Pediatric acquired brain injury resources for educators: a multi-year scan of Canadian-relevant internet resources.

BACKGROUND: Acquired Brain Injury (ABI) is the leading cause of death and disability in children, yet educators report a lack of knowledge about ABI and supporting students with ABI. With no formal learning about ABI, education professionals may turn to the internet for information. OBJECTIVES: To find online resources about supporting students with ABI, in any format, available freely and publicly, aimed toward elementary educators and that could be applied in a Canadian context. METHODS: We performed an environmental scan using keyword Google searches, key websites, and expert recommendations. The search was performed twice: 2018 and 2021. RESULTS: 96 resources were included after screening. The resources were published by organizations in the United States (n = 57), Canada (n = 19), United Kingdom (n = 16), Australia (n = 3) and New Zealand (n = 1). Traumatic brain injury and concussion were the most commonly addressed type of ABI, and Short Fact/Information sheets were the most common resource format. Between 2018 and 2021, 13 previously included resource links were no longer accessible. CONCLUSIONS: This scan suggests that there are many online resources available to educators in a variety of formats, and that information online can be transient. Future studies should evaluate the accuracy and quality of the resources available.

Evidence for top-down metre perception in infancy as shown by primed neural responses to an ambiguous rhythm.

From auditory rhythm patterns, listeners extract the underlying steady beat and perceptually group beats to form metres. While previous studies show infants discriminate different auditory metres, it remains unknown whether they can maintain (imagine) a metrical interpretation of an ambiguous rhythm through top-down processes. We investigated this via electroencephalographic mismatch responses. We primed 6-month-old infants (N = 24) to hear a 6-beat ambiguous rhythm either in duple metre (n = 13) or in triple metre (n = 11) through loudness accents either on every second or every third beat. Periods of priming were inserted before sequences of the ambiguous unaccented rhythm. To elicit mismatch responses, occasional pitch deviants occurred on either beat 4 (strong beat in triple metre; weak in duple) or beat 5 (strong in duple; weak in triple) of the unaccented trials. At frontal left sites, we found a significant interaction between beat and priming group in the predicted direction. Post-hoc analyses showed that mismatch response amplitudes were significantly larger for beat 5 in the duple-primed than triple-primed group (p = .047) and were non-significantly larger for beat 4 in the triple-primed than duple-primed group. Further, amplitudes were generally larger in infants with musically experienced parents. At frontal right sites, mismatch responses were generally larger for those in the duple compared with triple group, which may reflect a processing advantage for duple metre. These results indicate that infants can impose a top-down, internally generated metre on ambiguous auditory rhythms, an ability that would aid early language and music learning.

Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease.

BACKGROUND: Neutrophil extracellular traps (NETs) have been observed in the airway in patients with chronic obstructive pulmonary disease (COPD), but their clinical and pathophysiologic implications have not been defined. OBJECTIVE: We sought to determine whether NETs are associated with disease severity in patients with COPD and how they are associated with microbiota composition and airway neutrophil function. METHODS: NET protein complexes (DNA-elastase and histone-elastase complexes), cell-free DNA, and neutrophil biomarkers were quantified in soluble sputum and serum from patients with COPD during periods of disease stability and during exacerbations and compared with clinical measures of disease severity and the sputum microbiome. Peripheral blood and airway neutrophil function were evaluated by means of flow cytometry ex vivo and experimentally after stimulation of NET formation. RESULTS: Sputum NET complexes were associated with the severity of COPD evaluated by using the composite Global Initiative for Obstructive Lung Disease scale (P < .0001). This relationship was due to modest correlations between NET complexes and FEV1, symptoms evaluated by using the COPD assessment test, and higher levels of NET complexes in patients with frequent exacerbations (P = .002). Microbiota composition was heterogeneous, but there was a correlation between NET complexes and both microbiota diversity (P = .009) and dominance of Haemophilus species operational taxonomic units (P = .01). Ex vivo airway neutrophil phagocytosis of bacteria was reduced in patients with increased sputum NET complexes. Consistent results were observed regardless of the method of quantifying sputum NETs. Failure of phagocytosis could be induced experimentally by incubating healthy control neutrophils with soluble sputum from patients with COPD. CONCLUSION: NET formation is increased in patients with severe COPD and associated with more frequent exacerbations and a loss of microbiota diversity.

Genetic mannose binding lectin deficiency is associated with airway microbiota diversity and reduced exacerbation frequency in COPD.

