Rare and common variants in ROM1 and PRPH2 genes trans-modify Stargardt/ABCA4 disease.

Over 1,500 variants in the ABCA4 locus cause phenotypes ranging from severe, early-onset retinal degeneration to very late-onset maculopathies. The resulting ABCA4/Stargardt disease is the most prevalent Mendelian eye disorder, although its underlying clinical heterogeneity, including penetrance of many alleles, are not well-understood. We hypothesized that a share of this complexity is explained by trans-modifiers, i.e., variants in unlinked loci, which are currently unknown. We sought to identify these by performing exome sequencing in a large cohort for a rare disease of 622 cases and compared variation in seven genes known to clinically phenocopy ABCA4 disease to cohorts of ethnically matched controls. We identified a significant enrichment of variants in 2 out of the 7 genes. Moderately rare, likely functional, variants, at the minor allele frequency (MAF) <0.005 and CADD>25, were enriched in ROM1, where 1.3% of 622 patients harbored a ROM1 variant compared to 0.3% of 10,865 controls (p = 2.41E04; OR 3.81 95% CI [1.77; 8.22]). More importantly, analysis of common variants (MAF>0.1) identified a frequent haplotype in PRPH2, tagged by the p.Asp338 variant with MAF = 0.21 in the matched general population that was significantly increased in the patient cohort, MAF 0.25, p = 0.0014. Significant differences were also observed between ABCA4 disease subgroups. In the late-onset subgroup, defined by the hypomorphic p.Asn1868Ile variant and including c.4253+43G>A, the allele frequency for the PRPH2 p.Asp338 variant was 0.15 vs 0.27 in the remaining cohort, p = 0.00057. Known functional data allowed suggesting a mechanism by which the PRPH2 haplotype influences the ABCA4 disease penetrance. These associations were replicated in an independent cohort of 408 patients. The association was highly statistically significant in the combined cohorts of 1,030 cases, p = 4.00E-05 for all patients and p = 0.00014 for the hypomorph subgroup, suggesting a substantial trans-modifying role in ABCA4 disease for both rare and common variants in two unlinked loci.

Mice with a Pax2 missense variant display impaired glomerular repair.

PAX2 regulates kidney development, and its expression persists in parietal epithelial cells (PECs), potentially serving as a podocyte reserve. We hypothesized that mice with a Pax2 pathogenic missense variant (Pax2A220G/+) have impaired PEC-mediated podocyte regeneration. Embryonic wild-type mouse kidneys showed overlapping expression of PAX2/Wilms' tumor-1 (WT-1) until PEC and podocyte differentiation, reflecting a close lineage relationship. Embryonic and adult Pax2A220G/+ mice have reduced nephron number but demonstrated no glomerular disease under baseline conditions. Pax2A220G/+ mice compared with wild-type mice were more susceptible to glomerular disease after adriamycin (ADR)-induced podocyte injury, as demonstrated by worsened glomerular scarring, increased podocyte foot process effacement, and podocyte loss. There was a decrease in PAX2-expressing PECs in wild-type mice after adriamycin injury accompanied by the occurrence of PAX2/WT-1-coexpressing glomerular tuft cells. In contrast, Pax2A220G/+ mice showed no changes in the numbers of PAX2-expressing PECs after adriamycin injury, associated with fewer PAX2/WT-1-coexpressing glomerular tuft cells compared with injured wild-type mice. A subset of PAX2-expressing glomerular tuft cells after adriamycin injury was increased in Pax2A220G/+ mice, suggesting a pathological process given the worse outcomes observed in this group. Finally, Pax2A220G/+ mice have increased numbers of glomerular tuft cells expressing Ki-67 and cleaved caspase-3 compared with wild-type mice after adriamycin injury, consistent with maladaptive responses to podocyte loss. Collectively, our results suggest that decreased glomerular numbers in Pax2A220G/+ mice are likely compounded with the inability of their mutated PECs to regenerate podocyte loss, and together these two mechanisms drive the worsened focal segmental glomerular sclerosis phenotype in these mice.NEW & NOTEWORTHY Congenital anomalies of the kidney and urinary tract comprise some of the leading causes of kidney failure in children, but our previous study showed that one of its genetic causes, PAX2, is also associated with adult-onset focal segmental glomerular sclerosis. Using a clinically relevant model, our present study demonstrated that after podocyte injury, parietal epithelial cells expressing PAX2 are deployed into the glomerular tuft to assist in repair in wild-type mice, but this mechanism is impaired in Pax2A220G/+ mice.

