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Marek's Disease (MD), which can result in neurological damage and tumour formation, has large effects on the economy and animal welfare of the poultry industry worldwide. Previously, we mapped autosomal MD QTL regions (QTLRs) by individual genotyping of an F 6 population from a full-sib advanced intercross line. We further mapped MD QTLRs on the chicken Z chromosome (GGZ) using the same F 6 population, and by selective DNA pooling (SDP) of 8 elite egg production lines. Here we used SDP of the same pools used on GGZ to map autosomal MD QTLRs. Thirty-seven QTLRs were found. Seven of the QTLRs were tested by all sires from the same 8 lines, individually genotyped for QTLR markers. Five of the tested QTLRs were confirmed. Linkage disequilibrium (LD) was calculated for all QTLR markers on the same chromosome, and complex LD blocks were found. Distribution of P and LD values were used to assess the QTLR causative elements. Allele substitution effects were calculated based on both pooled SNP microarray genotypes, and individual genotypes of QTLRs markers. Substantial allele effect and contribution to the phenotypic and genotypic variation were obtained. The results explain part of the MD response, and provide targets for mitigating MD., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: Institutional Review Board Statement: The animal study protocol was approved by Hy-Line International Institutional Animal Care and Use Committee guidelines. Hy-Line do not have specific project identification codes. All of these samples had been collected in the past and stored frozen until use. At the termination of the study animals were humanely euthanized under the approval of the Hy-Line IACUC and supervision of licensed veterinarians., (© 2024. The Author(s).)

Intentional weight loss has been shown to increase bone loss short term but the long-term effects are not known. Data from the Look AHEAD clinical trial shows that a long term intentional weight loss intervention was associated with greater bone loss at the hip in men., Purpose: Intentional weight loss has been shown to increase bone loss short term and increase frailty fracture risk, but the long-term effects on bone mineral density (BMD) are not known., Methods: Data from a subgroup from the Look AHEAD (LA) multicenter, randomized clinical trial was used to evaluate whether a long term intentional weight loss intervention would increase bone loss. In a preplanned substudy, BMD was assessed at 5 of the 16 LA clinical centers using dual-energy X-ray absorptiometry at baseline, year 8, and the observational visit 12.6-16.3 years after randomization (year 12-16)., Results: At year 8, bone density loss (%) was greater in the Intensive Lifestyle Intervention (ILI) group compared with the control group (DSE) for the femoral neck (p = 0.0122) but this finding was not observed at the year 12-16 visit. In analyses stratified by gender, bone density loss (%) was greater at the total hip for men in the ILI group than the DSE group at both the year 8 and year 12-16 visits (year 8 p = 0.0263 and year 12-16 p = 0.0062). This finding was not observed among women., Conclusion: Long term intentional weight loss was associated with greater bone loss at the hip in men. These results taken with the previously published Look AHEAD data from the entire clinical trial showing increased frailty fracture risk with weight loss in the ILI group suggest that when intentional weight loss is planned, consideration of bone density preservation and fracture prevention strategies is warranted., Trial Registration: Clinicaltrials.gov Identifier: NCT00017953. June 21, 2001., (© 2023. The Author(s).)

Marek's Disease (MD) has a significant impact on both the global poultry economy and animal welfare. The disease pathology can include neurological damage and tumour formation. Sexual dimorphism in immunity and known higher susceptibility of females to MD makes the chicken Z chromosome (GGZ) a particularly attractive target to study the chicken MD response. Previously, we used a Hy-Line F 6 population from a full-sib advanced intercross line to map MD QTL regions (QTLRs) on all chicken autosomes. Here, we mapped MD QTLRs on GGZ in the previously utilized F 6 population with individual genotypes and phenotypes, and in eight elite commercial egg production lines with daughter-tested sires and selective DNA pooling (SDP). Four MD QTLRs were found from each analysis. Some of these QTLRs overlap regions from previous reports. All QTLRs were tested by individuals from the same eight lines used in the SDP and genotyped with markers located within and around the QTLRs. All QTLRs were confirmed. The results exemplify the complexity of MD resistance in chickens and the complex distribution of p -values and Linkage Disequilibrium (LD) pattern and their effect on localization of the causative elements. Considering the fragments and interdigitated LD blocks while using LD to aid localization of causative elements, one must look beyond the non-significant markers, for possible distant markers and blocks in high LD with the significant block. The QTLRs found here may explain at least part of the gender differences in MD tolerance, and provide targets for mitigating the effects of MD.

Background: Children with developmental disabilities are vulnerable to morbidity associated with COVID-19., Aims: To understand attitudes toward routine childhood vaccinations versus the COVID-19 vaccine in a population of families affected by mitochondrial disease (MtD), a form of developmental disability., Methods and Procedures: An online survey was administered via several advocacy groups for children with MtD., Outcomes and Result: Eighty-six percent of families reported being up to date with the childhood vaccine schedule and seventy percent reported that their affected child receives the annual flu shot. However, only fifty percent reported that the benefits of the COVID-19 vaccine outweighed the risk for their affected child. One quarter of families expressed concern that their child may become sick or deteriorate after the COVID-19 vaccine. In comparison to other routine childhood vaccines, families expressed less confidence in the COVID-19 vaccine., Conclusions and Implications: Families affected by this population of developmental disabilities are more comfortable with the vaccines included in the routine childhood immunization schedule than with the newly introduced COVID-19 vaccine, even despite this group's vulnerability., Competing Interests: Conflicts of Interest The authors have no conflicts of interest to disclose., (Published by Elsevier Ltd.)

