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Item does not contain fulltext, IMPORTANCE: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide. OBJECTIVE: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics. DESIGN, SETTING, AND PARTICIPANTS: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience). MAIN OUTCOMES AND MEASURES: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree. RESULTS: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In

Item does not contain fulltext, IMPORTANCE: A clear dosing regimen for methotrexate in psoriasis is lacking, and this might lead to a suboptimal treatment. Because methotrexate is affordable and globally available, a uniform dosing regimen could potentially optimize the treatment of patients with psoriasis worldwide. OBJECTIVE: To reach international consensus among psoriasis experts on a uniform dosing regimen for treatment with methotrexate in adult and pediatric patients with psoriasis and identify potential future research topics. DESIGN, SETTING, AND PARTICIPANTS: Between September 2020 and March 2021, a survey study with a modified eDelphi procedure that was developed and distributed by the Amsterdam University Medical Center and completed by 180 participants worldwide (55 [30.6%] resided in non-Western countries) was conducted in 3 rounds. The proposals on which no consensus was reached were discussed in a conference meeting (June 2021). Participants voted on 21 proposals with a 9-point scale (1-3 disagree, 4-6 neither agree nor disagree, 7-9 agree) and were recruited through the Skin Inflammation and Psoriasis International Network and European Academy of Dermatology and Venereology in June 2020. Apart from being a dermatologist/dermatology resident, there were no specific criteria for participation in the survey. The participants worked mainly at a university hospital (97 [53.9%]) and were experienced in treating patients with psoriasis with methotrexate (163 [91.6%] had more than 10 years of experience). MAIN OUTCOMES AND MEASURES: In a survey with eDelphi procedure, we tried to reach consensus on 21 proposals. Consensus was defined as less than 15% voting disagree (1-3). For the consensus meeting, consensus was defined as less than 30% voting disagree. RESULTS: Of 251 participants, 180 (71.7%) completed all 3 survey rounds, and 58 participants (23.1%) joined the conference meeting. Consensus was achieved on 11 proposals in round 1, 3 proposals in round 2, and 2 proposals in round 3. In

Objectives Larger sibships are associated with poorer cognitive and language outcomes but have different impacts on child emotional development. Previous studies have not taken into account sibling age, nor have impacts across multiple neurodevelopmental domains been considered in the same participant group. This study investigated the influence of family size indicators on early childhood cognitive, language and emotional-behavioural development. The effect of sibling age was considered by evaluating these relationships separately for different sibling age categories.Design Prospective birth cohort study. Setting Participants in the Barwon Infant Study were recruited from two major hospitals in the Barwon region of Victoria, Australia, between 2010 and 2013 (n=1074 children). Participants The 755 children with any neurodevelopmental data at age 2–3 years excluding twins and those with an acquired neurodisability. Outcome measures Cognitive and language development was assessed using the Bayley Scales of Infant and Toddler Development, Third Edition, and emotional-behavioural development was measured with the Child Behaviour Checklist for Ages 1½−5. Results Greater household size was associated with a reduced cognitive development score (adjusted mean difference (AMD) −0.66 per extra household member; 95% CI −0.96 to –0.37; p<0.001) without age-specific differences. However, poorer expressive language was only observed for exposure to siblings between 2–6 and 6–10 years older. Having siblings 2–6 years older was associated with less internalising behaviour (AMD −2.1 per sibling; 95% CI −3.1 to –1.0; p<0.001). These associations persisted after multiple comparison adjustment. Conclusions The influence of siblings on early childhood development varies substantially by sibling age and the neurodevelopmental outcome under study. Although family size alone appears important for cognitive devel

