Generation of an induced pluripotent stem cell line, JHUi005-A, from a Marfan Syndrome patient harboring a pathogenic c.3338-2A>C intronic splicing variant.

Marfan Syndrome, a connective tissue disorder caused by Fibrillin-1 (FBN1) gene mutations, induces disease in the ocular, musculoskeletal, and cardiovascular systems and increases aortic vulnerability to rupture associated with high mortality rates. We describe an induced pluripotent stem cell line (HFD1) generated from patient-derived human dermal fibroblasts harboring a heterozygous c.3338-2A>C intronic splice acceptor site variant preceding Exon 28 of FBN1. The clonal line, which produces abnormal FBN1 splice variants, has a normal karyotype, expresses appropriate stemness markers, and maintains trilineage differentiation potential. This line represents a valuable resource for studying how abnormal splicing variants contribute to Marfan Syndrome.

Risk Factors for Pediatric Critical COVID-19: A Systematic Review and Meta-Analysis.

BACKGROUND: Risk stratification is a cornerstone of the Pediatric Infectious Diseases Society COVID-19 treatment guidance. This systematic review and meta-analysis aimed to define the clinical characteristics and comorbidities associated with critical COVID-19 in children and adolescents. METHODS: Two independent reviewers screened the literature (Medline and EMBASE) for studies published through August 31, 2023, that reported outcome data on patients aged ≤21 years with COVID-19. Critical disease was defined as an invasive mechanical ventilation requirement, intensive care unit admission, or death. Random effects models were used to estimate pooled odds ratios (OR) with 95% confidence intervals (CI), and heterogeneity was explored through subgroup analyses. RESULTS: Among 10,178 articles, 136 studies met the inclusion criteria for review. Data from 70 studies, which collectively examined 172,165 children and adolescents with COVID-19, were pooled for meta-analysis. In previously healthy children, the absolute risk of critical disease from COVID-19 was 4% (95% CI, 1%-10%). Compared with no comorbidities, the pooled OR for critical disease was 3.95 (95% CI, 2.78-5.63) for the presence of one comorbidity and 9.51 (95% CI, 5.62-16.06) for ≥2 comorbidities. Key risk factors included cardiovascular and neurological disorders, chronic pulmonary conditions (excluding asthma), diabetes, obesity, and immunocompromise, all with statistically significant ORs >2.00. CONCLUSIONS: While the absolute risk for critical COVID-19 in children and adolescents without underlying health conditions is relatively low, the presence of one or more comorbidities was associated with markedly increased risk. These findings support the importance of risk stratification in tailoring pediatric COVID-19 management.

Guidance for prevention and management of COVID-19 in children and adolescents: A consensus statement from the Pediatric Infectious Diseases Society Pediatric COVID-19 Therapies Taskforce.

BACKGROUND: Since November 2019, the SARS-CoV-2 pandemic has created challenges for preventing and managing COVID-19 in children and adolescents. Most research to develop new therapeutic interventions or to repurpose existing ones has been undertaken in adults, and although most cases of infection in pediatric populations are mild, there have been many cases of critical and fatal infection. Understanding the risk factors for severe illness and the evidence for safety, efficacy, and effectiveness of therapies for COVID-19 in children is necessary to optimize therapy. METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacology, and pediatric intensive care medicine from 21 geographically diverse North American institutions was re-convened. Through a series of teleconferences and web-based surveys and a systematic review with meta-analysis of data for risk factors, a guidance statement comprising a series of recommendations for risk stratification, treatment, and prevention of COVID-19 was developed and refined based on expert consensus. RESULTS: There are identifiable clinical characteristics that enable risk stratification for patients at risk for severe COVID-19. These risk factors can be used to guide the treatment of hospitalized and non-hospitalized children and adolescents with COVID-19 and to guide preventative therapy where options remain available.

Inbreeding depression in a sexually selected weapon and the homologue in females.