Background: Pediatric patients undergoing intestinal rehabilitation (IR) using parenteral nutrition (PN) are at higher risk for intestinal failure-associated liver disease (IFALD). Nutrition support, growth, and liver enzymes must be closely monitored while incorporating hepatoprotective lipid injectable emulsions for optimal patient outcomes., Objective: Describe trends of liver profile and nutrition outcomes for pediatric patients undergoing IR using SMOFlipid[SO,MCT,OO,FO-ILE])., Methods: After IRB approval, patients undergoing IR using SO,MCT,OO,FO-ILE were observed prospectively from January 1, 2017, through December 1, 2019. The following values were documented monthly: aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TB), triene/tetraene ratio (TTR), micronutrient and trace element levels, z-scores for growth, and nutrition support regimen. Values were compared., Results: The group involved 16 pediatric patients for an average of 16.4 months on SO,MCT,OO,FO-ILE. By the end of the study, mean PN hours per day decreased by 34.7%, P < 0.0001. Mean PN calories per kilogram decreased from 60.4 to 48.3, P = 0.004. SO,MCT,OO,FO-ILE calories met the recommended dietary intake goal of 30% at the average 1.6 g/kg. Growth z-scores increased in those <2 YOA , although the body mass index decreased in our >2 YOA cohort. Total nutrition received from PN decreased to 62%: a 32% change, P = 0.001. There were no statistically significant changes in AST or ALT. TB decreased by 67.08%, P <0.05. No essential fatty acid deficiency was reported (TTR < 0.02). There were no changes in micronutrient and trace element deficiencies. There was zero new incidences of IFALD., Conclusions: SO,MCT,OO,FO-ILE may be used long term in pediatric patients while promoting growth and development., (© 2021 American Society for Parenteral and Enteral Nutrition.)

Background and Objectives: Anti-NMDA receptor encephalitis (anti-NMDARE) is one of the most common causes of encephalitis. It typically presents in adolescence and young adulthood, but little is known about its potential long-term consequences across the lifespan. Adaptive behavior describes an individual's ability to respond and adapt to environmental demands and unanticipated changes in daily routines. In this study, we evaluate the relationship between features from clinical presentation, including age, and long-term adaptive behavior in participants with anti-NMDARE., Methods: Cross-sectional informant-reported data were collected between 2017 and 2019 from 41 individuals/caregivers of individuals with anti-NMDARE treated at 3 major academic hospitals. Neurologic disability was assessed by record review using the modified Rankin Scale (mRS). Functional outcomes were assessed using the validated Adaptive Behavior Assessment System, Third Edition (ABAS-3)., Results: The mean age at the time of study enrollment was 23.4 years (SD 17.0 years), and the mean time from symptom onset to study enrollment was 4.0 years. Seventeen participants were aged <12 years at symptom onset, 19 participants were aged 12-30 years, and 5 participants were aged >30 years. Mean ABAS-3 scores at study enrollment for all participants were in the average range (mean general adaptive composite standard score 92.5, SD 18.7). Individuals aged <12 years at symptom onset had lower mean ABAS-3 scores and were in the below average range compared with those aged 12-30 years at symptom onset, whose mean scores were in the average range (87 vs 99, p < 0.05). Similar differences were seen in 3 of the individual subscales (functional academics, health and safety, and self-care). There were no significant differences in mRS scores between age groups ( p > 0.05)., Discussion: Although anti-NMDARE is associated with an overall favorable outcome, younger age at onset associates with worse long-term adaptive behavior despite no differences in neurologic disability. These findings suggest that the disease may have distinct consequences on the early developing brain. Future studies should evaluate behavioral recovery and quality of life after anti-NMDARE and identify additional factors associated with differential recovery., (© 2022 American Academy of Neurology.)

Background: A challenge during the COVID-19 pandemic has been widespread adherence to risk-reducing behaviors. Individuals with mitochondrial disease (MtD) are special population with an increased risk of morbidity associated with infection., Purpose: To measure risk mitigation behaviors (RMBs) in families affected by MtD and identify factors that may influence these behaviors., Methods: An online questionnaire was distributed in April and June 2020. Individuals with MtD or their caregivers completed the survey., Results: We received 529 eligible responses with n = 312 completing all questions for our multivariate regression model. The most common RMBs were increased hand washing (96%), social distancing (94%), and avoiding public gatherings (93%). Higher numbers of recent healthcare visits (b = 0.62, p < 0.05) and expressed fear of the MtD patient contracting COVID-19 (b = 0.92, p < 0.05) were associated with more RMBs. Living in a rural community (b = -0.99,p < 0.05) and a history of COVID-19 testing (b = -2.14,p < 0.01) were associated with fewer RMBs., Conclusions: Our results suggest that during the COVID-19 pandemic, families affected by MtD have near universal adherence to basic RMBs. This may be motivated by fear of the severe morbidity associated with infection in MtD. Patients with frequent healthcare visits may be sicker and therefore take more precautions. Living in a rural community may also impact these behaviors. People who practice fewer RMBs may be more likely to seek testing. Our findings may generalize to other chronic diseases., (© 2021 Published by Elsevier Inc.)