OBJECTIVES: Larger sibships are associated with poorer cognitive and language outcomes but have different impacts on child emotional development. Previous studies have not taken into account sibling age, nor have impacts across multiple neurodevelopmental domains been considered in the same participant group. This study investigated the influence of family size indicators on early childhood cognitive, language and emotional-behavioural development. The effect of sibling age was considered by evaluating these relationships separately for different sibling age categories. DESIGN: Prospective birth cohort study. SETTING: Participants in the Barwon Infant Study were recruited from two major hospitals in the Barwon region of Victoria, Australia, between 2010 and 2013 (n=1074 children). PARTICIPANTS: The 755 children with any neurodevelopmental data at age 2-3 years excluding twins and those with an acquired neurodisability. OUTCOME MEASURES: Cognitive and language development was assessed using the Bayley Scales of Infant and Toddler Development, Third Edition, and emotional-behavioural development was measured with the Child Behaviour Checklist for Ages 1½-5. RESULTS: Greater household size was associated with a reduced cognitive development score (adjusted mean difference (AMD) -0.66 per extra household member; 95% CI -0.96 to -0.37; p<0.001) without age-specific differences. However, poorer expressive language was only observed for exposure to siblings between 2-6 and 6-10 years older. Having siblings 2-6 years older was associated with less internalising behaviour (AMD -2.1 per sibling; 95% CI -3.1 to -1.0; p<0.001). These associations persisted after multiple comparison adjustment. CONCLUSIONS: The influence of siblings on early childhood development varies substantially by sibling age and the neurodevelopmental outcome under study. Although family size alone appears important for cognitive development, age-specific findings emphasise the importance of sibling inter

The unit commitment with transmission constraints in the alternating-current (AC) model is a challenging mixed-integer non-linear optimisation problem. We present an approach based on decomposition of a Mixed-Integer Semidefinite Programming (MISDP) problem into a mixed-integer quadratic (MIQP) master problem and a semidefinite programming (SDP) sub-problem. Between the master problem and the sub-problem, we pass novel classes of cuts. We analyse finite convergence to the optimum of the MISDP and report promising computational results on a test case from the Canary Islands, Spain.

In mice, the maternal microbiome influences fetal immune development and postnatal allergic outcomes. Westernized populations have high rates of allergic disease and low rates of gastrointestinal carriage of Prevotella, a commensal bacterial genus that produces short chain fatty acids and endotoxins, each of which may promote the development of fetal immune tolerance. In this study, we use a prebirth cohort (n = 1064 mothers) to conduct a nested case-cohort study comparing 58 mothers of babies with clinically proven food IgE mediated food allergy with 258 randomly selected mothers. Analysis of the V4 region of the 16S rRNA gene in fecal samples shows maternal carriage of Prevotella copri during pregnancy strongly predicts the absence of food allergy in the offspring. This association was confirmed using targeted qPCR and was independent of infant carriage of P. copri. Larger household size, which is a well-established protective factor for allergic disease, strongly predicts maternal carriage of P. copri.

AIM: To determine the incidence, risk factors and health service utilisation for infection in the first 12 months of life in a population-derived Australian pre-birth cohort. METHODS: The Barwon Infant Study is a population-derived pre-birth cohort with antenatal recruitment (n = 1074) based in Geelong, Victoria, Australia. Infection data were collected by parent report, and general practitioner and hospital records at 1, 3, 6, 9 and 12 months of age. We calculated the incidence of infection, attendance at a health service with infection and used multiple negative binomial regression to investigate the effects of a range of exposures on incidence of infection. RESULTS: In the first 12 months of life, infections of the upper and lower respiratory tract (henceforth 'respiratory infections'), conjunctivitis and gastroenteritis occurred at a rate of 0.35, 0.04 and 0.04 episodes per child-month, respectively. A total of 482 (72.4%) infants attended a general practitioner with an infection and 69 (10.4%) infants attended the emergency department. Maternal antibiotic exposure in pregnancy and having older siblings were associated with respiratory infection. Childcare attendance by 12 months of age was associated with respiratory infections and gastroenteritis. Breastfeeding, even if less than 4 weeks in total, was associated with reduced respiratory infection. CONCLUSION: Infection, especially of the respiratory tract, is a common cause of morbidity in Australian infants. Several potentially modifiable risk factors were identified, particularly for respiratory infections. Most infections were managed by general practitioners and 1 in 10 infants attended an emergency department with infection in the first year of life.