GM1 gangliosidosis type II: Results of a 10-year prospective study.

PURPOSE: GM1 gangliosidosis (GM1) a lysosomal disorder caused by pathogenic variants in GLB1, is characterized by relentless neurodegeneration. There are no approved treatments. METHODS: Forty-one individuals with type II (late-infantile and juvenile) GM1 participated in a single-site prospective observational study. RESULTS: Classification of 37 distinct variants using American College of Medical Genetics and Genomics criteria resulted in the upgrade of 6 and the submission of 4 new variants. In contrast to type I infantile disease, children with type II had normal or near normal hearing and did not have cherry-red maculae or hepatosplenomegaly. Some older children with juvenile onset disease developed thickened aortic and/or mitral valves. Serial magnetic resonance images demonstrated progressive brain atrophy, more pronounced in late infantile patients. Magnetic resonance spectroscopy showed worsening elevation of myo-inositol and deficit of N-acetyl aspartate that were strongly correlated with scores on the Vineland Adaptive Behavior Scale, progressing more rapidly in late infantile compared with juvenile onset disease. CONCLUSION: Serial phenotyping of type II GM1 patients expands the understanding of disease progression and clarifies common misconceptions about type II patients; these are pivotal steps toward more timely diagnosis and better supportive care. The data amassed through this 10-year effort will serve as a robust comparator for ongoing and future therapeutic trials.

The association between symptom burden and processing speed and executive functioning at 4 and 12 weeks following pediatric concussion.

OBJECTIVES: Symptoms and cognition are both utilized as indicators of recovery following pediatric concussion, yet their interrelationship is not well understood. This study aimed to investigate: 1) the association of post-concussion symptom burden and cognitive outcomes (processing speed and executive functioning [EF]) at 4 and 12 weeks after pediatric concussion, and 2) the moderating effect of sex on this association. METHODS: This prospective, multicenter cohort study included participants aged 5.00-17.99 years with acute concussion presenting to four Emergency Departments of the Pediatric Emergency Research Canada network. Five processing speed and EF tasks and the Post-Concussion Symptom Inventory (PCSI; symptom burden, defined as the difference between post-injury and retrospective [pre-injury] scores) were administered at 4 and 12 weeks post-concussion. Generalized least squares models were conducted with task performances as dependent variables and PCSI and PCSI*sex interaction as the main predictors, with important pre-injury demographic and injury characteristics as covariates. RESULTS: 311 children (65.0% males; median age = 11.92 [IQR = 9.14-14.21 years]) were included in the analysis. After adjusting for covariates, higher symptom burden was associated with lower Backward Digit Span (χ2 = 9.85, p = .043) and Verbal Fluency scores (χ2 = 10.48, p = .033) across time points; these associations were not moderated by sex, ps ≥ .20. Symptom burden was not associated with performance on the Coding, Continuous Performance Test, and Color-Word Interference scores, ps ≥ .17. CONCLUSIONS: Higher symptom burden is associated with lower working memory and cognitive flexibility following pediatric concussion, yet these associations were not moderated by sex. Findings may inform concussion management by emphasizing the importance of multifaceted assessments of EF.

Social adjustment in children diagnosed with sickle cell disease: A retrospective study.