BACKGROUND: In cystic fibrosis and bronchiectasis, genetic mannose binding lectin (MBL) deficiency is associated with increased exacerbations and earlier mortality; associations in COPD are less clear. Preclinical data suggest MBL interferes with phagocytosis of Haemophilus influenzae, a key COPD pathogen. We investigated whether MBL deficiency impacted on clinical outcomes or microbiota composition in COPD. METHODS: Patients with COPD (n=1796) underwent MBL genotyping; linkage to health records identified exacerbations, lung function decline and mortality. A nested subcohort of 141 patients, followed for up to 6 months, was studied to test if MBL deficiency was associated with altered sputum microbiota, through 16S rRNA PCR and sequencing, or airway inflammation during stable and exacerbated COPD. FINDINGS: Patients with MBL deficiency with COPD were significantly less likely to have severe exacerbations (incidence rate ratio (IRR) 0.66, 95% CI 0.48 to 0.90, p=0.009), or to have moderate or severe exacerbations (IRR 0.77, 95% CI 0.60 to 0.99, p=0.047). MBL deficiency did not affect rate of FEV1 decline or mortality. In the subcohort, patients with MBL deficiency had a more diverse lung microbiota (p=0.008), and were less likely to be colonised with Haemophilus spp. There were lower levels of airway inflammation in patients with MBL deficiency. INTERPRETATION: Patients with MBL deficient genotype with COPD have a lower risk of exacerbations and a more diverse lung microbiota. This is the first study to identify a genetic association with the lung microbiota in COPD.

Neutrophil Elastase Activity Is Associated with Exacerbations and Lung Function Decline in Bronchiectasis.

RATIONALE: Sputum neutrophil elastase and serum desmosine, which is a linked marker of endogenous elastin degradation, are possible biomarkers of disease severity and progression in bronchiectasis. This study aimed to determine the association of elastase activity and desmosine with exacerbations and lung function decline in bronchiectasis. METHODS: This was a single-center prospective cohort study using the TAYBRIDGE (Tayside Bronchiectasis Registry Integrating Datasets, Genomics, and Enrolment into Clinical Trials) registry in Dundee, UK. A total of 433 patients with high-resolution computed tomography-confirmed bronchiectasis provided blood samples for desmosine measurement, and 381 provided sputum for baseline elastase activity measurements using an activity-based immunosassay and fluorometric substrate assay. Candidate biomarkers were tested for their relationship with cross-sectional markers of disease severity, and with future exacerbations, mortality and lung function decline over 3 years. MEASUREMENT AND MAIN RESULTS: Elastase activity in sputum was associated with the bronchiectasis severity index (r = 0.49; P < 0.0001) and was also correlated with the Medical Research Council dyspnea score (r = 0.34; P < 0.0001), FEV1% predicted (r = -0.33; P < 0.0001), and the radiological extent of bronchiectasis (r = 0.29; P < 0.0001). During a 3-year follow-up, elevated sputum elastase activity was associated with a higher frequency of exacerbations (P < 0.0001) but was not independently associated with mortality. Sputum elastase activity was independently associated with FEV1 decline (ß coefficient, -0.139; P = 0.001). Elastase showed good discrimination for severe exacerbations with an area under the curve of 0.75 (95% confidence interval [CI], 0.72-0.79) and all-cause mortality (area under the curve, 0.70; 95% CI, 0.67-0.73). Sputum elastase activity increased at exacerbations (P = 0.001) and was responsive to treatment with antibiotics. Desmosine was correlated with sputum elastase (r = 0.42; P < 0.0001) and was associated with risk of severe exacerbations (hazard ratio 2.7; 95% CI, 1.42-5.29; P = 0.003) but not lung function decline. CONCLUSIONS: Sputum neutrophil elastase activity is a biomarker of disease severity and future risk in adults with bronchiectasis.

European Respiratory Society guidelines for the management of adult bronchiectasis.

Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines.The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature.A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy.These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes.

Exploring the adaptability of TeachABI as an online professional development module for high school educators.

