriate milestones and improvement in motor amplitudes on repeat nerve conduction studies. DISCUSSION: EDX testing is helpful in assessing NBS-positive Krabbe disease before confirmatory testing results become available. In conjunction with genetic confirmation and GALC enzyme levels, EDX test results were useful to counsel families that their seemingly normal newborn has severe disease and facilitated discussion toward timely treatment with HSCT. We suggest that EDX be included in the initial and follow-up evaluation of patients with Krabbe disease undergoing HSCT
Intermittent hypoxia and caffeine in infants born preterm: the ICAF Randomized Clinical Trial
No full textOBJECTIVE: To determine whether extending caffeine therapy through 43 weeks\u27 postmenstrual age (PMA) decreases intermittent hypoxia (IH) in convalescing preterm infants. Secondary objectives were to assess caffeine effects on changes in inflammation-related plasma biomarkers and brain MRI. DESIGN: Multicentre masked randomised trial. SETTING: 16 US hospitals. PATIENTS: Infants at \u3c30 weeks + 6 days gestational age on caffeine between 32 weeks and 36+5 days PMA in room air with routine caffeine discontinuation prior to 36 weeks +6 days. INTERVENTION: Randomisation to caffeine or placebo and treated through 42 completed weeks. Pulse oximetry was recorded from enrolment through 1 week after stopping study drug. Blood for 12 inflammation-related biomarkers obtained at enrolment and 38 weeks\u27 PMA and brain imaging after enrolment or \u3c3 days of randomisation, and study end. MAIN OUTCOME MEASURE: Seconds/hour of oxygen saturation \u3c90% from randomisation to study end. RESULTS: Randomised 160 subjects, 78 placebo, 82 caffeine. IH was less at every PMA with caffeine treatment from 34 (172.7 (123.4, 241.7); 84.7 (64.4, 111.4, p\u3c0.01) through 41 weeks (73.0 (51.3, 103.7); 26.6 (18.5, 38.2, p\u3c0.001). Adjusted TNF-α levels were 23% lower at follow-up in the caffeine group compared with placebo (p\u3c0.02), without other biomarker differences. Paired brain imaging found no significant differences. CONCLUSIONS: Extended caffeine reduced the burden of IH in very preterm infants and may reduce inflammation. Further study is needed to determine if this effect of caffeine is associated with reduced risk of adverse outcomes. TRIAL REGISTRATION NUMBER: NCT03321734
Prebiotic Administration to CKD Patients Modifies Their Microbiome and Metabolism
No full textBACKGROUND AND HYPOTHESIS: Prebiotics are believed to improve gut microbial dysbiosis and dysmetabolism in chronic kidney disease (CKD) patients. However, impact of prebiotics on gut microbial metagenome and dynamic changes in metabolome has not been clearly defined. METHODS: We conducted a non-randomized, open-label, three-phase pilot trial, to investigate the effect of daily oral oligofructose-enriched inulin (p-inulin) on stool functional metagenome and changes in plasma, urine and stool metabolites in 13 CKD patients. The study comprised a pre-treatment phase (8 weeks), p-inulin treatment phase (12 weeks), and post-treatment phase (8 weeks). RESULTS: During treatment phase, there was a significant increase in the abundance of Bifidobacterium adolescentis, Bifidobacterium longum, and Lachnospiraceae species. Microbial pathways related to carbohydrate degradation and amino acid biosynthesis were enriched during the treatment phase, but urea biosynthetic pathway was attenuated. In the plasma metabolic biosynthetic pathways for valine, leucine and isoleucine were activated during the treatment phase. Microbial genes related to lipid metabolism were enriched during post-treatment. Abundance of several polar and non-polar lipids were altered in plasma and stool samples during treatment and post-treatment phases. Pathway analysis for lipids indicated suppression of triglyceride biosynthesis in plasma and enhanced triglyceride degradation in stool during the treatment phase. Secondary bile acid levels in plasma, urine and stool were significantly reduced during p-inulin consumption. Urine levels of indoxyl sulfate and p-cresol sulfate were reduced during treatment phase. CONCLUSION: P-inulin administration to CKD patients resulted a distinct shift in toxin-generating proteolysis to amino acid biosynthesis and favorable changes in lipid metabolism
Adaptive Functioning in Pediatric Brain Tumor Survivors: The Role of Neurocognitive Risk Factors and Social Determinants of Health