Background: Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma-pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh-like syndromes., Methods and Results: Here, we describe a case of a 9-year-old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA, a known pathogenic variant (c.91C>T (p.R31*)), and a variant of unknown significance (c.454G>A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder., Conclusion: We, therefore, consider whether c.454G>A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Prenatal infections have long been recognized as important, preventable causes of developmental disabilities. The list of pathogens that are recognized to have deleterious effects on fetal brain development continues to grow, most recently with the association between Zika virus (ZIKV) and microcephaly. To answer clinical questions in real time about the impact of a novel infection on developmental disabilities, an historical framework is key. The lessons learned from three historically important pathogens: rubella, cytomegalovirus, and ZIKV, and how these lessons are useful to approach emerging congenital infections are discussed in this review. Congenital infections are preventable causes of developmental disabilities and several public health approaches may be used to prevent prenatal infection. When they cannot be prevented, the sequelae of prenatal infection may be treatable. WHAT THIS PAPER ADDS: The list of prenatal infections associated with developmental disabilities continues to increase. Lessons learned from rubella, cytomegalovirus, and Zika virus have implications for new pathogens. Severity of illness in the mother does not correlate with severity of sequelae in the infant., (© 2020 Mac Keith Press.)

Marek's disease (MD) represents a significant global economic and animal welfare issue. Marek's disease virus (MDV) is a highly contagious oncogenic and highly immune-suppressive α-herpes virus, which infects chickens, causing neurological effects and tumour formation. Though partially controlled by vaccination, MD continues to have a profound impact on animal health and on the poultry industry. Genetic selection provides an alternative and complementary method to vaccination. However, even after years of study, the genetic mechanisms underlying resistance to MDV remain poorly understood. The Major Histocompatability Complex (MHC) is known to play a role in disease resistance, along with a handful of other non-MHC genes. In this study, one of the largest to date, we used a multi-facetted approach to identify QTL regions (QTLR) influencing resistance to MDV, including an F 6 population from a full-sib advanced intercross line (FSIL) between two elite commercial layer lines differing in resistance to MDV, RNA-seq information from virus challenged chicks, and genome wide association study (GWAS) from multiple commercial lines. Candidate genomic elements residing in the QTLR were further tested for association with offspring mortality in the face of MDV challenge in eight pure lines of elite egg-layer birds. Thirty-eight QTLR were found on 19 chicken chromosomes. Candidate genes, miRNAs, lncRNAs and potentially functional mutations were identified in these regions. Association tests were carried out in 26 of the QTLR, using eight pure lines of elite egg-layer birds. Numerous candidate genomic elements were strongly associated with MD resistance. Genomic regions significantly associated with resistance to MDV were mapped and candidate genes identified. Various QTLR elements were shown to have a strong genetic association with resistance. These results provide a large number of significant targets for mitigating the effects of MDV infection on both poultry health and the economy, whether by means of selective breeding, improved vaccine design, or gene-editing technologies.

Objective: To examine the effects of an intensive lifestyle intervention (ILI) on cardiovascular disease (CVD), the Action for Health in Diabetes (Look AHEAD) trial randomized 5,145 participants with type 2 diabetes and overweight/obesity to a ILI or diabetes support and education. Although the primary outcome did not differ between the groups, there was suggestive evidence of heterogeneity for prespecified baseline CVD history subgroups (interaction P = 0.063). Event rates were higher in the ILI group among those with a CVD history (hazard ratio 1.13 [95% CI: 0.90-1.41]) and lower among those without CVD (hazard ratio 0.86 [95% CI: 0.72-1.02])., Methods: This study conducted post hoc analyses of the rates of the primary composite outcome and components, adjudicated cardiovascular death, nonfatal myocardial infarction (MI), stroke, and hospitalization for angina, as well as three secondary composite cardiovascular outcomes., Results: Interaction P values for the primary and two secondary composites were similar (0.060-0.064). Of components, the interaction was significant for nonfatal MI (P = 0.035). This interaction was not due to confounding by baseline variables, different intervention responses for weight loss and physical fitness, or hypoglycemic events. In those with a CVD history, statin use was high and similar by group. In those without a CVD history, low-density lipoprotein cholesterol levels were higher (P = 0.003) and statin use was lower (P ≤ 0.001) in the ILI group., Conclusions: Intervention response heterogeneity was significant for nonfatal MI. Response heterogeneity may need consideration in a CVD-outcome trial design., (© 2020 The Obesity Society.)