Objective: Educators often lack the knowledge and resources to assist students with acquired brain injury (ABI). TeachABI, an education module, was created to help elementary school teachers support students with ABI in classrooms. This study examined the adaptability of TeachABI for high school educators. Methods: A qualitative descriptive study explored high school educators' (n = 9) experiences reviewing TeachABI and its adaptability for high school through semi-structured interviews. The interview guide was informed by implementation and adaptation frameworks. Transcripts were examined using directed content analysis. Results: Teachers felt TeachABI was a good foundation for creating a high school-based education module. Adaptations were highlighted, such as streamlining content (e.g., mental health) and strategies (e.g., supporting test taking), to better meet educator needs. Conclusions: Using implementation science and adaptation frameworks provided a structured approach to explore the adaptive elements of TeachABI. The module was perceived as a suitable platform for teaching high school educators about ABI. Innovation: TeachABI is an innovative, user informed education module, providing a multi-modal (e.g., case study, videos) and replicable approach to learning about ABI. Applying frameworks from different fields provides concepts to consider when tailoring resources to align with educator needs (e.g., grade, class environment) and facilitate innovation uptake.

Participatory development of a community mental wellbeing support package for people affected by skin neglected tropical diseases in the Kasai province, Democratic Republic of Congo.

BACKGROUND: Skin neglected tropical diseases (NTDs) produce signs and symptoms that are often physically challenging, stigmatizing and have a negative impact on the mental wellbeing of people affected. In the Democratic Republic of Congo (DRC), little is known about the mental wellbeing experiences of people affected by skin NTDs and support is lacking. We collaborated with ongoing NTD programs, the Ministry of Health and people affected to evidence experiences and opportunities for change and co-developed a mental wellbeing support package for people affected and local health system actors. METHODS: This implementation research study used the photovoice method alongside key-informant interviews to evidence mental wellbeing challenges in people affected by skin NTDs and explore opportunities for change. These were used to co-develop a skin NTD mental wellbeing support package with people affected, community members and local health system actors through a participatory workshop. RESULTS: Stigma, discrimination, decreased livelihoods and mental wellbeing challenges were evidenced by people affected by skin NTDs, their communities and health system actors. Participants identified and co-established community-led peer support groups, strengthened with basic knowledge on psychosocial support, and income-generating or recreational initiatives to support mental wellbeing of people affected by skin NTDs. CONCLUSIONS: Co-developing a support package with persons affected, community members and health system actors is a step towards holistic care for people affected by skin NTDs and promotes uptake and ownership of intervention components. CONTEXTE: Les maladies tropicales négligées (MTN) cutanées produisent des signes et des symptômes qui sont souvent difficiles à supporter physiquement, ils sont également stigmatisants et ont un impact négatif sur le bien-être mental des personnes touchées. En République Démocratique du Congo (RDC), on sait peu de choses sur le bien-être mental des personnes atteintes de MTN cutanées, et le soutien fait défaut. Nous avons collaboré avec les programmes de lutte contre les MTN en cours, le ministère de la santé et les personnes touchées pour mettre en évidence les expériences et les possibilités de changement, et nous avons élaboré un programme de soutien au bien-être mental pour les personnes touchées et les acteurs du système de santé local. MÉTHODES UTILISÉES: Cette étude de recherche sur la mise en œuvre a utilisé la méthode photovoice, ainsi que des entretiens avec des informateurs clés, afin de mettre en évidence les problèmes de bien-être mental des personnes touchées par les MNT cutanées. Ces éléments ont été utilisés pour élaborer un programme de soutien au bien-être mental des MNT cutanées avec les personnes concernées, les membres de la communauté et les acteurs du système de santé local dans le cadre d'un atelier participatif. RÉSULTATS: La stigmatisation, la discrimination, la diminution des moyens de subsistance et les problèmes de bien-être mental ont été mis en évidence par les personnes atteintes de MTN cutanées, leurs communautés et les acteurs du système de santé. Les participants ont identifié et mis en place des groupes communautaires de soutien par les pairs, renforcés par des connaissances de base en matière de soutien psychosocial, et des initiatives génératrices de revenus/récréatives pour soutenir le bien-être mental des personnes touchées par les MTN cutanées. CONCLUSIONS: L'élaboration d'un ensemble de mesures de soutien en collaboration avec les personnes concernées, les membres de la communauté et les acteurs du système de santé, constitue une étape vers une prise en charge holistique des personnes atteintes de MNT cutanées et favorise l'adoption et l'appropriation des composantes de l'intervention. ANTECEDENTES: Las enfermedades tropicales desatendidas (ETDs) cutáneas producen signos y síntomas que a menudo suponen un reto físico, estigmatizan y tienen un impacto negativo en el bienestar mental de las personas afectadas. En la República Democrática del Congo (RDC), se sabe poco sobre las experiencias de bienestar mental de las personas afectadas por ETDs cutáneas, y falta apoyo. Colaboramos con los programas en curso sobre las ETDs, el Ministerio de Sanidad y las personas afectadas para poner de manifiesto las experiencias y las oportunidades de cambio, y desarrollamos de manera conjunta un paquete de apoyo al bienestar mental para las personas afectadas y los agentes del sistema sanitario local. MÉTODOS: Este estudio de investigación utilizó el método fotovoz, junto con entrevistas a informantes clave, para poner de manifiesto los desafíos de bienestar mental de las personas afectadas por ETDs cutáneas y explorar las oportunidades de cambio. Estos datos se utilizaron para desarrollar un paquete de apoyo al bienestar mental de manera conjunta con las personas afectadas por las ETDs cutáneas, los miembros de la comunidad y los actores del sistema sanitario local a través de un taller participativo. RESULTADOS: El estigma, la discriminación, la disminución de los medios de subsistencia y los problemas de bienestar mental fueron evidenciados por las personas afectadas por ETD cutáneas, sus comunidades y los agentes del sistema sanitario. Los participantes identificaron y establecieron conjuntamente grupos de apoyo entre pares dirigidos por la comunidad, fortalecidos con conocimientos básicos sobre apoyo psicosocial e iniciativasrecreativas y generadoras de ingresos para apoyar el bienestar mental de las personas afectadas por las ETD cutáneas. CONCLUSIÓNS: El desarrollo conjunto de un paquete de medidas de apoyo con las personas afectadas, los miembros de la comunidad y los actores del sistema sanitario es un paso hacia la atención holística de las personas afectadas por las NTDs a y promueve la adopción y apropiación de los componentes de la intervención.