BACKGROUND: Despite intense interest in the relationship between gut microbiota and brain development, longitudinal data from human studies are lacking. This study aimed to investigate the relationship between the composition of gut microbiota during infancy and subsequent behavioural outcomes. METHODS: A subcohort of 201 children with behavioural outcome measures was identified within a longitudinal, Australian birth-cohort study. The faecal microbiota were analysed at 1, 6, and 12 months of age. Behavioural outcomes were measured at 2 years of age. FINDINGS: In an unselected birth cohort, we found a clear association between decreased normalised abundance of Prevotella in faecal samples collected at 12 months of age and increased behavioural problems at 2 years, in particular Internalizing Problem scores. This association appeared independent of multiple potentially confounding variables, including maternal mental health. Recent exposure to antibiotics was the best predictor of decreased Prevotella. INTERPRETATION: Our findings demonstrate a strong association between the composition of the gut microbiota in infancy and subsequent behavioural outcomes; and support the importance of responsible use of antibiotics during early life. FUNDING: This study was funded by the National Health and Medical Research Council of Australia (1082307, 1147980, 1129813), The Murdoch Children's Research Institute, Barwon Health, Deakin University, Perpetual Trustees, and The Shepherd Foundation. The funders had no involvement in the data collection, analysis or interpretation, trial design, recruitment or any other aspect pertinent to the study.

AIM: The burden of wheezing illnesses in Australian infants has not been documented since the success of initiatives to reduce maternal cigarette smoking. We aimed to determine the incidence of wheeze and related health-care utilisation during the first year of life among a contemporary Australian birth cohort. METHODS: A birth cohort of 1074 infants was assembled between 2010 and 2013. Parents completed questionnaires periodically. Several non-exclusive infant respiratory disease phenotypes were defined, including any wheeze, wheeze with shortness of breath and recurrent wheeze. Skin prick testing was performed to determine atopic wheeze. Health-care utilisation for respiratory disease was determined from questionnaires and hospital medical records. RESULTS: Retention to 1 year was 840/1074 (83%). The incidence of any wheeze was 51.8% (95% confidence interval (CI) 48.3-55.2%), wheeze with shortness of breath 20.6% (95% CI 17.9-23.5), recurrent wheeze 19.4% (95% CI 16.8-22.2) and atopic wheeze 6% (95% CI 4.6-7.8). Respiratory illness resulted in primary health-care utilisation in 82.2% (95% CI 79.3-84.8) of participants and hospital presentation in 8.8% (95% CI 7.2-10.6). Maternal smoking during pregnancy was uncommon (15.7%) and was not associated with wheeze or health resource utilisation. Male gender, familial atopy and asthma and smaller household size were associated with a higher incidence of wheeze. CONCLUSIONS: The incidence of wheezing illness among Australian infants remains high despite relatively low rates of maternal smoking during pregnancy. The majority of the health-care burden is borne by primary health-care services. Further research is required to inform novel prevention strategies.

Cutaneous sun exposure is an important determinant of circulating vitamin D. Both sun exposure and vitamin D have been inversely associated with risk of autoimmune disease. In juvenile idiopathic arthritis (JIA), low circulating vitamin D appears common, but disease-related behavioral changes may have influenced sun exposure. We therefore aimed to determine whether predisease sun exposure is associated with JIA. Using validated questionnaires, we retrospectively measured sun exposure for 202 Caucasian JIA case-control pairs born in Victoria Australia, matched for birth year and time of recruitment. Measures included maternal sun exposure at 12 weeks of pregnancy and child sun exposure across the life-course prediagnosis. We converted exposure to UVR dose and looked for case-control differences using logistic regression, adjusting for potential confounders. Higher cumulative prediagnosis UVR exposure was associated with reduced risk of JIA, with a clear dose-response relationship (trend P = 0.04). UVR exposure at 12 weeks of pregnancy was similarly inversely associated with JIA (trend P = 0.011). Associations were robust to sensitivity analyses for prediagnosis behavioral changes, disease duration and knowledge of the hypothesis. Our data indicate that lower UVR exposure may increase JIA risk. This may be through decreased circulating vitamin D, but prospective studies are required to confirm this.

