CUL3-Related Neurodevelopmental Disorder: Clinical Phenotype of 20 New Individuals and Identification of a Potential Phenotype-Associated Episignature.

Neurodevelopmental disorder with or without autism or seizures (NEDAUS; OMIM #619239) is a neurodevelopmental disorder characterized by global developmental delay, speech delay, seizures, autistic features and/or behavior abnormalities. It is caused by CUL3 (Cullin-3 ubiquitin ligase; OMIM #603136) haploinsufficiency. We collected clinical and molecular data from twenty-six individuals carrying pathogenic variants and variants of uncertain significance (VUS) in the CUL3 gene, including twenty previously unreported cases. By comparing their DNA methylation (DNAm) classifiers with those of healthy controls and other neurodevelopmental disorders characterized by established episignatures, we aimed to create a diagnostic biomarker (episignature) and gain more knowledge into the molecular pathophysiology. We discovered a sensitive and specific DNAm episignature for patients with pathogenic variants in CUL3 and utilized it to reclassify patients carrying a VUS in the CUL3 gene. Comparative epigenomic analysis revealed similarities between NEDAUS and several other rare genetic neurodevelopmental disorders with previously identified episignatures, highlighting the broader implication of our findings. In addition, we preformed genotype-phenotype correlation studies to explain the variety in clinical presentation between the cases. We discovered a highly accurate DNAm episignature serving as a robust diagnostic biomarker for NEDAUS. Furthermore, we broadened the phenotypic spectrum by identifying twenty new individuals and confirming five previously reported cases of NEDAUS.

An evaluation of ravulizumab for the treatment of neuromyelitis optica spectrum disorder.

INTRODUCTION: Following the CHAMPION-NMOSD trial, the FDA recently granted approval for ravulizumab, a humanized monoclonal antibody against complement C5 protein in AQP-4 seropositive neuromyelitis optica spectrum disorder (NMOSD). Similar to eculizumab, ravulizumab offers near complete prevention of NMOSD relapses, but has a longer half-life, providing decreased infusion frequency and increased convenience for patients. While targeting the complement pathway has clear advantages, patients are at risk for infection with encapsulated organisms, in particular Neisseria meningitidis. AREAS COVERED: In this paper, we discuss the details of the CHAMPION-NMOSD trial and discuss challenges in meningitis prevention and strategies for switching therapies. EXPERT OPINION: Ravulizumab improves on eculizumab's success as a highly effective NMOSD therapy by decreasing infusion frequency, thereby increasing patient convenience. We predict ravulizumab will eventually replace eculizumab, but may not have a similar impact on inebelizumab or satralizumab. Patients taking C5 complement inhibitors have an increased risk of serious meningococcal infections, such as invasive meningococcal disease (IMD), and have incomplete protection against IMD despite immunization. Thus, we recommend that in addition to standard pre-immunizations against Neisseria meningitidis, patients should also be assessed for starting on appropriate antibiotic prophylaxis against IMD, based on local resistance patterns.

Epigenomic and phenotypic characterization of DEGCAGS syndrome.

Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities syndrome (DEGCAGS, MIM #619488) is caused by biallelic, loss-of-function (LoF) ZNF699 variants, and is characterized by variable neurodevelopmental disability, discordant organ anomalies among full siblings and infant mortality. ZNF699 encodes a KRAB zinc finger protein of unknown function. We aimed to investigate the genotype-phenotype spectrum of DEGCAGS and the possibility of a diagnostic DNA methylation episignature, to facilitate the diagnosis of a highly variable condition lacking pathognomonic clinical findings. We collected data on 30 affected individuals (12 new). GestaltMatcher analyzed fifty-three facial photographs from five individuals. In nine individuals, methylation profiling of blood-DNA was performed, and a classification model was constructed to differentiate DEGCAGS from controls. We expand the ZNF699-related molecular spectrum and show that biallelic, LoF, ZNF699 variants cause unique clinical findings with age-related presentation and a similar facial gestalt. We also identified a robust episignature for DEGCAGS syndrome. DEGCAGS syndrome is a clinically variable recessive syndrome even among siblings with a distinct methylation episignature which can be used as a screening, diagnostic and classification tool for ZNF699 variants. Analysis of differentially methylated regions suggested an effect on genes potentially implicated in the syndrome's pathogenesis.