Current clinical status, glucose control, and complication rates of children and youth with type 1 diabetes in Rwanda.

OBJECTIVE: To describe the clinical status of youth and adolescents (≤ 25 yr) in the Rwanda Life For A Child (LFAC) program who had their first HbA1c measure in 2009 or 2010, and to identify factors which may relate to glycemic control (HbA1c) and complication status. RESEARCH DESIGN AND METHODS: Data were collected from June 2009 to November 2010 for the LFAC program in Rwanda and comprise clinical data from when participants' first HbA1c reading was obtained. RESULTS: From June 2009 to November 2010, 286 youth aged ≤25 yr had their first HbA1c. Mean age, duration, and age at diagnosis were 18.6 ± 4.5 yr, 3.4 ± 3.1 yr and 15.1 ± 4.8 yr, respectively. Mean HbA1c was 11.2 ± 2.7% with 15.7% (n = 45) having HbA1c <8%, while 30.8% (n = 88) had HbA1c >14%. Five (2.1%) had either abnormal tuning fork vibratory sensation or monofilament response, 21% (n = 31) had microalbuminuria (MA, A/C ratio >30 mg/g) and 5% (n = 7) had nephropathy (A/C ratio >300 mg/g). Diabetes duration and insulin dose/kg were positively associated with higher HbA1c, while residing in the southern province was associated with lower HbA1c. Duration, diastolic blood pressure, and HbA1c were positively associated with developing MA, while age was protective. CONCLUSIONS: These data from the LFAC program for 2009-2010 show that there is a urgent need for dramatically improved care, as many patients have greatly elevated HbA1c measures, often >14%. We have identified correlates of better control (e.g., living in the Southern province) and MA (e.g., diastolic blood pressure), which provide potential avenues to improved quality of care.

The PAM-1 aminopeptidase regulates centrosome positioning to ensure anterior-posterior axis specification in one-cell C. elegans embryos.

In the one-cell Caenorhabditis elegans embryo, the anterior-posterior (A-P) axis is established when the sperm donated centrosome contacts the posterior cortex. While this contact appears to be essential for axis polarization, little is known about the mechanisms governing centrosome positioning during this process. pam-1 encodes a puromycin sensitive aminopeptidase that regulates centrosome positioning in the early embryo. Previously we showed that pam-1 mutants fail to polarize the A-P axis. Here we show that PAM-1 can be found in mature sperm and in cytoplasm throughout early embryogenesis where it concentrates around mitotic centrosomes and chromosomes. We provide further evidence that PAM-1 acts early in the polarization process by showing that PAR-1 and PAR-6 do not localize appropriately in pam-1 mutants. Additionally, we tested the hypothesis that PAM-1's role in polarity establishment is to ensure centrosome contact with the posterior cortex. We inactivated the microtubule motor dynein, DHC-1, in pam-1 mutants, in an attempt to prevent centrosome movement from the cortex and restore anterior-posterior polarity. When this was done, the aberrant centrosome movements of pam-1 mutants were not observed and anterior-posterior polarity was properly established, with proper localization of cortical and cytoplasmic determinants. We conclude that PAM-1's role in axis polarization is to prevent premature movement of the centrosome from the posterior cortex, ensuring proper axis establishment in the embryo.