OBJECTIVES: The incidence of pediatric inflammatory bowel disease (IBD) is increasing worldwide. Ecological studies show higher incidence in regions at higher latitude or lower ambient ultraviolet radiation; individual-level associations with sun exposure have not been assessed. METHODS: We recruited children (0-17 years) with IBD from 2 large hospitals in Melbourne, Australia. Control participants were recruited from the day surgery unit of one of the same hospitals. Questionnaires provided data on demographics, past sun exposure, the likelihood of sunburn (skin sensitivity) or tanning following sun exposure, use of sun protection, physical activity, and parental smoking and education. Grandparent ancestry was used to determine participant ethnicity. Cases and controls were matched on age and sex. We used conditional logistic regression to test the association between being an IBD case and past sun exposure at different ages, adjusted for a range of other factors. RESULTS: After matching, n = 99 cases and n = 396 controls were included in the analysis. In multivariable analysis, for each 10 min increment in leisure-time sun exposure in summer or winter there was a linear 6% reduction in the odds of having IBD (P = 0.002). Results were similar in sensitivity analyses including only the most recently diagnosed cases, only Caucasian cases and controls, only those with symptom onset within the year before study entry, or additionally adjusted for age or physical activity. CONCLUSIONS: Higher sun exposure in the previous summer or winter was associated with a reduced risk of having IBD. There are plausible pathways that could mediate this effect.

OBJECTIVES: The incidence of pediatric inflammatory bowel disease (IBD) is increasing worldwide. Ecological studies show higher incidence in regions at higher latitude or lower ambient ultraviolet radiation; individual-level associations with sun exposure have not been assessed.

© 2019 American Speech-Language-Hearing Association. Purpose: The purpose of this letter is to respond to Marcotte’s (2019) letter to the editor, “The Influence of Treatment on Children’s Recovery from Stuttering: Comments on Kefalianos et al. (2017) and Leech et al. (2017),” published by the Journal of Speech, Language, and Hearing Research.

© 2019 American Speech-Language-Hearing Association. Purpose: The purpose of this letter is to respond to Marcotte’s (2019) letter to the editor, “The Influence of Treatment on Children’s Recovery from Stuttering: Comments on Kefalianos et al. (2017) and Leech et al. (2017),” published by the Journal of Speech, Language, and Hearing Research.

We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008–2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples. Parent occupational social contact was assessed by the number of well or sick children, adults or animals contacted daily through work. Higher parental occupational social contact was strongly associated with reduced T1D risk with evidence of dose response (contact with the well or sick score, Adjusted odds ratio (AOR) per category: 0.73 (95% Confidence Interval (CI): 0.66, 0.81); P<0.001 or AOR 0.63 (95% CI: 0.53, 0.75); P<0.001) respectively). Nine of the ten parental social contact indices, were significant mediated through one or more enteroviral indices. The strength of association between enterovirus presence and T1D onset increased with child age (1.2 fold increase per year; P = 0.05). Lower child hand hygiene enhanced the adverse effect of low parental occupational contact with the sick; Synergy Index 5.16 (95% CI: 3.61, 7.36). The interaction between hand washing and parental occupational contact is more consistent with protection against parental enteroviral shedding than the sharing of a protective infectious agent or microbiome.