Endoscopic third ventriculostomy assisted by augmented reality.

Augmented reality (AR) technology has witnessed remarkable advancements in recent years, revolutionizing various fields, including medicine and surgery. In neurosurgery, AR holds immense promise for improving the accuracy, efficiency, and safety of various procedures. Augmented reality allows a user to visualize digital information such as 3D models, superimposed on their real-world field of view. Lately, there has been increased use of this technology for various procedures such as tumor resection, ventriculostomy, and pedicle screw insertion. Despite this, integration of AR into the field of neurosurgery is still in its infancy. As such, it is imperative that physicians continue to explore and document new clinical uses of AR. In this report, we describe the novel integration of AR into an endoscopic third ventriculostomy (ETV) case. ETV is a minimally invasive technique used to treat hydrocephalus, which involves creating a new pathway for cerebrospinal fluid (CSF) drainage within the brain's ventricular system. The integration of AR into ETV procedures offers unprecedented opportunities to enhance surgical visualization, navigation, and decision-making, ultimately leading to improved patient outcomes. Traditionally, neurosurgeons rely on pre-operative imaging, intraoperative neuronavigation systems, and their anatomical knowledge to perform an ETV. However, the complex neuroanatomy and variability among patients pose challenges to accurate navigation and spatial orientation prior to and during surgery. AR technology addresses these challenges by overlaying digital information-such as three-dimensional models, anatomical landmarks, and surgical trajectories-onto the surgeon's view of the patient in real-time.

Oral immunotherapy improves the quality of life of adults with food allergy.

BACKGROUND: Oral immunotherapy (OIT) has become the standard of care for children with food allergy (FA) and has substantially improved their quality of life. The effect of OIT on the quality of life in adults, however, has been studied to a much lesser degree. METHODS: Patients with food allergy aged ≥ 18 years who underwent OIT at Shamir Medical Center completed the Food Allergy Quality of Life Questionnaire-Adult Form (FAQLQ-AF) before and at the end of treatment. Adults with FA not undergoing OIT who completed the FAQLQ-AF at 2 time points, served as controls. RESULTS: A total of 44 adults, median age 23.4 years, who underwent OIT for milk (n = 19), egg (n = 2), peanut (n = 9), sesame (n = 6), and tree nuts (n = 8), and 11 controls were studied. The median OIT starting dose was 23.8 mg protein. 33 patients (75%) reached full desensitization within a median of 10.3 months. The FAQLQ-AF baseline scores were comparable between the study and control groups for all items except for Food Allergy related Health (FAH) item in which the study group had a significantly better score (p = 0.02). At the second time point, the study group had significantly better scores in all items (Allergen Avoidance and Dietary Restrictions (AADR), p = 0.02; and Emotional Impact (EI), Risk of Allergen Exposure (RAE), FAH and the Total Score, p < 0.01). The change in scores for the study group was significantly better, statistically and clinically, in AADR, p = 0.04; EI, p < 0.01; RAE, p = 0.01, and in the total score, p = 0.01. CONCLUSIONS: OIT significantly improves quality of life of adults with FA. This finding adds important support for providing OIT in this population.

Coeliac disease as a model for understanding multiple sclerosis.

The genetic architecture of multiple sclerosis (MS) is similar to that of coeliac disease, with human leukocyte antigen (HLA) being the greatest genetic determinant in both diseases. Furthermore, similar to the involvement of gluten in coeliac disease, Epstein-Barr virus (EBV) infection is now widely considered to be an important environmental factor in MS. The molecular basis for the HLA association in coeliac disease is well defined, and B cells have a clear role in antigen presentation to gluten-specific CD4+ T cells. By contrast, the mechanisms underlying the HLA association of MS are unknown but accumulating evidence indicates a similar role of B cells acting as antigen-presenting cells. The growing parallels suggest that much could be learned about the mechanisms of MS by using coeliac disease as a model. In this Perspective article, we discuss the insights that could be gained from these parallels and consider the possibility of antiviral treatment against EBV as a therapy for MS that is analogous to the gluten-free diet in coeliac disease.

CD4 T cells restricted to DRB1*15:01 recognize two Epstein-Barr virus glycoproteins capable of intracellular antigen presentation.