Theory predicts that traits with heightened condition dependence, such as sexually selected traits, should be affected by inbreeding to a greater degree than other traits. The presence of environmental stress may compound the negative consequences of inbreeding depression. In this study, we examined inbreeding depression across multiple traits and whether it increased with a known form of environmental stress. We conducted our experiment using both sexes of the sexually dimorphic leaf-footed cactus bug, Narnia femorata (Hemiptera: Coreidae). Adult male cactus bugs have enlarged hind legs used as weapons in male-male contests; these traits, and their homologue in females, have been previously found to exhibit high condition dependence. In this study, we employed a small developmental group size as an environmental stress challenge. Nymph N. femorata aggregate throughout their juvenile stages, and previous work has shown the negative effects of small group size on survivorship and body size. We found evidence of inbreeding depression for survival and seven of the eight morphological traits measured in both sexes. Inbreeding depression was higher for the size of the male weapon and the female homolog. Additionally, small developmental group size negatively affected survival to adulthood. However, small group size did not magnify the effects of inbreeding on morphological traits. These findings support the hypothesis that traits with heightened condition dependence exhibit higher levels of inbreeding depression.

Applying data science methodologies with artificial intelligence variant reinterpretation to map and estimate genetic disorder prevalence utilizing clinical data.

Data science methodologies can be utilized to ascertain and analyze clinical genetic data that is often unstructured and rarely used outside of patient encounters. Genetic variants from all genetic testing resulting to a large pediatric healthcare system for a 5-year period were obtained and reinterpreted utilizing the previously validated Franklin© Artificial Intelligence (AI). Using PowerBI©, the data were further matched to patients in the electronic healthcare record to associate with demographic data to generate a variant data table and mapped by ZIP codes. Three thousand and sixty-five variants were identified and 98% were matched to patients with geographic data. Franklin© changed the interpretation for 24% of variants. One hundred and fifty-six clinically actionable variant reinterpretations were made. A total of 739 Mendelian genetic disorders were identified with disorder prevalence estimation. Mapping of variants demonstrated hot-spots for pathogenic genetic variation such as PEX6-associated Zellweger Spectrum Disorder. Seven patients were identified with Bardet-Biedl syndrome and seven patients with Rett syndrome amenable to newly FDA-approved therapeutics. Utilizing readily available software we developed a database and Exploratory Data Analysis (EDA) methodology enabling us to systematically reinterpret variants, estimate variant prevalence, identify conditions amenable to new treatments, and localize geographies enriched for pathogenic variants.

Risk Factors for Pediatric Critical COVID-19: A Systematic Review and Meta-Analysis.

Background: Risk stratification is a cornerstone of the Pediatric Infectious Diseases Society COVID-19 treatment guidance. This systematic review and meta-analysis aimed to define the clinical characteristics and comorbidities associated with critical COVID-19 in children and adolescents. Methods: Two independent reviewers screened the literature (Medline and EMBASE) for studies published through August 2023 that reported outcome data on patients aged ≤21 years with COVID-19. Critical disease was defined as an invasive mechanical ventilation requirement, intensive care unit admission, or death. Random effects models were used to estimate pooled odds ratios (OR) with 95% confidence intervals (CI), and heterogeneity was explored through subgroup analyses. Results: Among 10,178 articles, 136 studies met the inclusion criteria for review. Data from 70 studies, which collectively examined 172,165 children and adolescents with COVID-19, were pooled for meta-analysis. In previously healthy children, the absolute risk of critical disease from COVID-19 was 4% (95% CI, 1%-10%). Compared with no comorbidities, the pooled OR for critical disease was 3.95 (95% CI, 2.78-5.63) for presence of one comorbidity and 9.51 (95% CI, 5.62-16.06) for ≥2 comorbidities. Key risk factors included cardiovascular and neurological disorders, chronic pulmonary conditions (excluding asthma), diabetes, obesity, and immunocompromise, all with statistically significant ORs >2.00. Conclusions: While the absolute risk for critical COVID-19 in children and adolescents without underlying health conditions is relatively low, the presence of one or more comorbidities was associated with markedly increased risk. These findings support the importance of risk stratification in tailoring pediatric COVID-19 management.