Ethanol tolerance, a polygenic trait of the yeast Saccharomyces cerevisiae , is the primary factor determining industrial bioethanol productivity. Until now, genomic elements affecting ethanol tolerance have been mapped only at low resolution, hindering their identification. Here, we explore the genetic architecture of ethanol tolerance, in the F6 generation of an Advanced Intercrossed Line (AIL) mapping population between two phylogenetically distinct, but phenotypically similar, S. cerevisiae strains (a common laboratory strain and a wild strain isolated from nature). Under ethanol stress, 51 quantitative trait loci (QTLs) affecting growth and 96 QTLs affecting survival, most of them novel, were identified, with high resolution, in some cases to single genes, using a High-Resolution Mapping Package of methodologies that provided high power and high resolution. We confirmed our results experimentally by showing the effects of the novel mapped genes: MOG1 , MGS1 , and YJR154W. The mapped QTLs explained 34% of phenotypic variation for growth and 72% for survival. High statistical power provided by our analysis allowed detection of many loci with small, but mappable effects, uncovering a novel "quasi-infinitesimal" genetic architecture. These results are striking demonstration of tremendous amounts of hidden genetic variation exposed in crosses between phylogenetically separated strains with similar phenotypes; as opposed to the more common design where strains with distinct phenotypes are crossed. Our findings suggest that ethanol tolerance is under natural evolutionary fitness-selection for an optimum phenotype that would tend to eliminate alleles of large effect. The study provides a platform for development of superior ethanol-tolerant strains using genome editing or selection., (Copyright © 2019 Haas, Horev, Lipkin, Kesten, Portnoy, Buhnik-Rosenblau, Soller and Kashi.)

Improving feed efficiency (FE) is a major goal for the livestock industry. Previously, we have identified 48 SNP markers distributed over 32 genes significantly associated with residual feed intake (RFI) in Israeli Holstein male calves, the most significant of which are located in the bovine FABP4 gene. In the present study, we tested associations of eight of the FABP4 markers with RFI and feed conversion ratio (FCR), along with milk composition and feeding behavioral traits, in 114 lactating Israeli Holstein cows. Large allele effects were found, along with large contributions of FABP4 markers to the phenotypic variation [mean contribution of all significant markers ( P < 0.05), 15.4 and 12.0% for RFI and FCR, respectively] and genotypic variation [means of all significant markers ( P < 0.05), 75.7 and 32.4% in RFI and FCR, respectively]. However, the association of all significant FABP4 markers with FE and milk content traits was found in opposite directions, such that improved FE was accompanied by decreased milk content. Hence, before inclusion in breeding programs, the gain in FE must be economically balanced with the loss in milk contents. On the other hand, these findings imply that in any current improvement program concentrated on milk traits alone, without taking into account the effect on FE, the progress in milk composition is probably accompanied by deterioration of FE. These results, if confirmed in other populations and breeds, set FABP4 as a prime candidate in any marker-assisted selection program targeting FE as a whole and RFI in particular.

Clinicians who treat children with neurodevelopmental disabilities may encounter infants with congenital Zika syndrome or those exposed to Zika virus (ZIKV), either in utero or postnatally, in their practice and may have questions about diagnosis, management, and prognosis. In this special report, we reviewed the current literature to provide a comprehensive understanding of the findings and needs of children exposed to ZIKV in utero and postnatally. The current literature is sparse, and thus, this review is preliminary. We found that infants and children exposed to ZIKV in utero have a variety of health and developmental outcomes that suggest a wide range of lifelong physical and developmental needs. Postnatal exposure does not seem to have significant long-lasting health or developmental effects. We provide a comprehensive examination of the current knowledge on health and developmental care needs in children exposed to Zika in utero and postnatally. This can serve as a guide for health care professionals on the management and public health implications of this newly recognized population.

Aim: To quantify characteristics in acute flaccid myelitis (AFM) at acute and convalescent stages., Method: This was a retrospective case series of children with AFM evaluated at a single institution in the USA (2014-2017). Acute inflammatory/ischemic myelopathies were excluded. Neurological assessments and segmental quantitative analysis of signal abnormalities on magnetic resonance imaging (MRI) of the brain and spinal cord were performed., Results: Sixteen patients (11 males, five females) were evaluated. Median age at onset was 4 years (interquartile range [IQR] 3-6y). All had parainfectious acute-onset limb weakness, lower motor neuron examination, and spinal fluid pleocytosis. On acute spinal cord MRI, longitudinally extensive T2 hyperintensities were identified throughout the spinal cord mostly within grey matter; five out of 12 patients had dorsal brainstem T2 hyperintensities. At a median of 2 months follow-up (IQR 2-3mo), spinal cord MRI improved in seven out of nine patients although focal T2 hyperintensities persisted in cervical and lumbar grey matter. At a median follow-up of 4 months (IQR 2-6mo), Medical Research Council sum score rose from a median of 29 to 32; distal muscle groups improved more than proximal ones; four out of 16 patients were ventilator-dependent; and two out of 16 patients were quadriplegic., Interpretation: While patients may show marked improvement on neuroimaging from acute to convalescent stages, the majority of children with AFM have limited motor recovery and continued disability. Clinicians should consider the timing of clinical and neuroimaging exams when assessing diagnosis and prognosis., What This Paper Adds: During the 2014 to 2017 acute flaccid myelitis outbreak in the USA, clinical recovery was better in distal than proximal muscle groups. Lumbar spinal cord showed more residual abnormalities at convalescence., (© 2018 Mac Keith Press.)