Both genetic and environmental factors contribute to multiple sclerosis (MS) risk. Infection with the Epstein-Barr virus (EBV) is the strongest environmental risk factor, and HLA-DR15 is the strongest genetic risk factor for MS. We employed computational methods and in vitro assays for CD4 T cell activation to investigate the DR15-restricted response to EBV. Using a machine learning-based HLA ligand predictor, the EBV glycoprotein B (gB) was predicted to be enriched in epitopes restricted to presentation by DRB1*15:01. In DR15-positive individuals, two epitopes comprised the major CD4 T cell response to gB. Surprisingly, the expression of recombinant gB in a DR15-homozygous B cell line or primary autologous B cells elicited a CD4 T cell response, indicating that intracellular gB was loaded onto HLA class II molecules. By deleting the signal sequence of gB, we determined that this pathway for direct activation of CD4 T cells was dependent on trafficking to the endoplasmic reticulum (ER) within the B cell. We screened seven recombinant EBV antigens from the ER compartment for immune responses in DR15-negative vs. DR15-homozygous individuals. In addition to gB, gH was a key CD4 T cell target in individuals homozygous for DR15. Compared to non-DR15 controls, DR15-homozygotes had significantly higher T cell responses to both gB and gH but not to EBV latent or lytic antigens overall. Responses to gB and gH were slightly elevated in DR15 homozygotes with MS. Our results link MS environmental and genetic risk factors by demonstrating that HLA-DR15 dictates CD4 T cell immunity to EBV antigens.

Patient follow-up after discharge from the paediatric intensive care unit: A scoping review.

BACKGROUND: Most children admitted to a paediatric intensive care unit (PICU) now survive because of improvements in care. Many studies have identified the psychological, functional, cognitive and social impact of PICU admission on a child and their family. However, expert recommendations on follow-up are lacking. AIM: To identify the strategies of clinical follow-up after PICU discharge performed from 2001 to 2021. STUDY DESIGN: This scoping review was undertaken between January and April 2021 using three databases: PubMed, EMBASE and CINAHL. The search strategy consisted of a combination of keywords, including PICU, post-PICU discharge and follow-up in articles published between 2001 and 2021. The results are reported according to PRISMA-ScR guidelines. RESULTS: Six-hundred and fifty-two articles were identified and 68 were analysed. Median age was 4.5 years and the two main reasons for PICU admission were cardiorespiratory failure and sepsis. Median length of PICU stay was 8 days. Most follow-up was carried out by research units (88%), while 6% of studies reported follow-up by a multidisciplinary PICU team. The most common follow-up schedule included an assessment at PICU discharge, and then at 3, 6 and 12 months. Follow-up for >1 year was reported in 20% of studies. One third of studies focused on follow-up quality of life and neurological outcomes. Parental emotional impact was assessed in 7% of studies. CONCLUSION: Follow-up after PICU discharge was highly heterogeneous regarding timing, health care professionals involved and assessment methods. There is an urgent need for standardization and coordination of PICU follow-up because of the increasing number of patients impacted by a PICU stay. RELEVANCE TO CLINICAL PRACTICE: Although most patients admitted to a paediatric intensive care unit (PICU) now survive; they may develop paediatric post-intensive care syndrome (PICS-P). To our knowledge, there are currently no clinical guidelines regarding follow-up after PICU discharge. This review summarizes current approaches to follow-up after PICU discharge, including how it is carried out, who is involved and what the main aims of assessment are.

Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.

BACKGROUND: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype. METHODS: We collected patients with duplications encompassing ARID1A and ARID1B duplications. RESULTS: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1-1.2 Mb(1-44 genes) for ARID1A and 0.9-10.3 Mb(2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation re-analysis, resulting in the reclassification of two ARID1A and two ARID1B duplications as pathogenic. CONCLUSION: Our findings reveal that ARID1B duplications manifest a clinical phenotype and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole gene duplication rather than haploinsufficiency.

Characterizing Prehospital Wall Fall Injuries at the US-Mexico Border.

This cross-sectional study examines treatment received for falls from a section of the US-Mexico border wall with a focus on emergency medical services activation and type of treatment.

Genomic Characterization of a Dog-Mediated Rabies Outbreak in El Pedregal, Arequipa, Peru.