The evolution of multi-component weapons in the superfamily of leaf-footed bugs.

Sexually selected weapons, such as the antlers of deer, claws of crabs, and tusks of beaked whales, are strikingly diverse across taxa and even within groups of closely related species. Phylogenetic comparative studies have typically taken a simplified approach to investigate the evolution of weapon diversity, examining the gains and losses of entire weapons, major shifts in size or type, or changes in location. Less understood is how individual weapon components evolve and assemble into a complete weapon. We addressed this question by examining weapon evolution in the diverse, multi-component hind-leg and body weapons of leaf-footed bugs, superfamily Coreoidea (Hemiptera: Heteroptera). Male leaf-footed bugs use their morphological weapons to fight for access to mating territories. We used a large multilocus dataset comprised of ultraconserved element loci for 248 species and inferred evolutionary transitions among component states using ancestral state estimation. Our results suggest that weapons added components over time with some evidence of a cyclical evolutionary pattern-gains of components followed by losses and then gains again. Furthermore, our best estimate indicated that certain trait combinations evolved repeatedly across the phylogeny, suggesting that they function together in battle or that they are genetically correlated. This work reveals the remarkable and dynamic evolution of weapon form in the leaf-footed bugs and provides insights into weapon assembly and disassembly over evolutionary time.

Host Plant Effects on Sexual Selection Dynamics in Phytophagous Insects.

Natural selection is notoriously dynamic in nature, and so, too, is sexual selection. The interactions between phytophagous insects and their host plants have provided valuable insights into the many ways in which ecological factors can influence sexual selection. In this review, we highlight recent discoveries and provide guidance for future work in this area. Importantly, host plants can affect both the agents of sexual selection (e.g., mate choice and male-male competition) and the traits under selection (e.g., ornaments and weapons). Furthermore, in our rapidly changing world, insects now routinely encounter new potential host plants. The process of adaptation to a new host may be hindered or accelerated by sexual selection, and the unexplored evolutionary trajectories that emerge from these dynamics are relevant to pest management and insect conservation strategies. Examining the effects of host plants on sexual selection has the potential to advance our fundamental understanding of sexual conflict, host range evolution, and speciation, with relevance across taxa.

Progressive shingles in a toddler due to reactivation of Varicella Zoster vaccine virus four days after infection with SARS-CoV-2; a case report.

BACKGROUND: Herpes zoster (HZ) is the clinical syndrome associated with reactivation of latent varicella-zoster virus (VZV). Several factors have been implicated to promote VZV reactivation; these include immunosuppression, older age, mechanical trauma, physiologic stress, lymphopenia, and more recently, infection with severe acute respiratory syndrome coronavirus-2 (SARS- CoV-2). Recent reports suggest an increase in the number of HZ cases in the general population during the global COVID-19 pandemic. However, it is unknown what proportion of HZ during the pandemic is due to reactivation of wild-type or vaccine-strain VZV. CASE: Here we report the first known case of HZ concomitant with SARS-CoV2 infection in a 20-month-old female who was treated with a single dose of dexamethasone, due to reactivation of the vaccine-type strain of VZV after presenting with a worsening vesicular rash. CONCLUSION: In this case, we were able to show vaccine-strain VZV reactivation in the context of a mild acute symptomatic COVID-19 infection in a toddler. Being able to recognize HZ quickly and effectively in a pediatric patient can help stave off the significant morbidity and mortality associated with disease process.

Adult presence does not ameliorate juvenile feeding challenges in a leaf-footed bug.