BACKGROUND: Children with sickle cell disease (SCD) are at risk for physical, psychological, and social adjustment challenges. This study sought to investigate social adjustment and related factors in children living with SCD. METHODS: Data from 32 children (50% male, mean age = 10.32 years, SD = 3.27) were retrospectively collected from a neuropsychology clinic at a tertiary care pediatric hospital. Social adjustment was measured using the Behavior Assessment System for Children (BASC-3) parent-proxy, withdrawal subscale, and the Pediatric Quality of Life Inventory (PedsQL) Generic Module Social Functioning self- and parent-proxy subscales. Other measures captured executive functioning (i.e., Behavior Rating Inventory of Executive Function, Second Edition (BRIEF-2) Parent Form) and non-disease-related associations with social adjustment, including number of years in Canada and family functioning (i.e., PedsQL Family Impact Module). RESULTS: Sixteen percent of patients reported elevated social adjustment difficulties. Multiple linear regression found better family functioning [B = .48, t = 2.65, p = .016], and higher executive functioning [B = -.43, t = -2.39, p = .028] were related to higher scores on the PedsQL parent-proxy ratings of social adjustment [F(4,18) = 5.88, p = .003]. Male sex [B = .54, t = 3.08, p = .005], and having lived more years in Canada [B = .55, t = 2.81, p = .009], were related to higher PedsQL self-reported social adjustment [F(4,23) = 3.75, p = .017]. The model examining the BASC-3 withdrawal subscale was not statistically significant [F(4,16) = 1.63, p = .22]. IMPLICATIONS: Social adjustment in children diagnosed with SCD warrants future research to understand the influence of executive function, and non-disease-related factors, particularly focusing on sociocultural factors.

OUTER RETINAL MICROCAVITATIONS IN RETINITIS PIGMENTOSA : A Novel Optical Coherence Tomography Finding Common in RP1 -Related Retinopathy.

PURPOSE: To describe a novel optical coherence tomography (OCT) finding of outer retina microcavitations in RP1 -related retinopathy and other retinal degenerations. METHODS: Medical charts and OCT images of 28 patients with either autosomal dominant retinitis pigmentosa or autosomal recessive retinitis pigmentosa RP1 -related retinopathy were reviewed. Outer retina microcavitations were defined as hyporeflective OCT structures of at least 30 µ m in diameter between the ellipsoid zone and retinal pigment epithelium. Comparison was made based on the following metrics: (1) functional measures including best-corrected visual acuity and color discrimination errors on D-15 test; and (2) structural measures, including central subfield, average macular thickness, and preserved transfoveal ellipsoid zone width. Mann-Whitney tests were used for comparisons with significance set at P < 0.05. The specificity of microcavitations for RP1 -related retinopathy was estimated against 26 patients with non- RP1 retinitis pigmentosa. RESULTS: Among 15 included patients, microcavitations were found in at least one eye of all patients with arRP and 7/12 (58%) of patients with adRP. Patients with adRP and microcavitations were older at the time of examination (51 vs. 43 years of age; P = 0.04) and their eyes demonstrated worse best-corrected visual acuity (0.09 vs. 0 logMAR; P = 0.008), reduced central subfield (256 vs. 293 µ m; P = 0.01), average macular thickness (241 vs. 270 µ m; P = 0.02), and shorter transfoveal ellipsoid zone widths (1.67 vs. 4.98 mm; P < 0.0001). The finding of microcavitations showed a specificity of 0.92 for RP1 -related retinopathy. CONCLUSION: A novel OCT finding of outer retina microcavitations was commonly observed in patients with RP1 -related retinopathy. Eyes with outer retinal OCT microcavitations had worse visual function and more affected central retinal structure.

Patterns of WISC-V Performance in Children with Congenital Heart Disease.