Background: Rabies, a re-emerging zoonosis with the highest known human case fatality rate, has been largely absent from Peru, except for endemic circulation in the Puno region on the Bolivian border and re-emergence in Arequipa City in 2015, where it has persisted. In 2021, an outbreak occurred in the rapidly expanding city of El Pedregal near Arequipa, followed by more cases in 2022 after nearly a year of epidemiological silence. While currently under control, questions persist regarding the origin of the El Pedregal outbreak and implications for maintaining rabies control in Peru. Methods: We sequenced 25 dog rabies virus (RABV) genomes from the El Pedregal outbreak (n=11) and Arequipa City (n=14) from 2021-2023 using Nanopore sequencing in Peru. Historical genomes from Puno (n=4, 2010-2012) and Arequipa (n=5, 2015-2019), were sequenced using an Illumina approach in the UK. In total, 34 RABV genomes were analyzed, including archived and newly obtained samples. The genomes were analyzed phylogenetically to understand the outbreak's context and origins. Results: Phylogenomic analysis identified two genetic clusters in El Pedregal: 2021 cases stemmed from a single introduction unrelated to Arequipa cases, while the 2022 sequence suggested a new introduction from Arequipa rather than persistence. In relation to canine RABV diversity in Latin America, all new sequences belonged to a new minor clade, Cosmopolitan Am5, sharing relatives from Bolivia, Argentina, and Brazil. Conclusion: Genomic insights into the El Pedregal outbreak revealed multiple introductions over a 2-year window. Eco-epidemiological conditions, including migratory worker patterns, suggest human-mediated movement drove introductions. Despite outbreak containment, El Pedregal remains at risk of dog-mediated rabies due to ongoing circulation in Arequipa, Puno, and Bolivia. Human-mediated movement of dogs presents a major risk for rabies re-emergence in Peru, jeopardizing regional dog-mediated rabies control. Additional sequence data is needed for comprehensive phylogenetic analyses.

Irrigation, migration and infestation: a case study of Chagas disease vectors and bed bugs in El Pedregal, Peru.

BACKGROUND: The city of El Pedregal grew out of a desert, following an agricultural irrigation project in southern Peru. OBJECTIVES: To describe infestation patterns by triatomines and bed bugs and their relationship to migration and urbanization. METHODS: We conducted door-to-door entomological surveys for triatomines and bed bugs. We assessed spatial clustering of infestations and compared the year of construction of infested to un-infested households. To gain a better understanding of the context surrounding triatomine infestations, we conducted in-depth interviews with residents to explore their migration histories, including previous experiences with infestation. FINDINGS: We inspected 5,164 households for Triatoma infestans (known locally as the Chirimacha); 21 (0.41%) were infested. These were extremely spatially clustered (Ripley's K p-value < 0.001 at various spatial scales). Infested houses were older than controls (Wilcoxon rank-sum: W = 33; p = 0.02). We conducted bed bug specific inspections in 34 households; 23 of these were infested. These were spatially dispersed across El Pedregal, and no difference was observed in construction age between bed bug infested houses and control houses (W = 6.5, p = 0.07). MAIN CONCLUSIONS: The establishment of agribusiness companies in a desert area demanded a permanent work force, leading to the emergence of a new city. Migrant farmers, seeking work opportunities or escaping from adverse climatic events, arrived with few resources, and constructed their houses with precarious materials. T. infestans, a Chagas disease vector, was introduced to the city and colonized houses, but its dispersal was constrained by presence of vacant houses. We discuss how changes in the socioeconomic and agricultural landscape can increase vulnerability to vector-borne illnesses.

EUS for the evaluation of esophageal injury after catheter ablation for atrial fibrillation.