No full textBACKGROUND: Pediatric brain tumor (PBT) survivors are at risk for impaired executive functioning (EF) and downstream disruption of adaptive functioning (AF), impacting the transition to adulthood. We aimed to examine variables related to AF among PBT survivors to identify targets for intervention supporting the transition to adulthood. We hypothesized that intelligence, EF, and social determinants of health (SDOH) would be associated with AF, and that the relationship between EF and AF would be stronger at lower SDOH. PROCEDURE: Retrospective neuropsychological data were extracted for 78 clinically referred PBT survivors (8-24 years). Assessments included performance-based measures of intelligence and EF, and parent-proxy reported EF and AF. The Childhood Opportunity Index 2.0 (COI) measured SDOH. Statistics included correlations, t-tests, and regressions. RESULTS: Participants (56.4% male, mean age 14.03 [4.09]) had an average intelligence of 87.18 (impairment rate of 43.6%) and an average AF composite of 84.86 (impairment rate 50%). Parent proxy EF and a performance-based measure of cognitive flexibility, but not working memory, was associated with overall AF and practical and conceptual subdomains of AF. Cognitive regulation, specifically initiation and working memory, was more associated with AF than behavioral and emotional regulation. COI was associated with intelligence, AF, and working memory. CONCLUSIONS: Executive functioning is significantly associated with AF in PBT survivors, even more so than intelligence or medical factors. Initiation, working memory, and cognitive flexibility are important intervention targets to facilitate independent skill development and support the transition to adulthood, particularly for those with fewer neighborhood resources
Connectivity, Computation, and Plasticity of the Early Visual System
No full textThe visual system is a complex hierarchical structure that processes diverse visual information to guide cognition and behavior. Elucidating the principles that govern the development and function of the visual system\u27s circuitry is a central goal in visual neuroscience. This review examines connectivity, computation, and plasticity within the early mammalian visual system, focusing on three key structures: the retina, the superior colliculus (SC), and the primary visual cortex (V1). The retina serves as the initial site for visual information processing, culminating in activation of highly selective retinal ganglion cells (RGCs), which convey all visual information to the brain. The SC is a primary retinorecipient region that integrates visual information to guide appropriate behavioral responses, exhibiting visual processing both similar to and distinct from RGCs. Retinal information is also relayed via the thalamus to V1, which extracts detailed visual features through spatial and temporal integration, forming the basis of conscious visual perception. The development of these structures involves a coarse-to-fine maturation of functional networks driven by intrinsic mechanisms, including molecular cues and spontaneous patterns of activity. In addition, experience-dependent plasticity in the SC and V1 allows the visual system to adapt to changes of sensory inputs during development. Recent work has significantly advanced our understanding of the complex neuronal computations executed in these early visual regions and the molecular and circuit mechanisms underlying development and plasticity. This knowledge has significant implications for both basic neuroscience and clinical applications, particularly in the context of visual system disorders
Neurological and neurodevelopmental effects of Covid and MIS-C on children
No full textSevere Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been shown to cause a unique disease phenotype in the paediatric population compared to adults, following the emergence of Multisystem Inflammatory Syndrome of Children (MIS-C) and Paediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS). Over the course of the pandemic, neurological symptoms associated with SARS-CoV-2 have been reported in the paediatric population. The neurological and neurodevelopmental sequelae of both acute SARS-CoV-2 infection and MIS-C/PIMS-TS in the paediatric population are not well understood. Little is known about the underlying pathophysiology and the potential neurovirulence of SARS-CoV-2. Further awareness and research are needed on the neurological sequelae and long-term consequences of SARS-CoV-2 on the developing brain. IMPACT: Detailed review of the current knowledge on neurological and neurodevelopmental effects of SARS-CoV-2 and MIS-C on the paediatric population. Emphasise the importance of acknowledging the potential direct effects of SARS-CoV-2 and MIS-C on neurological and neurodevelopmental outcomes. Highlight the need for further research and inclusion of paediatric patients in follow up studies of long-term effects of SARS-CoV-2 and MIS-C focusing on neurodevelopmental and neurological sequelae