Objective: To assess the inpatient hospitalization burden and costs of patients with autoimmune encephalitis (AE) at a tertiary care institution., Methods: Adult inpatients with AE were identified retrospectively from July 1, 2005, to June 30, 2015. Demographic and clinical data were collected and analyzed. Billing data were compared to those of patients with herpes simplex encephalitis (HSE). Charges were adjusted for inflation., Results: Of 244 admissions for encephalitis reviewed, 63 patients met criteria for probable or definite AE. Thirty-one (49%) patients were antibody positive, and 27 (43%) were admitted to the intensive care unit (ICU). Median hospital charges per patient with AE were more than $70,000; median length of stay (LOS) was 15 days; and in-hospital mortality was 6%. Patients admitted to the ICU had substantially higher median hospital charges (ICU $173,000 per admission vs non-ICU $50,000 per admission, p < 0.001). LOS was strongly associated with charges and was driven by delay in diagnosis of AE, prolonged treatment courses, and lack of response to therapy. Compared with HSE, median hospital charges per patient with AE were nearly 4 times higher, median AE LOS was 3 times higher, and total charges over the study period were nearly twice as high., Conclusions: Patients with AE used more inpatient health care resources per patient during a 10-year period than patients with HSE at our institution. ICU-admitted patients with AE were responsible for a substantially higher financial burden than non-ICU-admitted patients with AE. Our data underscore the need for the development of novel diagnostic and therapeutic modalities to improve patient outcomes and to decrease hospital burden in AE., (© 2019 American Academy of Neurology.)

Importance: Acute flaccid myelitis (AFM) is an emerging poliolike illness of children whose clinical spectrum and associated pathogens are only partially described. The case definition is intentionally encompassing for epidemiologic surveillance to capture all potential AFM cases. Defining a restrictive, homogenous subpopulation may aid our understanding of this emerging disease., Objective: To evaluate the extent to which the US Centers for Disease Control and Prevention (CDC) case definition of AFM incorporates possible alternative diagnoses and to assess the plausibility of a case definition that enriches the biological homogeneity of AFM for inclusion in research studies., Design, Setting, and Participants: Retrospective case analysis of children younger than 18 years diagnosed as having AFM between 2012 and 2016 using the CDC case definition. Group 1 included patients recruited from the United States and Canada based on the CDC case definition of AFM. Group 2 included patients referred to the Johns Hopkins Transverse Myelitis Center for evaluation of suspected AFM. Patients' records and imaging data were critically reviewed by 3 neurologists to identify those cases with definable alternative diagnoses, and the remaining patients were categorized as having restrictively defined AFM (rAFM). Clinical characteristics were compared between patients with rAFM (cases) and those with alternative diagnoses, and a case description distinguishing these AFM groups was identified. Interrater reliability of this description was confirmed for a subset of cases by a fourth neurologist. Data were analyzed between May 2017 and November 2018., Main Outcomes and Measures: Proportion of patients with possible alternative diagnosis., Results: Of the 45 patients who met the CDC AFM case definition and were included, the mean age was 6.1 years; 27 were boys (60%); and 37 were white (82%), 3 were Asian (7%), 1 was Hispanic (2%), and 4 were mixed race/ethnicity (9%). Of the included patients, 34 were classified as having rAFM, and 11 had alternate diagnoses (including transverse myelitis, other demyelinating syndromes, spinal cord stroke, Guillain-Barre syndrome, Chiari I myelopathy, and meningitis). Factors differing between groups were primarily asymmetry of weakness, lower motor neuron signs, preceding viral syndrome, symptoms evolving over hours to days, absence of sensory deficits, and magnetic resonance imaging findings. A case description was able to reliably define the rAFM group., Conclusions and Relevance: We present an approach for defining a homogeneous research population that may more accurately reflect the pathogenesis of the prototypical poliomyelitis-like subgroup of AFM. The definition of rAFM forms a blueprint for inclusion criteria in future research efforts, but more work is required for refinement and external validation.