BACKGROUND AND AIMS: Atrial fibrillation (AF) ablation is an increasingly used rhythm control strategy that can damage adjacent structures in the mediastinum including the esophagus. Atrioesophageal fistulas and esophagopericardial fistulas are life-threatening adverse events that are believed to progress from early esophageal mucosal injury (EI). EUS has been proposed as a superior method to EGD to survey EI and damage to deeper structures. We evaluated the safety of EUS in categorizing postablation EI and quantified EUS-detected lesions and their correlation with injury severity and clinical course. METHODS: We retrospectively reviewed 234 consecutive patients between 2006 and 2020 who underwent AF ablation followed by EUS for the purpose of EI screening. The Kansas City classification was used to classify EI (type 1, type 2a/b, or type 3a/b). RESULTS: EUS identified pleural effusions in 31.6% of patients, mediastinal adventitia changes in 22.2%, mediastinal lymphadenopathy in 14.1%, pulmonary vein changes in 10.6%, and esophageal wall changes in 7.7%. EGD revealed 175 patients (75%) without and 59 (25%) with EI. Patients with type 2a/b EI and no EI were compared with multivariate logistic regression, and the presence of esophageal wall abnormality on EUS (odds ratio [OR], 72.85; 95% confidence interval [CI], 13.9-380.7), female sex (OR, 3.97; 95% CI 1.3-12.3), and number of energy deliveries (OR, 1.01; 95% CI, 1.003-1.03) were associated with EI type 2a or 2b. Preablation use of proton pump inhibitors was not associated with a decreased risk of EI. CONCLUSIONS: EUS safely assesses mediastinal damage after ablation for AF and may excel over EGD in evaluating mucosal lesions of uncertain significance, with a reduced risk of gas embolization in the setting of a full-thickness injury (enterovascular fistula). We propose an EUS-first guided approach to post-AF ablation examination, followed by EGD if it is safe to do so.

Consensus Statement of the National Association of EMS Physicians International Association of Fire Chiefs and the International Association of Chiefs of Police: Best Practices for Collaboration Between Law Enforcement and Emergency Medical Services During Acute Behavioral Emergencies.

Emergency Medical Services (EMS) and law enforcement (LE) frequently work as a team in encounters with individuals experiencing acute behavioral emergencies manifesting with severe agitation and aggression. The optimal management is a rehearsed, coordinated effort by law enforcement and EMS providing the necessary interventions to address behaviors that endanger the patient, the responders, and the public. The purpose of this document is to provide guidance and direction in the shared responsibility of managing and caring for a person displaying behavioral instability with irrational, agitated, and/or violent behavior. This is a discussion of the roles of law enforcement, 9-1-1 call centers (hereafter referred to as the Emergency Call Centers or "ECCs"), Fire, and EMS. A coordinated and unified response enhances the safety and effective management of potentially serious situations posed by individuals experiencing such acute behavioral emergencies. This paper provides the framework for an approach endorsed by NAEMSP, IACP, and the IAFC.

Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement.

Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.

Discovery of DNA methylation signature in the peripheral blood of individuals with history of antenatal exposure to valproic acid.

PURPOSE: Valproic acid or valproate is an effective antiepileptic drug; however, embryonic exposure to valproate can result in a teratogenic disorder referred to as fetal valproate syndrome (OMIM #609442). Currently there are no diagnostic biomarkers for the condition. This study aims to define an episignature biomarker for teratogenic antenatal exposure to valproate. METHODS: DNA extracted from peripheral blood of individuals with teratogenic antenatal exposure to valproate was processed using DNA methylation microarrays. Subsequently, methylation profiling and construction of support vector machine classifiers were performed in R. RESULTS: Genomic DNA methylation analysis was applied, and a distinct DNA methylation profile was identified in the majority of affected individuals. This profile was used to develop a diagnostic episignature classifier. The valproate exposure episignature exhibited high sensitivity and specificity relative to a large reference data set of unaffected controls and individuals with a wide spectrum of syndromic disorders with episignatures. Gene set enrichment analysis demonstrated an enrichment for terms associated with cell adhesion, including significant overrepresentation of the cadherin superfamily. CONCLUSION: This study provides evidence of a robust peripheral blood-based diagnostic epigenetic biomarker for a prenatal teratogenic disorder.

The Path to a Match for Interventional Cardiology Fellowship: A Major SCAI Initiative.

The field of interventional cardiology (IC) has evolved dramatically over the past 40 years. Training and certification in IC have kept pace, with the development of accredited IC fellowship training programs, training statements, and subspecialty board certification. The application process, however, remained fragmented with lack of a universal process or time frame. In recent years, growing competition among training programs for the strongest candidates resulted in time-limited offers and high-pressure situations that disadvantaged candidates. A grassroots effort was recently undertaken by a Society for Cardiovascular Angiography & Interventions task force, to create equity in the system by establishing a national Match for IC fellowship. This manuscript explores the rationale, process, and implications of this endeavor.