Congenital heart disease (CHD) is one of the most common congenital birth defects. As surgical and interventional techniques have improved, the mortality has been greatly reduced and the focus has shifted to quality of life and long-term outcomes. The impact of CHD on development and cognition is becoming increasingly recognized. However, more research is needed to understand how children with CHD perform across various cognitive and intellectual domains. This study explored the performance of children with CHD on the newest version of the Wechsler Intelligence Scale for Children compared to normative controls. Children with CHD performed more poorly than normal controls across all indices and most subtests with large effect sizes. Additionally, we explored the patterns of impairment across indices and subtests, as well as the relationships between heard disease variables and WISC-V performance. Block design, Digit Span, and Similarities were the most commonly impaired scores in children with CHD, while Symbol Search, Picture Span, Figure Weights, and Vocabulary were least likely to be impaired.

Genome-wide screening reveals the genetic basis of mammalian embryonic eye development.

BACKGROUND: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. RESULTS: Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. CONCLUSIONS: Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

Zebrafish model of RERE syndrome recapitulates key ophthalmic defects that are rescued by small molecule inhibitor of shh signaling.

BACKGROUND: RERE is a highly conserved transcriptional co-regulator that is associated with a human neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH, OMIM: 616975). RESULTS: We show that the zebrafish rerea mutant (babyface) robustly recapitulates optic fissure closure defects resulting from loss of RERE function, as observed in humans. These defects result from expansion of proximal retinal optic stalk (OS) and reduced expression of some of the ventral retinal fate genes due to deregulated protein signaling. Using zebrafish and cell-based assays, we determined that NEDBEH-associated human RERE variants function as hypomorphs in their ability to repress shh signaling and some exhibit abnormal nuclear localization. Inhibiting shh signaling by the protein inhibitor HPI-1 rescues coloboma, confirming our observation that coloboma in rerea mutants is indeed due to deregulation of shh signaling. CONCLUSIONS: Zebrafish rerea mutants exhibit OS and optic fissure closure defects. The optic fissure closure defect was rescued by an shh signaling inhibitor, suggesting that this defect could arise due to deregulated shh signaling.

Structural brain network lateralization across childhood and adolescence.

Developmental lateralization of brain function is imperative for behavioral specialization, yet few studies have investigated differences between hemispheres in structural connectivity patterns, especially over the course of development. The present study compares the lateralization of structural connectivity patterns, or topology, across children, adolescents, and young adults. We applied a graph theory approach to quantify key topological metrics in each hemisphere including efficiency of information transfer between regions (global efficiency), clustering of connections between regions (clustering coefficient [CC]), presence of hub-nodes (betweenness centrality [BC]), and connectivity between nodes of high and low complexity (hierarchical complexity [HC]) and investigated changes in these metrics during development. Further, we investigated BC and CC in seven functionally defined networks. Our cross-sectional study consisted of 211 participants between the ages of 6 and 21 years with 93% being right-handed and 51% female. Global efficiency, HC, and CC demonstrated a leftward lateralization, compared to a rightward lateralization of BC. The sensorimotor, default mode, salience, and language networks showed a leftward asymmetry of CC. BC was only lateralized in the salience (right lateralized) and dorsal attention (left lateralized) networks. Only a small number of metrics were associated with age, suggesting that topological organization may stay relatively constant throughout school-age development, despite known underlying changes in white matter properties. Unlike many other imaging biomarkers of brain development, our study suggests topological lateralization is consistent across age, highlighting potential nonlinear mechanisms underlying developmental specialization.

Ophthalmic Manifestations of ROSAH (Retinal Dystrophy, Optic Nerve Edema, Splenomegaly, Anhidrosis, and Headache) Syndrome, an Inherited NF κB-Mediated Autoinflammatory Disease with Retinal Dystrophy.