Objective: Optical coherence tomography (OCT)-derived measures of the retina correlate with disability and cortical gray matter atrophy in multiple sclerosis (MS); however, whether such measures predict long-term disability is unknown. We evaluated whether a single OCT and visual function assessment predict the disability status 10 years later., Methods: Between 2006 and 2008, 172 people with MS underwent Stratus time domain-OCT imaging [160 with measurement of total macular volume (TMV)] and high and low-contrast letter acuity (LCLA) testing ( n  = 150; 87%). All participants had Expanded Disability Status Scale (EDSS) assessments at baseline and at 10-year follow-up. We applied generalized linear regression models to assess associations between baseline TMV, peripapillary retinal nerve fiber layer (pRNFL) thickness, and LCLA with 10-year EDSS scores (linear) and with clinically significant EDSS worsening (binary), adjusting for age, sex, optic neuritis history, and baseline disability status., Results: In multivariable models, lower baseline TMV was associated with higher 10-year EDSS scores (mean increase in EDSS of 0.75 per 1 mm 3 loss in TMV (mean difference = 0.75; 95% CI: 0.11-1.39; P  = 0.02). In analyses using tertiles, individuals in the lowest tertile of baseline TMV had an average 0.86 higher EDSS scores at 10 years (mean difference = 0.86; 95% CI: 0.23-1.48) and had over 3.5-fold increased odds of clinically significant EDSS worsening relative to those in the highest tertile of baseline TMV (OR: 3.58; 95% CI: 1.30-9.82; P trend  = 0.008). pRNFL and LCLA predicted the 10-year EDSS scores only in univariate models., Interpretation: Lower baseline TMV measured by OCT significantly predicts higher disability at 10 years, even after accounting for baseline disability status., Competing Interests: A.R., O.C.M., K.F., E.G.L., J.R., E.M., E.S.S., S.B.S.M., J.N., N.G.C., D.R., and C.C has nothing to report. S.D.N. has received consultant fees for scientific advisory boards from Biogen, Genentech, Celgene, EMD Serono and has received research funding from Biogen, Novartis, and Genentech (paid directly to institution). L.J.B. has received consulting fees from Biogen. E.F. has received speaker and consulting fees from Genzyme, Acorda, Novartis, and TEVA. T.F. has received speaker and consulting fees from Acorda, Genzyme, and Novartis. S.S. has received consulting fees from Medical Logix for the development of CME programs in neurology, consulting fees from Axon Advisors LLC and served on scientific advisory boards for Biogen‐Idec, Genzyme, Genentech Corporation & Novartis. He receives research support from Genentech Corporation and Biogen Idec, and received support from the Race to Erase MS foundation. P.A.C. has received personal honorariums for consulting from Biogen and Disarm Therapeutics. He is PI on research grants to Johns Hopkins from MedImmune, Annexon, Biogen, and Genzyme.

GM3 synthase deficiency is due to biallelic pathogenic variants in ST3GAL5, which encodes a sialyltransferase that synthesizes ganglioside GM3. Key features of this rare autosomal recessive condition include profound intellectual disability, failure to thrive and infantile onset epilepsy. We expand the phenotypic spectrum with 3 siblings who were found by whole exome sequencing to have a homozygous pathogenic variant in ST3GAL5, and we compare these cases to those previously described in the literature. The siblings had normal birth history, subsequent developmental stagnation, profound intellectual disability, choreoathetosis, failure to thrive, and visual and hearing impairment. Ichthyosis and self-injurious behavior are newly described in our patients and may influence clinical management. We conclude that GM3 synthase deficiency is a neurodevelopmental disorder with consistent features of profound intellectual disability, choreoathetosis, and deafness. Other phenotypic features have variable expressivity, including failure to thrive, epilepsy, regression, vision impairment, and skin findings. Our analysis demonstrates a broader phenotypic range of this potentially under-recognized disorder.

Leukodystrophies are a heterogeneous class of genetic diseases affecting the white matter in the central nervous system with a broad range of clinical manifestations and a frequently progressive course. An interest in precision medicine has emerged over the last several decades, and biomedical research in leukodystrophies has made exciting advances along this front through therapeutic target discovery and novel disease model systems. In this review, we discuss current and emerging therapeutic approaches in leukodystrophies, including gene therapy, antisense oligonucleotide therapy, CRISPR/CAS-based gene editing, and cell and stem cell based therapies.

We delineate the clinical characteristics, incidence, and prevalence of pediatric-onset multiple sclerosis in Abu Dhabi, United Arab Emirates, from 2010 to 2014. Eighty-two patients (65% female) were identified. Fifty-three (64.6%) were Emiratis (45 from Abu Dhabi and 8 from 5 other emirates) and 29 were expatriates. Mean age of onset was 15.9 years overall, 15.3 years in males and 16.3 years in females. Patients with onset before age 12 years presented with visual symptoms while those with onset after age 12 years presented with a mixture of visual, motor and sensory symptoms. Interferon beta-1a was the most frequently used disease-modifying therapy (48%). In Abu Dhabi Emirati nationals, the age- and sex-adjusted prevalences were 26/100 000 for males and 36/100 000 for females. The total incidence in Emirati nationals from 2010 to 2014 was 2.3/100 000 for ages 10 to 14 years and 7.2/100 000 for ages 15 to 19 years. By comparison with international cohorts, the incidence of pediatric-onset multiple sclerosis in Abu Dhabi is higher whereas gender distribution is similar.

Objectives: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. Understanding the endophenotype of children with both ASD and ADHD may impact clinical management. In this study, we compare the comorbidity of anxiety and mood disorders in children with ASD, with and without ADHD., Methods: We performed a cross-sectional study of children with ASD who were enrolled in the Interactive Autism Network, an Internet-mediated, parent-report, autism research registry. Children ages 6 to 17 years with a parent-reported, professional, and questionnaire-verified diagnosis of ASD were included. Data were extracted regarding parent-reported diagnosis and/or treatment of ADHD, anxiety disorder, and mood disorder. ASD severity was measured by using Social Responsiveness Scale total raw scores., Results: There were 3319 children who met inclusion criteria. Of these, 1503 (45.3%) had ADHD. Comorbid ADHD increased with age ( P < .001) and was associated with increased ASD severity ( P < .001). A generalized linear model revealed that children with ASD and ADHD had an increased risk of anxiety disorder (adjusted relative risk 2.20; 95% confidence interval 1.97-2.46) and mood disorder (adjusted relative risk 2.72; 95% confidence interval 2.28-3.24) compared with children with ASD alone. Increasing age was the most significant contributor to the presence of anxiety disorder and mood disorder., Conclusions: Co-occurrence of ADHD is common in children with ASD. Children with both ASD and ADHD have an increased risk of anxiety and mood disorders. Physicians who care for children with ASD should be aware of the coexistence of these treatable conditions., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