Language disorder (LD) and social-emotional and behavioural (SEB) difficulties are common childhood problems that often co-occur. While there is clear evidence of these associations from clinical samples, less is known about community samples. This paper examines these associations in children aged 4–7 years from a community-based longitudinal study. 771 families provided questionnaire and assessment data at 4, 5 and 7 years. Parent-reported SEB difficulties were measured at each point (SDQ). Child language was directly assessed at 4 (CELF-P2), 5 and 7 years (CELF-4). Linear regression analysis was used to compare cross-sectional differences in mean SDQ scores between children with and without LD at each time point. Linear regression was then used to examine how patterns of language development (language disordered at three time points; never disordered; disordered at one or two time points, i.e. ‘unstable’ group) related to SEB difficulties at each age, adjusted for potential confounders, as in the previous analyses. Higher hyperactivity/inattention scores were associated with LD at each age. In fully adjusted models, there was little difference in mean emotional symptoms scores between children with and without LD. The ‘never’ LD group had lower mean SDQ scores at each time point than the ‘unstable’ group. Findings highlight that children with persistent LD from preschool to early primary school may be more likely to have concomitant SEB difficulties, particularly behavioural difficulties. Those with unstable LD may also have co-occurring SEB difficulties, showing a need for education and health professionals to monitor early language and SEB development.

Purpose: For a community cohort of children confirmed to have stuttered by the age of 4 years, we report (a) the recovery rate from stuttering, (b) predictors of recovery, and (c) comorbidities at the age of 7 years. Method: This study was nested in the Early Language in Victoria Study. Predictors of stuttering recovery included child, family, and environmental measures and first-degree relative history of stuttering. Comorbidities examined at 7 years included temperament, language, nonverbal cognition, and health-related quality of life. Results: The recovery rate by the age of 7 years was 65%. Girls with stronger communication skills at the age of 2 years had higher odds of recovery (adjusted OR = 7.1, 95% CI [1.3, 37.9], p = .02), but similar effects were not evident for boys (adjusted OR = 0.5, 95% CI [0.3, 1.1], p = .10). At the age of 7 years, children who had recovered from stuttering were more likely to have stronger language skills than children whose stuttering persisted (p = .05). No evident differences were identified on other outcomes including nonverbal cognition, temperament, and parent-reported quality of life. Conclusion: Overall, findings suggested that there may be associations between language ability and recovery from stuttering. Subsequent research is needed to explore the directionality of this relationship.

We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008-2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples. Parent occupational social contact was assessed by the number of well or sick children, adults or animals contacted daily through work. Higher parental occupational social contact was strongly associated with reduced T1D risk with evidence of dose response (contact with the well or sick score, Adjusted odds ratio (AOR) per category: 0.73 (95% Confidence Interval (CI): 0.66, 0.81); P<0.001 or AOR 0.63 (95% CI: 0.53, 0.75); P<0.001) respectively). Nine of the ten parental social contact indices, were significant mediated through one or more enteroviral indices. The strength of association between enterovirus presence and T1D onset increased with child age (1.2 fold increase per year; P = 0.05). Lower child hand hygiene enhanced the adverse effect of low parental occupational contact with the sick; Synergy Index 5.16 (95% CI: 3.61, 7.36). The interaction between hand washing and parental occupational contact is more consistent with protection against parental enteroviral shedding than the sharing of a protective infectious agent or microbiome.

Language disorder (LD) and social-emotional and behavioural (SEB) difficulties are common childhood problems that often co-occur. While there is clear evidence of these associations from clinical samples, less is known about community samples. This paper examines these associations in children aged 4-7 years from a community-based longitudinal study. 771 families provided questionnaire and assessment data at 4, 5 and 7 years. Parent-reported SEB difficulties were measured at each point (SDQ). Child language was directly assessed at 4 (CELF-P2), 5 and 7 years (CELF-4). Linear regression analysis was used to compare cross-sectional differences in mean SDQ scores between children with and without LD at each time point. Linear regression was then used to examine how patterns of language development (language disordered at three time points; never disordered; disordered at one or two time points, i.e. 'unstable' group) related to SEB difficulties at each age, adjusted for potential confounders, as in the previous analyses. Higher hyperactivity/inattention scores were associated with LD at each age. In fully adjusted models, there was little difference in mean emotional symptoms scores between children with and without LD. The 'never' LD group had lower mean SDQ scores at each time point than the 'unstable' group. Findings highlight that children with persistent LD from preschool to early primary school may be more likely to have concomitant SEB difficulties, particularly behavioural difficulties. Those with unstable LD may also have co-occurring SEB difficulties, showing a need for education and health professionals to monitor early language and SEB development.