PURPOSE: We aimed to characterize the ocular phenotype of patients with ROSAH (retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and headache) syndrome and their response to therapy. DESIGN: Single-center observational case study. PARTICIPANTS: Eleven patients with a diagnosis of ROSAH syndrome and mutation in ALPK1 were included. METHODS: Patients with molecularly confirmed ROSAH syndrome underwent ophthalmic evaluation, including visual acuity testing, slit-lamp and dilated examinations, color fundus and autofluorescence imaging, fluorescein angiography, OCT, and electrophysiologic testing. MAIN OUTCOME MEASURES: Visual acuity, electrophysiology, fluorescein angiography, and OCT findings. RESULTS: Eleven individuals (6 female and 5 male patients) from 7 families ranging in age from 7.3 to 60.2 years at the time of the initial evaluation were included in this study. Seven patients were followed up for a mean of 2.6 years (range, 0.33-5.0 years). Best-corrected visual acuity at baseline ranged from 20/16 to no light perception. Variable signs or sequelae of intraocular inflammation were observed in 9 patients, including keratic precipitates, band keratopathy, trace to 2+ anterior chamber cells, cystoid macular edema, and retinal vasculitis on fluorescein angiography. Ten patients were observed to show optic disc elevation and demonstrated peripapillary thickening on OCT. Seven patients showed retinal degeneration consistent with a cone-rod dystrophy, with atrophy tending to involve the posterior pole and extending peripherally. One patient with normal electroretinography findings and visual evoked potential was found to have decreased Arden ratio on electro-oculography. CONCLUSIONS: Leveraging insights from the largest single-center ROSAH cohort described to date, this study identified 3 main factors as contributing to changes in visual function of patients with ROSAH syndrome: optic nerve involvement; intraocular inflammation, including cystoid macular edema; and retinal degeneration. More work is needed to determine how to arrest the progressive vision loss associated with ROSAH syndrome. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

DDX58(RIG-I)-related disease is associated with tissue-specific interferon pathway activation.

BACKGROUND: Singleton-Merten syndrome (SGMRT) is a rare immunogenetic disorder that variably features juvenile open-angle glaucoma (JOAG), psoriasiform skin rash, aortic calcifications and skeletal and dental dysplasia. Few families have been described and the genotypic and phenotypic spectrum is poorly defined, with variants in DDX58 (DExD/H-box helicase 58) being one of two identified causes, classified as SGMRT2. METHODS: Families underwent deep systemic phenotyping and exome sequencing. Functional characterisation with in vitro luciferase assays and in vivo interferon signature using bulk and single cell RNA sequencing was performed. RESULTS: We have identified a novel DDX58 variant c.1529A>T p.(Glu510Val) that segregates with disease in two families with SGMRT2. Patients in these families have widely variable phenotypic features and different ethnic background, with some being severely affected by systemic features and others solely with glaucoma. JOAG was present in all individuals affected with the syndrome. Furthermore, detailed evaluation of skin rash in one patient revealed sparse inflammatory infiltrates in a unique distribution. Functional analysis showed that the DDX58 variant is a dominant gain-of-function activator of interferon pathways in the absence of exogenous RNA ligands. Single cell RNA sequencing of patient lesional skin revealed a cellular activation of interferon-stimulated gene expression in keratinocytes and fibroblasts but not in neighbouring healthy skin. CONCLUSIONS: These results expand the genotypic spectrum of DDX58-associated disease, provide the first detailed description of ocular and dermatological phenotypes, expand our understanding of the molecular pathogenesis of this condition and provide a platform for testing response to therapy.

A Prospective Cohort Study of the Association Between Preinjury Psychosocial Function and Postconcussive Symptoms in Pediatric Mild Traumatic Brain Injury: An A-CAP Study.