Differences in inflammatory bowel disease phenotype between South Asians and Northern Europeans living in North West London, UK.

OBJECTIVES: The incidence and prevalence of inflammatory bowel disease (IBD) is increasing throughout Asia. Since the 1950s, there has been substantial migration from South Asia (India, Pakistan, and Bangladesh) to the United Kingdom. The aim of this study was to define the clinical phenotype of IBD in UK South Asians living in North West London, and to compare the results with a white Northern European IBD cohort. METHODS: The phenotypic details of 367 South Asian IBD patients (273 ulcerative colitis (UC) and 94 Crohn's disease (CD)), undergoing active follow-up in five North West London hospitals, were compared with those of 403 consecutively collected white Northern European IBD patients (188 UC and 215 CD). RESULTS: The phenotype of IBD differed significantly between the two populations. 63.0% of South Asian UC patients had extensive colitis compared with 42.5% of the Northern European cohort (P < 0.0001). Proctitis was uncommon in South Asian UC patients (9.9 vs. 26.1% in Northern European patients, P<0.0001). In the South Asian CD cohort, disease location was predominantly colonic (46.8%). CD behavior differed significantly between the groups, with less penetrating disease compared with Northern Europeans (P=0.01) and a reduced need for surgery (P=0.003). CONCLUSIONS: The phenotype of IBD in South Asians living in North West London is significantly different from that of a white Northern European IBD cohort. Knowledge of ethnic variations in disease phenotype may help to identify key genetic, environmental, and behavioral factors contributing to the development of IBD.

Extra-Curricular Activities and Well-Being: Results From a Survey of Undergraduate University Students During COVID-19 Lockdown Restrictions.

Participation in extra-curricular activities has been found to associate with increased well-being. Here we investigated in a survey (n = 786) what activities university students at a Canadian university engaged in during the stressful COVID-19 pandemic lockdown in April, 2020, which coincided with a novel online exam period, and how these activities related to perceived well-being, anxiety (STAI-S), social aspects of activities, and personality. Sixty-five percentage of students scored in the high anxiety category of the STAI-S, an alarming statistic given that only 24% had reached out for professional supports. This is consistent with reports that current supports on university campuses are inadequate. Listening to music (92%) and watching movies/series (92%) were engaged in most frequently, followed by socializing virtually (89%) and engaging in social media (85%). The activities students rated as most helpful to their well-being were somewhat different, with outdoor exercise rated highest, followed by socializing virtually and listening to music. While all activities were rated as beneficial, those with a social component tended to have high ratings, consistent with students attempting to replace lost social interactions. Linear regression models found few associations between STAI-S scores and other measures, likely because of large individual differences and lack of a pre-pandemic baseline needed to assess changes in anxiety. The importance of individual differences was evident in that those higher in conscientiousness or extraversion or emotional stability were more likely to engage in exercise, while those higher in openness to experience were more likely to engage in journaling, playing a musical instrument, or singing, with a trend for higher engagement in song writing. Individual differences were also evident in that equal numbers of students gave positive and negative comments related to their well-being during the pandemic. The individual differences uncovered here suggest that having a variety of proactive interventions would likely reach more students. Indeed, 52% indicated an interest in online group music therapy, 48% in art therapy and 40% in verbal therapy, despite music and art therapies being virtually non-existent on campuses. In sum, the findings highlight the importance of choice in extra-curricular activities and therapies that support well-being.

Evaluation of the quality of 'do not use' medication abbreviation audits: a key enabler to successful implementation of audit and feedback.