Herbivores often grapple with structural defences in their host plants, which may pose especially difficult challenges for juveniles due to their underdeveloped feeding morphology. The degree to which juvenile herbivore survival is limited by structural defences as well as the strategies used to overcome them are not well understood. We hypothesized that juveniles benefit from feeding near adults because adults pierce through physical barriers while feeding, enabling juveniles to access nutrients that they otherwise could not. We tested this feeding facilitation hypothesis in the leaf-footed bug Leptoglossus zonatus (Hemiptera: Coreidae). Bugs were raised with an adult or a juvenile conspecific and fed a diet of pecans with or without shells. As predicted, we found that juveniles suffered greater mortality when fed nuts with shells than when fed nuts without shells. Contrary to our expectations, the presence of an adult feeding on the same nut did not lessen this effect. Therefore, the presence of an adult does not ameliorate the feeding difficulties faced by juvenile L. zonatus, despite evidence for feeding facilitation in related insect species. This study adds to our understanding of how host plant defences can limit the survival of even highly generalist herbivores.

Seizure as Presenting Symptom of Multisystem Inflammatory Syndrome in Children.

We describe the case of a 13-year-old girl who presented with a new-onset seizure and fever and subsequently developed severe cardiac dysfunction, coronary artery dilation, and shock due to the surprising diagnosis of multisystem inflammatory syndrome in children (MIS-C). Although the clinical entity we now call MIS-C was first mentioned in the medical literature in April 2020, the full picture of this disease process is still evolving. Neurologic involvement has been described in cases with MIS-C; however, seizures are not a typical presenting symptom. Additionally, because children infected with SARS-CoV-2 are often asymptomatic, a documented preceding COVID-19 infection might not be available to raise suspicion of MIS-C early on. Febrile seizures, meningitis, and encephalitis are childhood illnesses that pediatricians are generally familiar with, but associating these clinical pictures with MIS-C is uncommon. Given the possibility of rapid clinical cardiogenic decline, as seen in our patient, a prompt diagnosis and appropriate monitoring and treatment are of utmost importance. This case report aims to raise awareness that new-onset seizures with fevers can be early or the first presenting symptoms in children with MIS-C, and further workup and close monitoring may be required.

Open-Source Artificial Intelligence System Supports Diagnosis of Mendelian Diseases in Acutely Ill Infants.

Mendelian disorders are prevalent in neonatal and pediatric intensive care units and are a leading cause of morbidity and mortality in these settings. Current diagnostic pipelines that integrate phenotypic and genotypic data are expert-dependent and time-intensive. Artificial intelligence (AI) tools may help address these challenges. Dx29 is an open-source AI tool designed for use by clinicians. It analyzes the patient's phenotype and genotype to generate a ranked differential diagnosis. We used Dx29 to retrospectively analyze 25 acutely ill infants who had been diagnosed with a Mendelian disorder, using a targeted panel of ~5000 genes. For each case, a trio (proband and both parents) file containing gene variant information was analyzed, alongside patient phenotype, which was provided to Dx29 by three approaches: (1) AI extraction from medical records, (2) AI extraction with manual review/editing, and (3) manual entry. We then identified the rank of the correct diagnosis in Dx29's differential diagnosis. With these three approaches, Dx29 ranked the correct diagnosis in the top 10 in 92-96% of cases. These results suggest that non-expert use of Dx29's automated phenotyping and subsequent data analysis may compare favorably to standard workflows utilized by bioinformatics experts to analyze genomic data and diagnose Mendelian diseases.

Evolution of stridulatory mechanisms: vibroacoustic communication may be common in leaf-footed bugs and allies (Heteroptera: Coreoidea).