We aimed to examine the association between parental occupational social contact and hygiene factors on type 1 diabetes (T1D) risk and possible mediation of these effects through child enteroviral infection. We interviewed 333 incident T1D cases and 660 controls from 2008-2011 in Melbourne, Australia. Enteroviral indices (ribonucleic acid by reverse transcription polymerase chain reaction and Coxsackie B virus antibody levels) in peripheral blood were measured in nested case control samples. Parent occupational social contact was assessed by the number of well or sick children, adults or animals contacted daily through work. Higher parental occupational social contact was strongly associated with reduced T1D risk with evidence of dose response (contact with the well or sick score, Adjusted odds ratio (AOR) per category: 0.73 (95% Confidence Interval (CI): 0.66, 0.81); P<0.001 or AOR 0.63 (95% CI: 0.53, 0.75); P<0.001) respectively). Nine of the ten parental social contact indices, were significant mediated through one or more enteroviral indices. The strength of association between enterovirus presence and T1D onset increased with child age (1.2 fold increase per year; P = 0.05). Lower child hand hygiene enhanced the adverse effect of low parental occupational contact with the sick; Synergy Index 5.16 (95% CI: 3.61, 7.36). The interaction between hand washing and parental occupational contact is more consistent with protection against parental enteroviral shedding than the sharing of a protective infectious agent or microbiome.

Aim: A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this female bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. The JIA genetic risk variant, PTPN22 rs2476601, has been reported to show female-specific association in type 1 diabetes. We sought to determine whether rs2476601 exhibits a female-specific association in JIA. Method(s): The discovery sample was drawn from the Australian CLARITY JIA biobank. Rs2476601 was genotyped in 413 cases (67% female, mean age at recruitment 9.1 years) and 690 healthy controls (42% female, mean age at recruitment 7.1 years). We used logistic regression to assess the association of rs2476601 with JIA in the total sample (males and females). We then explored the role of sex in this association: we adjusted the regression analysis for sex, stratified by sex, and performed a genotype-bysex interaction analysis. We sought to replicate the sex-specific associations in an independent JIA case-control sample collected from the USA and Norway and held at the Children's Hospital of Philadelphia (1008 JIA cases and 9287 controls). Analyses were performed using Stata or PLINK. Result(s): PTPN22 rs2476601 was associated with JIA in both datasets (Discovery OR = 1.71,95% CI 1.26-2.33,p = 0.00066; Replication OR = 1.30, 95% CI 1.09-1.55, p = 0.0068). The association remained when adjusted for sex (Discovery OR = 1.63, 95% CI 1.18-2.24, p = 0.0028; Replication OR = 1.30, 95% CI 1.08-1.56, p = 0.0051). Discovery sample sex stratified analyses demonstrated association in females (OR = 2.35, 95% CI 1.52-3.63, p = 0.00011) but not males (OR = 0.91, 95% CI 0.52-1.60, p = 0.75).This was also observed in the replication sample (Female OR = 1.38, 95% CI 1.09-1.73, p = 0.0068; MaleOR = 1.19,95% CI 0.88-1.63, p = 0.26). There was evidence for genotype-by-sex interaction (p interaction = 0.0087). Conclusion(s): We have demonstrated that the