OBJECTIVE: We evaluated the moderating effect of preinjury psychosocial function on postconcussion symptoms for children with mild traumatic brain injury (mTBI). DESIGN, SETTING, AND POPULATION: We conducted a prospective cohort study of children ages 8.0 to 16.9 years with mTBI ( n = 633) or orthopedic injury (OI; n = 334), recruited from 5 pediatric emergency departments from September 2016 to December 2018. MAIN MEASURES: Participants completed baseline assessments within 48 hours of injury, and postconcussion symptoms assessments at 7 to 10 days, weekly to 3 months, and biweekly to 6 months post-injury. Preinjury psychosocial function was measured using parent ratings on the Pediatric Quality of Life Inventory (PedsQL) and the Strengths and Difficulties Questionnaire (SDQ), retrospectively evaluating their child's status prior to the injury. Parent and child ratings on the Health and Behavior Inventory (HBI) (cognitive and somatic subscales) and the Post-Concussion Symptom Interview (PCS-I) were used as measures of postconcussion symptoms. We fitted 6 longitudinal regression models, which included 747 to 764 participants, to evaluate potential interactions between preinjury psychosocial function and injury group as predictors of child- and parent-reported postconcussion symptoms. RESULTS: Preinjury psychosocial function moderated group differences in postconcussion symptoms across the first 6 months post-injury. Higher emotional and conduct problems were significantly associated with more severe postconcussion symptoms among children with mTBI compared with OI. Wald's χ 2 for interaction terms (injury group × SDQ subscales) ranged from 6.3 to 10.6 ( P values <.001 to .043) across parent- and child-reported models. In contrast, larger group differences (mTBI > OI) in postconcussion symptoms were associated with milder hyperactivity (Wald's χ 2 : 15.3-43.0, all P < .001), milder peer problems (Wald's χ 2 : 11.51, P = .003), and higher social functioning (Wald's χ 2 : 12.435, P = .002). CONCLUSIONS: Preinjury psychosocial function moderates postconcussion symptoms in pediatric mTBI, highlighting the importance of assessing preinjury psychosocial function in children with mTBI.

Genotype-Phenotype Association in ABCA4-Associated Retinopathy.

Stargardt disease (STGD1) is the most common inherited retina degeneration. It is caused by biallelic ABCA4 variants, and no treatment is available to date. STGD1 shows marked phenotypic variability, especially regarding the age of onset. The underlying genotype can partially explain this variability. Notably, a subset of ABCA4 variants was previously associated with an earlier disease onset than truncating ABCA4 variants, pointing toward pathogenic mechanisms beyond the loss of gene function in these patients. On the other end of the spectrum, variants such as p.Gly1961Glu were associated with markedly slower extrafoveal disease progression. Given that these drastic differences in phenotype are based on genotype (resulting in important prognostic implications for patients), this chapter reviews previous approaches to genotype-phenotype correlation analyses in STGD1.

Are Self-Reported and Parent-Reported Attention Problems and Hyperactivity Associated With Higher Rates of Concussion in Youth Ice Hockey Players?

OBJECTIVE: To examine the association between self-reported and parent-reported attention problems and hyperactivity and rates of injury and concussion in Canadian youth ice hockey players. DESIGN: Secondary analyses of 2 prospective cohort studies. SETTING: Canadian youth ice hockey teams. PARTICIPANTS: Ice hockey players (ages 11-17 years) were recruited by team, over 4 seasons (2011-2016). A combined 1709 players contributing 1996 player-seasons were analyzed (257 players participated in more than one season). ASSESSMENT OF RISK FACTORS: Data were collected from preseason baseline questionnaires, including child and parent proxy forms of the Behavior Assessment System for Children, second edition. MAIN OUTCOME MEASURES: Injury and concussion rates and incidence rate ratios (IRR) comparing players with and without self-identified or parent-identified attention problems and hyperactivity, adjusted for covariates (ie, body checking policy, previous injury/concussion, and age) and a random effect for team, were estimated using multiple multilevel negative binomial regression. RESULTS: When analyzed continuously, rates of concussion increased with higher self-reported and parent-reported measures of attention problems [IRR SELF = 1.025; 95% confidence interval (CI): 1.011-1.040; IRR PARENT = 1.032; 95% CI: 1.008-1.057]. Self-reported hyperactivity was significantly associated with concussion (IRR = 1.021; 95% CI: 1.007-1.035), but parent-reported hyperactivity was not (IRR = 1.005; 95% CI: 0.983-1.028). A T score ≥ 60 cutoff combining attention problems and hyperactivity scores (an estimate of probable attention-deficit hyperactivity disorder) was not significantly associated with rates of injury or concussion. CONCLUSIONS: Attention problems and hyperactivity may place youth ice hockey players at increased risk of concussion and injury. Preseason assessments could identify players for targeted concussion education and risk reduction strategies.