Emerging viral infections of the nervous system represent a major global public health concern in the 21st century. They are caused primarily by RNA viruses and are mostly associated with acute or subacute encephalitis. The spectrum of associated central or peripheral nervous system disorders is broad, and results either from a direct viral effect or due to the host immune responses against the infection. Emerging viral infections impose substantial neurological morbidity and mortality, particularly in low- and middle-income regions. In the past five decades, vector-borne viruses primarily transmitted by arthropods, or arboviruses, have been responsible for epidemics with a high burden of neurological disease, like the 2015-2016 Zika virus epidemic in the Americas. Viruses that have become neurovirulent for humans after geographical expansion include West Nile, Dengue, and Zika viruses. Factors such as animal migration, disruption of ecological niches, and cross-species contact have caused old viruses to reappear and cause neurological disease, as is the case of Ebola virus. In addition to these biological challenges, current preventive strategies, vaccination, and diagnostic and therapeutic approaches remain limited. We review the clinical-virological features and global impact of the most relevant emerging viral infections of the nervous system as they are projected over the 21st century., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

This study evaluates long-term neurobehavioral function in patients with clinically diagnosed autoimmune encephalitis (AE) of various etiologies through retrospective chart review and a cross-sectional structured telephone interview. Of 77 patients meeting clinical diagnostic criteria for AE over a ten year period, 39/77 (51%) patients had known AE-associated antibodies, and 38/77 (49%) had no detected antibody. 9/77 (12%) died, and 26/77 (34%) had "poor" neurologic disability score (mRS 3-5) at the last documented follow-up. 44 participants enrolled in the telephone interview, of whom 38/44 (86%) endorsed ongoing difficulties with fatigue, emotional lability, short-term memory, and/or concentration. On standardized assessment of adaptive behavior (ABAS-3), 23/44 (52%) scored "below average" (general adaptive composite: mean 86.95, standard deviation 18.45). Of the participants with "good" neurologic disability outcome (mRS 0-2), 12/30 (40%) scored "below average" in adaptive behavior. In summary, patients with AE frequently have persistent impairments in neurologic disability, neurocognitive symptomatology, and adaptive behavior, which may not be adequately captured by routine neurologic assessments. Comprehensively elucidating these persistent neurobehavioral impairments and predicting which patients are at highest risk will allow for optimal care of patients and their families., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This study compared neurologic disability and adaptive function in children and adults >1 year following anti- N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis diagnosis. Retrospective record review identified 12 patients with anti-NMDAR encephalitis. At last follow-up, all surviving patients had "good" modified Rankin Score (0-2). Four children, 6 adults, and their families participated in a telephone interview. Median duration since diagnosis was similar for children (2.42 years, interquartile range 2.12-3.32) and adults (3.55 years, interquartile range 2.08-5.50 years). 3/4 (75%) pediatric and 3/5 (60%) adult patients reported neuropsychiatric symptoms (fatigue, emotional lability, short-term memory deficits or concentration deficits). On the Adaptive Behavior Assessment System (ABAS-3), although overall adaptive function was intact for adults (general adaptive composite standard score: median 104.5, interquartile range 98.8-112.5), the median for children was below average (General Adaptive Composite Standard Score: median 82.0, interquartile range 79.0-89.0). Children with anti-NDMAR encephalitis may have long-term effects impacting daily life while adults regain normal function.

Introduction: Multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, is increasingly being recognized in children and adolescents. Pediatric MS follows a relapsing-remitting course at onset, with a risk for early cognitive impairment. Areas covered: In this review, we discuss the clinical features of acute demyelinating syndromes in children and risk factors that increase the likelihood of a diagnosis of MS. We also address the application of diagnostic criteria for MS in children, immunological features, therapeutic options and psychosocial considerations for children and adolescents with MS. Expert commentary: Collaborative multicenter clinical trials and research efforts are key to the advancement in understanding the pathophysiology and therapeutic strategies for multiple sclerosis across the lifespan.

We examined longitudinal neurodevelopmental outcomes in a series of infants with microcephaly. Retrospective review identified neonatal intensive care unit follow-up clinic patients with a diagnostic code of microcephaly, verified by head circumference less than the fifth precentile (WHO growth curves). Data were collected regarding clinical history and developmental assessments by Capute Scales and gross motor age equivalent. Developmental Quotient (DQ) was age adjusted up until 2 years for preterm infants. Twenty-two infants had microcephaly. At latest follow-up (3-66 months, mean 27.2), 73% had delay (DQ < 70) in ≥1 area of development: gross motor 65% (mean DQ 56.8), visual-motor 59% (mean DQ 62.7), and language 59% (mean DQ 65.9). In this sample, postnatal onset and diagnosis of epilepsy were associated with lower DQs. We conclude that infants with microcephaly are at significant risk for delay across all aspects of development and for long-term disability. Postnatal etiologies of microcephaly and infants with comorbid epilepsy had worse outcomes.