Intra- and interspecific communication is crucial to fitness via its role in facilitating mating, territoriality and defence. Yet, the evolution of animal communication systems is puzzling-how do they originate and change over time? Studying stridulatory morphology provides a tractable opportunity to deduce the origin and diversification of a communication mechanism. Stridulation occurs when two sclerotized structures rub together to produce vibratory and acoustic (vibroacoustic) signals, such as a cricket 'chirp'. We investigated the evolution of stridulatory mechanisms in the superfamily Coreoidea (Hemiptera: Heteroptera), a group of insects known for elaborate male fighting behaviours and enlarged hindlegs. We surveyed a large sampling of taxa and used a phylogenomic dataset to investigate the evolution of stridulatory mechanisms. We identified four mechanisms, with at least five evolutionary gains. One mechanism, occurring only in male Harmostini (Rhopalidae), is described for the first time. Some stridulatory mechanisms appear to be non-homoplastic apomorphies within Rhopalidae, while others are homoplastic or potentially homoplastic within Coreidae and Alydidae, respectively. We detected no losses of these mechanisms once evolved, suggesting they are adaptive. Our work sets the stage for further behavioural, evolutionary and ecological studies to better understand the context in which these traits evolve and change.

SON-Related Zhu-Tokita-Takenouchi-Kim Syndrome With Recurrent Hemiplegic Migraine: Putative Role of PRRT2.

Background and Objectives: Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM 617140) is a recently identified neurodevelopmental disorder caused by heterozygous loss-of-function (LoF) variants in SON. Because the SON protein functions as an RNA-splicing regulator, it has been shown that some clinical features of ZTTK syndrome can be attributed to abnormal RNA splicing. Several neurologic features have been observed in patients with ZTTK syndrome, including seizure/epilepsy and other EEG abnormalities. However, a relationship between SON LoF in ZTTK syndrome and hemiplegic migraine remains unknown. Methods: We identified a patient with a pathogenic variant in SON who shows typical clinical features of ZTTK syndrome and experienced recurrent episodes of hemiplegic migraine. To define clinical features, brain MRI and EEG during and after episodes of hemiplegic migraine were characterized. To identify molecular mechanisms for this clinical presentation, we investigated the impact of small interfering RNA (siRNA)-mediated SON knockdown on mRNA expression of the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes, known to be associated with hemiplegic migraine, by quantitative RT-PCR. Pre-mRNA splicing of PRRT2 on SON knockdown was further examined by RT-PCR using primers targeting specific exons. Results: Recurrent episodes of hemiplegic migraine in our patient typically followed modest closed head injuries, and recurrent seizures occurred during the most severe of these episodes. Transient hemispheric cortical interstitial edema and asymmetric EEG slowing were identified during episodes. Our siRNA experiments revealed that SON knockdown significantly reduces PRRT2 mRNA levels in U87MG and SH-SY5Y cell lines, although a reduction in CACNA1A, ATP1A2, and SCN1A mRNA expression was not observed. We further identified that SON knockdown leads to failure in intron 2 removal from PRRT2 pre-mRNA, resulting in a premature termination codon that blocks the generation of functionally intact full-length PRRT2. Discussion: This report identifies recurrent hemiplegic migraine as a novel clinical manifestation of ZTTK syndrome, further characterizes this clinical feature, and provides evidence for downregulation of PRRT2 caused by SON LoF as a mechanism causing hemiplegic migraine. Examination of the SON gene may be indicated in individuals with recurrent hemiplegic migraine.

How does the timing of weapon loss influence reproductive traits and trade-offs in the insect Narnia femorata?

A longstanding goal of evolutionary biology is to understand among-individual variation in resource allocation decisions and the timing of these decisions. Recent studies have shown that investment in elaborate and costly weapons can result in trade-offs with investment in testes. In this study, we ask the following questions: At what point plasticity in resource allocation to these different structures ceases during development, if at all? Furthermore, can individuals tailor their reproductive behavior to accompany structural changes? We experimentally addressed these questions in the insect Narnia femorata, quantifying resource reallocation across development for the first time, using a phenotypic engineering approach. To investigate whether allocation plasticity diminishes throughout ontogeny, we induced weapon loss at a range of different developmental stages and examined subsequent testes mass and reproductive behavior. We found that relative testes mass increased as weapon investment decreased, implying a direct trade-off between testes and weapon investment. However, autotomy postadulthood ceased to induce larger testes mass. Intriguingly, losing a weapon while young was associated with extended adult mating duration, potentially enabling compensation for reduced fighting ability. Our results highlight the importance of examining the ontogeny of trade-offs between reproductive traits and the flexibility of the relationship between reproductive morphology and behavior.