Background Hospital pharmacy audit and feedback of 'do not use' medication abbreviations improves patient safety. For audit and feedback systems to be effective, the data captured must be of high quality such that end-users trust the information to guide practice change. The quality of data captured during monthly standardized pharmacy 'do not use' abbreviation audits is currently unknown. Objective We aimed to assess pharmacy 'do not use' abbreviation audit data quality. Method Primary audit data quality was assessed by examining a random sample of handwritten medication prescriptions for the presence and type of 'do not use' abbreviations. This data was compared with the pharmacy monthly audit data to determine data capture agreement and consistency over time. Results There were 1132 prescriptions from July, October, and December 2019 included. Data capture agreement between the pharmacy audit and the secondary assessment using Cohen's Kappa ranged from 0.53 to 0.63. The primary audit under-reported 'do not use' abbreviation rates, however this did not vary over time (χ2 = 1.215, p = 0.545). Conclusion Pharmacy staff audits under-reported 'do not use' abbreviation rates, however this was consistent over time. The quality of pharmacy audits should be assessed and disseminated to end-users prior to implementing feedback.

Differences in gut microbial metabolism are responsible for reduced hippurate synthesis in Crohn's disease.

BACKGROUND: Certain urinary metabolites are the product of gut microbial or mammalian metabolism; others, such as hippurate, are mammalian-microbial 'co-metabolites'. It has previously been observed that Crohn's disease (CD) patients excrete significantly less hippurate than controls. There are two stages in the biosynthesis of this metabolite: 1) gut microbial metabolism of dietary aromatic compounds to benzoate, and 2) subsequent hepatorenal conjugation of benzoate with glycine, forming hippurate. Differences in such urinary co-metabolites may therefore reflect systemic consequences of altered gut microbial metabolism, though altered host metabolic pathways may also be involved. METHODS: It was hypothesised that reduced hippurate excretion in CD patients was due to alterations in the gut microbiota, and not differences in dietary benzoate, nor defective host enzymatic conjugation of benzoate. 5 mg/kg sodium benzoate were administered orally to 16 CD patients and 16 healthy controls on a low-benzoate diet. Baseline and peak urinary hippurate excretion were measured. RESULTS: Baseline hippurate levels were significantly lower in the CD patients (p = 0.0009). After benzoate ingestion, peak urinary levels of hippurate did not differ significantly between the cohorts. Consequently the relative increase in excretion was significantly greater in CD (p = 0.0007). CONCLUSIONS: Lower urinary hippurate levels in CD are not due to differences in dietary benzoate. A defect in the enzymatic conjugation of benzoate in CD has been excluded, strongly implicating altered gut microbial metabolism as the cause of decreased hippurate levels in CD.

Increased Neural Progenitor Proliferation in a hiPSC Model of Autism Induces Replication Stress-Associated Genome Instability.

The association between macrocephaly and autism spectrum disorder (ASD) suggests that the mechanisms underlying excessive neural growth could contribute to ASD pathogenesis. Consistently, neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSCs) of ASD individuals with early developmental brain enlargement are inherently more proliferative than control NPCs. Here, we show that hiPSC-derived NPCs from ASD individuals with macrocephaly display an altered DNA replication program and increased DNA damage. When compared with the control NPCs, high-throughput genome-wide translocation sequencing (HTGTS) demonstrates that ASD-derived NPCs harbored elevated DNA double-strand breaks in replication stress-susceptible genes, some of which are associated with ASD pathogenesis. Our results provide a mechanism linking hyperproliferation of NPCs with the pathogenesis of ASD by disrupting long neural genes involved in cell-cell adhesion and migration.

Characterization of inflammatory bowel disease with urinary metabolic profiling.

OBJECTIVES: Distinguishing between the inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC) is important for both management and prognostic reasons. Discrimination using noninvasive techniques could be an adjunct to conventional diagnostics. Differences have been shown between the intestinal microbiota of CD and UC patients and controls; the gut bacteria influence specific urinary metabolites that are quantifiable using proton high-resolution nuclear magnetic resonance (NMR) spectroscopy. This study tested the hypothesis that such metabolites differ between IBD and control cohorts, and that using multivariate pattern-recognition analysis, the cohorts could be distinguished by urine NMR spectroscopy. METHODS: NMR spectra were acquired from urine samples of 206 Caucasian subjects (86 CD patients, 60 UC patients, and 60 healthy controls). Longitudinal samples were collected from 75 individuals. NMR resonances specific for metabolites influenced by the gut microbes were studied, including hippurate, formate, and 4-cresol sulfate. Multivariate analysis of all urinary metabolites involved principal components analysis (PCA) and partial least squares discriminant analysis (PLS-DA). RESULTS: Hippurate levels were lowest in CD patients and differed significantly between the three cohorts (P<0.0001). Formate levels were higher and 4-cresol sulfate levels lower in CD patients than in UC patients or controls (P=0.0005 and P=0.0002, respectively). PCA revealed clustering of the groups; PLS-DA modeling was able to distinguish the cohorts. These results were independent of medication and diet and were reproducible in the longitudinal cohort. CONCLUSIONS: Specific urinary metabolites related to gut microbial metabolism differ between CD patients, UC patients, and controls. The emerging technique of urinary metabolic profiling with multivariate analysis was able to distinguish these cohorts.