Explaining subgroup findings using spline regression: Risk of kidney failure in patients with heart failure and normal kidney function receiving RAS inhibitors
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Exercise Counseling in Congenital Heart Disease: A Guide for the Pediatric and Congenital Cardiologist
No full textExercise is a critical determinant of both immediate and long-term health for individuals with congenital heart disease (CHD). While pediatric cardiologists increasingly recognize the importance of promoting physical activity, formal training in exercise counseling remains limited. Exercise cardiology is an evolving subspecialty, with growing educational and training opportunities for congenital cardiologists to develop diagnostic and therapeutic approaches and expand access to exercise resources for patients with CHD. As part of this effort, the Global Coalition for Fitness and CHD (GloCo) convened a multi-institutional Education Working Group to develop practical, evidence- and consensus-based guidance for exercise counseling in children, adolescents, and young adults with CHD. This guide outlines foundational elements of exercise counseling, including strategies for obtaining an exercise history, performing cardiac risk assessments, shared decision-making, and tailoring exercise recommendations to individual patient needs. Exercise counseling in CHD must be personalized, taking into consideration the patient\u27s medical status, psychosocial context, and available resources. Core components include risk assessment through multimodal imaging, rhythm monitoring, and exercise assessment, including but not limited to cardiopulmonary exercise tests. Based on these evaluations, clinicians can provide or recommend general physical activity promotion, formal exercise prescriptions, or structured programs such as cardiac fitness and rehabilitation. Importantly, the aim is not simply meeting physical activity targets but fostering positive attitudes toward lifelong exercise and instilling the confidence to sustain it. By aligning exercise plans with patient and family preferences, motivations, goals, and resources, clinicians can promote sustainable engagement and improved overall fitness. This guide aims to support pediatric and congenital cardiologists in providing safe and effective exercise counseling to their patients with CHD to help them achieve optimal physical and psychosocial well-being
Estimation of prevention-effective CAB-LA concentrations among men who have sex with men (MSM) and transgender women (TGW) in HPTN 083
No full textBACKGROUND: The HIV Prevention Trials Network (HPTN) 083 Trial demonstrated the superiority of long-acting, injectable cabotegravir (CAB) over daily oral tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis among cisgender men (MSM) and transgender women (TGW) who have sex with men. Plasma CAB concentrations associated with HIV protection in humans are unknown. METHODS: We conducted a nested case-control study among HPTN 083 participants to investigate the association between plasma CAB concentrations and HIV risk. Plasma CAB concentrations were estimated for participants with confirmed HIV and for HIV-negative controls, who were matched on region, gender, and race. The window of HIV acquisition for cases was defined as the time between the last HIV-negative visit and the first HIV-positive visit; this window was used to evaluate CAB exposure for cases and their matched controls. Participants were categorized by the minimum estimated CAB concentration (CABmin) during this window relative to the protein-adjusted 90% CAB inhibitory concentration (1x PA-IC90) and 4x PA-IC90. HIV risk was modeled using conditional logistic regression. RESULTS: Plasma CABmin was ≥4x PA-IC90 in 26% of HIV-positive cases, compared to 76% of matched controls. Plasma CABmin ≥4x PA-IC90 was associated with a 93% reduction in risk of HIV acquisition compared to CABmin \u3c1x PA-IC90 (95% CI: 76%, 98%, p\u3c0.001). CABmin between 1x and 4x PA-IC90 had an estimated risk reduction of 79% compared to CABmin \u3c1x PA-IC90 (95% CI: -19%, 96%, p=0.07). CONCLUSIONS: Consistent plasma CAB concentrations ≥4x PA-IC90 were estimated to provide 93% protection against HIV in MSM and TGW