The endogenous repertoire harbors self-reactive CD4+ T cell clones that adopt a follicular helper T cell-like phenotype at steady state.

The T cell repertoire of healthy mice and humans harbors self-reactive CD4+ conventional T (Tconv) cells capable of inducing autoimmunity. Using T cell receptor profiling paired with in vivo clonal analysis of T cell differentiation, we identified Tconv cell clones that are recurrently enriched in non-lymphoid organs following ablation of Foxp3+ regulatory T (Treg) cells. A subset of these clones was highly proliferative in the lymphoid organs at steady state and exhibited overt reactivity to self-ligands displayed by dendritic cells, yet were not purged by clonal deletion. These clones spontaneously adopted numerous hallmarks of follicular helper T (TFH) cells, including expression of Bcl6 and PD-1, exhibited an elevated propensity to localize within B cell follicles at steady state, and produced interferon-γ in non-lymphoid organs following sustained Treg cell depletion. Our work identifies a naturally occurring population of self-reactive TFH-like cells and delineates a previously unappreciated fate for self-specific Tconv cells.

Rapid genome sequencing identifies a novel de novo SNAP25 variant for neonatal congenital myasthenic syndrome.

Congenital myasthenic syndrome (CMS) is a group of 32 disorders involving genetic dysfunction at the neuromuscular junction resulting in skeletal muscle weakness that worsens with physical activity. Precise diagnosis and molecular subtype identification are critical for treatment as medication for one subtype may exacerbate disease in another (Engel et al., Lancet Neurol 14: 420 [2015]; Finsterer, Orphanet J Rare Dis 14: 57 [2019]; Prior and Ghosh, J Child Neurol 36: 610 [2021]). The SNAP25-related CMS subtype (congenital myasthenic syndrome 18, CMS18; MIM #616330) is a rare disorder characterized by muscle fatigability, delayed psychomotor development, and ataxia. Herein, we performed rapid whole-genome sequencing (rWGS) on a critically ill newborn leading to the discovery of an unreported pathogenic de novo SNAP25 c.529C > T; p.Gln177Ter variant. In this report, we present a novel case of CMS18 with complex neonatal consequence. This discovery offers unique insight into the extent of phenotypic severity in CMS18, expands the reported SNAP25 variant phenotype, and paves a foundation for personalized management for CMS18.

Reduction of Infusion Time Using a 10% Intravenous Immunoglobulin Formulation With a 15-Minute Rate Escalation Protocol During Staffing Shortages Due to COVID-19.

The COVID-19 pandemic changed home infusion nursing dramatically by increasing demand for home infusion nurses while decreasing their availability. Home infusion of intravenous immunoglobulin (IVIg) is an option for treatment of numerous conditions and requires considerable infusion time. Use of a higher-concentration IVIg product and shorter escalation increments may decrease required infusion time. The authors conducted a retrospective database analysis that identified 23 patients receiving IVIg before transitioning to a 10% IVIg product with a 15-minute rate escalation protocol (Gammaplex 10% IVIg) and evaluated the total infusion time before and after the transition. Among the 23 who received IVIg, the mean ± SD IVIg dose per dosing cycle before transitioning was 1.2 ± 0.7 g/kg given in 1 to 5 infusions per cycle. The mean ± SD time per infusion was 2.8 ± 0.8 hours before the transition and 2.6 ± 0.7 hours per infusion after the transition. The infusion time decreased after transition in 13 patients (56.5%), did not change in 5 patients (21.7%), and increased in 5 patients (21.7%). Nurse education on IVIg rate escalation may facilitate faster achievement of the maximum safe infusion rate and reduce infusion times. A trial transition to this 10% IVIg product with a 15-minute rate escalation protocol may also reduce infusion times.