Association between heat shock protein 70/Hom genetic polymorphisms and uveitis in patients with sarcoidosis.

PURPOSE: The predisposition to sarcoidosis, a systemic granulomatous disorder of unknown etiology, is genetically determined, and genetics appears also to drive the disease down distinct phenotypic pathways. This study was undertaken to test the hypothesis that sarcoidosis-related uveitis represents a genetically distinct disease subset, by investigating single nucleotide polymorphisms (SNPs) in the HSP-70/1 and HSP-70/Hom genes. HSP70 molecules play a key role in the immune response by functioning both as chaperones and as inducers of proinflammatory cytokine secretion. METHODS: By sequence-specific primers-polymerase chain reaction (SSP-PCR) five SNPs were evaluated in 270 white patients with sarcoidosis, including 88 with sarcoid-related uveitis, and in 347 matched control subjects. One hundred twenty-five patients with idiopathic anterior uveitis (IAU) and 56 with idiopathic intermediate uveitis (IIU) were also included in the study as disease control subjects. RESULTS: The HSP-70/Hom rs2075800 G allele frequency was higher in the sarcoid-uveitis group than in both the sarcoid-non-uveitis and control groups (83% vs. 71%, OR = 2.00, P(c) = 0.01; and 83% vs. 66%, OR = 2.45, P(c) = 0.00005, respectively). Similar results were observed when considering the carriage frequency of the associated haplotype (HSP-70 haplotype 2) across the three study groups (47% vs. 29%, OR = 2.17, P(c) = 0.03; and 47% vs. 21%, OR = 3.26, P(c) = 0.0003, respectively). In addition, the carriage frequency of the HSP-70 haplotype 2 discriminated among sarcoid-related uveitis, IAU, and IIU (47% vs. 19%, OR = 3.26, P(c) = 0.001; and 47% vs. 23%, OR = 2.81, P(c) = 0.04, respectively). CONCLUSIONS: A strong association was found between HSP-70/Hom rs2075800 G and uveitis in patients with sarcoidosis. Further studies are needed to understand the molecular mechanisms underlying this association.

Genetics of inflammatory bowel disease: the role of the HLA complex.

The human leucocyte antigen (HLA) complex on chromosome 6p21.3 is the most extensively studied genetic region in Inflammatory bowel disease (IBD). Consistent evidence of linkage to IBD3 (6p21.1-23), an area which encompasses the HLA complex, has been demonstrated for both Crohn's disease and ulcerative colitis, and a number of replicated associations with disease susceptibility and phenotype have recently emerged. However, despite these efforts the HLA susceptibility gene (s) for IBD remain elusive, a consequence of strong linkage disequilibrium, extensive polymorphism and high gene density across this region. This article reviews current knowledge of the role of HLA complex genes in IBD susceptibility and phenotype, and discusses the factors currently limiting the translation of this knowledge to clinical practice.

Application of muscadine grape (Vitis rotundifolia Michx.) pomace extract to reduce carcinogenic acrylamide.

Acrylamide is a byproduct of the Maillard reaction and is formed in a variety of heat-treated commercial starchy foods. It is known to be toxic and potentially carcinogenic to humans. Muscadine grape polyphenols and standard phenolic compounds were examined on the reduction of acrylamide in an equimolar asparagine/glucose chemical model, a potato chip model, and a simulated physiological system. Polyphenols were found to significantly reduce acrylamide in the chemical model, with reduced rates higher than 90% at 100 µg/ml. In the potato chip model, grape polyphenols reduced the acrylamide level by 60.3% as concentration was increased to 0.1%. However, polyphenols exhibited no acrylamide reduction in the simulated physiological system. Results also indicated no significant correlation between the antioxidant activities of polyphenols and their acrylamide inhibition. This study demonstrated muscadine grape extract can mitigate acrylamide formation in the Maillard reaction, which provides a new value-added application for winery pomace waste.