Psychosocial Factors Associated With Time to Recovery After Concussion in Adolescent Ice Hockey Players.

OBJECTIVE: To investigate the association between psychosocial factors and physician clearance to return to play (RTP) in youth ice hockey players after sport-related concussion. DESIGN: Prospective cohort study, Safe to Play (2013-2018). SETTING: Youth hockey leagues in Alberta and British Columbia, Canada. PARTICIPANTS: Three hundred fifty-three ice hockey players (aged 11-18 years) who sustained a total of 397 physician-diagnosed concussions. INDEPENDENT VARIABLES: Psychosocial variables. MAIN OUTCOME MEASURES: Players and parents completed psychosocial questionnaires preinjury. Players with a suspected concussion were referred for a study physician visit, during which they completed the Sport Concussion Assessment Tool (SCAT3/SCAT5) and single question ratings of distress and expectations of recovery. Time to recovery (TTR) was measured as days between concussion and physician clearance to RTP. Accelerated failure time models estimated the association of psychosocial factors with TTR, summarized with time ratios (TRs). Covariates included age, sex, body checking policy, days from concussion to the initial physician visit, and symptom severity at the initial physician visit. RESULTS: Self-report of increased peer-related problems on the Strengths and Difficulties Questionnaire (TR, 1.10 [95% CI, 1.02-1.19]), higher ratings of distress about concussion outcomes by participants (TR, 1.06 [95% CI, 1.01-1.11]) and parents (TR, 1.05 [95% CI, 1.01-1.09]), and higher parent ratings of distress about their child's well-being at the time of injury (TR, 1.06 [95% CI, 1.02-1.09]) were associated with longer recovery. CONCLUSIONS: Greater pre-existing peer-related problems and acute distress about concussion outcomes and youth well-being predicted longer TTR. Treatment targeting these psychosocial factors after concussion may promote recovery.

Targeting Novel LPXTG Surface Proteins with Monoclonal Antibodies for Immunomagnetic Separation of Listeria monocytogenes.

The Gram-positive bacterium Listeria monocytogenes causes a significantly high percentage of fatalities among human foodborne illnesses. Surface proteins, specifically expressed from a wide range of L. monocytogenes serotypes under selective enrichment culture conditions, can serve as targets for the isolation of this pathogen using antibody-based methods to facilitate molecular detection. In this study, monoclonal antibodies (MAbs), previously raised against the L. monocytogenes LPXTG surface proteins LMOf2365_0639 and LMOf2365_0148, were investigated for their ability to isolate L. monocytogenes from bacterial samples with immunomagnetic separation (IMS). Only 1 out of 35 MAbs against LMOf2365_0639, M3644, was capable of capturing L. monocytogenes. Among all the 24 MAbs examined against LMOf2365_0148, 4 MAbs, M3686, M3697, M3699, and M3700, were capable of capturing L. monocytogenes cells specifically from abbreviated primary selective enrichment cultures in either Palcam or LEB/UVM1 media or from mixed samples containing target and nontarget bacteria. MAb M3686 showed a unique specificity with the capability to capture strains of seven L. monocytogenes serotypes (1/2a, 1/2b, 1/2c, 3a, 4a, 4b, and 4d). These promising MAbs were subsequently characterized by quantitative measurements of antigen-binding affinity using surface plasmon resonance analysis and epitope mapping using overlapping recombinant polypeptides. The usefulness of these MAbs to LMOf2365_0148 in bacterial capture was consistent with their high affinities with KD constants in the nanomolar range and can be explored further for the development of an automated IMS method suitable for routine isolation of L. monocytogenes from food and environmental samples.