Optical coherence tomography (OCT) is a relatively new imaging technology that has been introduced as a powerful biomarker in neurological disease, including multiple sclerosis. In this review, OCT as an imaging technique, its reproducibility and validation in multiple sclerosis, application to other neurodegenerative diseases and future technological directions are discussed., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: The effect of a weight-loss intervention on the masses of lean tissues and organs in humans is not well known., Objective: We studied the effects of a diet and exercise weight-loss intervention on skeletal muscle (SM) mass and selected organs over 2 y using MRI in overweight adults with type 2 diabetes., Design: Participants were 53 women and 39 men [mean ± SD: age 58 ± 7 y; body mass index (BMI; in kg/m 2 ) 32 ± 3] enrolled in the Look AHEAD (Action for Health in Diabetes) trial and randomly assigned to an intensive lifestyle intervention (ILI) or diabetes support and education (DSE) on whom 2 y of data were collected. MRI-derived measurements of SM, heart, liver, kidney, spleen, and pancreas were acquired., Results: Adjusted for baseline weight, height, age, sex, and ethnicity, the ILI group weighed (mean ± SE) 6.6 ± 0.7 kg less after 1 y and 5.2 ± 0.7 kg less after 2 y, whereas the DSE group did not change significantly (-0.4 ± 0.6 and -1.0 ± 0.7 kg after 1 and 2 y, respectively; P-interaction < 0.001). Total SM decreased in both groups during year 1 (-1.4 ± 0.2 kg; P < 0.001) with appendicular SM regained during year 2. Liver and spleen masses decreased in the ILI group (-0.12 ± 0.02 and -0.006 ± 0.003 kg, respectively) but were unchanged in the DSE group (0.00 ± 0.02 and 0.004 ± 0.003 kg, respectively). Kidney mass decreased by 0.013 ± 0.003 kg (P < 0.001) over 2 y in both groups., Conclusions: Decreases in liver (in Caucasians but not African Americans) and spleen were detected after a 6.2-kg weight reduction compared with a control group. SM and kidney mass decreased in both groups. Appendicular SM was regained during the second year whereas trunk SM was not. No evidence of a disproportionate loss of high-metabolic rate organs (heart, liver, kidney, spleen) compared with SM was found., (© 2017 American Society for Nutrition.)

The process from initial concerns to diagnosis of autism spectrum disorder (ASD) can be a long and complicated process. The traditional model for evaluation and diagnosis of ASD often consists of long wait-lists and evaluations that result in a 2-year difference between the earliest signs of ASD and mean age of diagnosis. Multiple factors contribute to this diagnostic bottleneck, including time-consuming evaluations, cost of care, lack of providers, and lack of comfort of primary care providers to diagnose autism. This article explores innovative clinical models that have been implemented to address this as well as future directions and opportunities., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Ecological and economic concerns drive the need to improve feed utilization by domestic animals. Residual feed intake (RFI) is one of the most acceptable measures for feed efficiency (FE). However, phenotyping RFI-related traits is complex and expensive and requires special equipment. Advances in marker technology allow the development of various DNA-based selection tools. To assimilate these technologies for the benefit of RFI-based selection, reliable phenotypic measures are prerequisite. In the current study, we identified single nucleotide polymorphisms (SNPs) associated with RFI phenotypic consistency across different ages and diets (named RFI 1-3), using DNA samples of high or low RFI ranked Holstein calves. Using targeted sequencing of chromosomal regions associated with FE- and RFI-related traits, we identified 48 top SNPs significantly associated with at least one of three defined RFIs. Eleven of these SNPs were harbored by the fatty acid binding protein 4 (FABP4). While 10 significant SNPs found in FABP4 were common for RFI 1 and RFI 3, one SNP (FABP4&#95;5; A

Bovine respiratory disease (BRD) is the leading cause of morbidity and mortality in feedlot cattle, caused by multiple pathogens that become more virulent in response to stress. As clinical signs often go undetected and various preventive strategies failed, identification of genes affecting BRD is essential for selection for resistance. Selective DNA pooling (SDP) was applied in a genome wide association study (GWAS) to map BRD QTLs in Israeli Holstein male calves. Kosher scoring of lung adhesions was used to allocate 122 and 62 animals to High (Glatt Kosher) and Low (Non-Kosher) resistant groups, respectively. Genotyping was performed using the Illumina BovineHD BeadChip according to the Infinium protocol. Moving average of -logP was used to map QTLs and Log drop was used to define their boundaries (QTLRs). The combined procedure was efficient for high resolution mapping. Nineteen QTLRs distributed over 13 autosomes were found, some overlapping previous studies. The QTLRs contain polymorphic functional and expression candidate genes to affect kosher status, with putative immunological and wound healing activities. Kosher phenotyping was shown to be a reliable means to map QTLs affecting BRD morbidity.