Convergent Validity of Myheartsmap: A Pediatric Psychosocial Health Screening Tool.

Recognition of pediatric mental health concerns often depends on assessment by parents, educators, and primary care professionals. Therefore, a psychosocial screening instrument suitable for routine use in schools and primary care is needed. The Pediatric Quality of Life (PedsQL) and the Strengths and Difficulties Questionnaire (SDQ) are widely used for screening but lack adolescent-specific mental health measures. MyHEARTSMAP is an instrument assessing aspects of youth psychosocial health via four domains: Psychiatry, Function, Social, and Youth Health. We evaluated MyHEARTSMAP convergent validity with PedsQL and SDQ among 122 child-parent dyads participating in a larger concussion study. Convergent validity was assessed via correlations: MyHEARTSMAP Psychiatry and Function domains correlated strongly (r ≥ 0.44) and Social domain correlated weakly (r ≤ 0.25) to corresponding PedsQL and SDQ subscales, while Youth Health domain correlated moderately (r ≥ 0.31) to the tools' total scales. In conclusion, MyHEARTSMAP converges with PedsQL and SDQ, and benefits from the inclusion of adolescent-specific psychosocial measures.

Systematic analysis of physical examination characteristics of 94 individuals with Joubert syndrome: Keys to suspecting the diagnosis.

Joubert syndrome (JS) is a neurodevelopmental disorder characterized by hypotonia and developmental delay, as well as the obligatory molar tooth sign on brain imaging. Since hypotonia and developmental delay are nonspecific features, there must be a high level of clinical suspicion of JS so that the diagnostic brain imaging and/or molecular testing for the >38 genes associated with JS is/are obtained. The goal of this study was to analyze clinical photographs of a cohort of patients with JS to define a list of physical examination features that should prompt investigation for JS. Analysis of photographs from 94 individuals with JS revealed that there is a recognizable pattern of facial features in JS that changes over time as individuals age. Macrocephaly, head tilting even when looking straight ahead, eye movement abnormalities (oculomotor apraxia, nystagmus, strabismus), and ptosis are common in those with JS. Distinctive features in younger children include triangular-shaped open mouth with tongue protrusion; in older children and adults, mandibular prognathia and prominent nasal bridge are common.

The vitamin B12 processing enzyme, mmachc, is essential for zebrafish survival, growth and retinal morphology.

Cobalamin C (cblC) deficiency, the most common inborn error of intracellular cobalamin metabolism, is caused by mutations in MMACHC, a gene responsible for the processing and intracellular trafficking of vitamin B12. This recessive disorder is characterized by a failure to metabolize cobalamin into adenosyl- and methylcobalamin, which results in the biochemical perturbations of methylmalonic acidemia, hyperhomocysteinemia and hypomethioninemia caused by the impaired activity of the downstream enzymes, methylmalonyl-CoA mutase and methionine synthase. Cobalamin C deficiency can be accompanied by a wide spectrum of clinical manifestations, including progressive blindness, and, in mice, manifests with very early embryonic lethality. Because zebrafish harbor a full complement of cobalamin metabolic enzymes, we used genome editing to study the loss of mmachc function and to develop the first viable animal model of cblC deficiency. mmachc mutants survived the embryonic period but perished in early juvenile life. The mutants displayed the metabolic and clinical features of cblC deficiency including methylmalonic acidemia, severe growth retardation and lethality. Morphologic and metabolic parameters improved when the mutants were raised in water supplemented with small molecules used to treat patients, including hydroxocobalamin, methylcobalamin, methionine and betaine. Furthermore, mmachc mutants bred to express rod and/or cone fluorescent reporters, manifested a retinopathy and thin optic nerves (ON). Expression analysis using whole eye mRNA revealed the dysregulation of genes involved in phototransduction and cholesterol metabolism. Zebrafish with mmachc deficiency recapitulate the several of the phenotypic and biochemical features of the human disorder, including ocular pathology, and show a response to established treatments.