Aim: Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by the interplay of genes and environment. The environmental factors remain largely unknown. The 'hygiene hypothesis' suggests that exposure to siblings may protect against the development of immune disorders via increased beneficial early life microbial exposure. We therefore tested the hypothesis that sibling exposure may be associated with JIA. Method(s): Cases (n = 302; mean age 8.5 y +/- 4.7 SD; 67% female) and controls (n = 676; mean age 7.1 y +/- 4.1 SD; 41% female) were drawn from the CLARITY JIA biobank. Birthdates of the index child and siblings, along with data on other potential confounders, were collected via questionnaire. We compared birth order, only-child status, total number of siblings, and cumulative years of sibling exposure by age six, between cases and controls using logistic regression. Result(s): Compared to being an only child, having any siblings was associated with a reduced risk of JIA (adjusted OR = 0.46, 95% CI 0.28-0.74, p = 0.001).The protective association appeared to increase with increasing number of siblings (e.g. >=3 siblings born within 18 y of the index child vs no siblings, adjusted OR = 0.25, 95% CI 0.13-0.48, p < 0.001). A protective association of siblings was also observed when we considered cumulative sibling years by age 6 (e.g. >=3 y exposure vs no exposure, adjusted OR = 0.49, 95% CI 0.30-0.79, p = 0.003). There was no association between birth order and JIA. We also compared cases to a second control sample (n = 341, mean age 8.1 y +/- 3.6 SD; 45% female) collected from the community and weighted to represent the Victorian child population. ORs were found to be similar in magnitude by this approach. Conclusion(s): Sibling exposure is associated with a reduced risk of disease in our sample. This is consistent with a role for the 'hygiene hypothesis' in the development of JIA.

Aim: A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this female bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. The JIA genetic risk variant, PTPN22 rs2476601, has been reported to show female-specific association in type 1 diabetes. We sought to determine whether rs2476601 exhibits a female-specific association in JIA. Method(s): The discovery sample was drawn from the Australian CLARITY JIA biobank. Rs2476601 was genotyped in 413 cases (67% female, mean age at recruitment 9.1 years) and 690 healthy controls (42% female, mean age at recruitment 7.1 years). We used logistic regression to assess the association of rs2476601 with JIA in the total sample (males and females). We then explored the role of sex in this association: we adjusted the regression analysis for sex, stratified by sex, and performed a genotype-bysex interaction analysis. We sought to replicate the sex-specific associations in an independent JIA case-control sample collected from the USA and Norway and held at the Children's Hospital of Philadelphia (1008 JIA cases and 9287 controls). Analyses were performed using Stata or PLINK. Result(s): PTPN22 rs2476601 was associated with JIA in both datasets (Discovery OR = 1.71,95% CI 1.26-2.33,p = 0.00066; Replication OR = 1.30, 95% CI 1.09-1.55, p = 0.0068). The association remained when adjusted for sex (Discovery OR = 1.63, 95% CI 1.18-2.24, p = 0.0028; Replication OR = 1.30, 95% CI 1.08-1.56, p = 0.0051). Discovery sample sex stratified analyses demonstrated association in females (OR = 2.35, 95% CI 1.52-3.63, p = 0.00011) but not males (OR = 0.91, 95% CI 0.52-1.60, p = 0.75).This was also observed in the replication sample (Female OR = 1.38, 95% CI 1.09-1.73, p = 0.0068; MaleOR = 1.19,95% CI 0.88-1.63, p = 0.26). There was evidence for genotype-by-sex interaction (p interaction = 0.0087). Conclusion(s): We have demonstrated that the

Aim: Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by the interplay of genes and environment. The environmental factors remain largely unknown. The 'hygiene hypothesis' suggests that exposure to siblings may protect against the development of immune disorders via increased beneficial early life microbial exposure. We therefore tested the hypothesis that sibling exposure may be associated with JIA. Method(s): Cases (n = 302; mean age 8.5 y +/- 4.7 SD; 67% female) and controls (n = 676; mean age 7.1 y +/- 4.1 SD; 41% female) were drawn from the CLARITY JIA biobank. Birthdates of the index child and siblings, along with data on other potential confounders, were collected via questionnaire. We compared birth order, only-child status, total number of siblings, and cumulative years of sibling exposure by age six, between cases and controls using logistic regression. Result(s): Compared to being an only child, having any siblings was associated with a reduced risk of JIA (adjusted OR = 0.46, 95% CI 0.28-0.74, p = 0.001).The protective association appeared to increase with increasing number of siblings (e.g. >=3 siblings born within 18 y of the index child vs no siblings, adjusted OR = 0.25, 95% CI 0.13-0.48, p < 0.001). A protective association of siblings was also observed when we considered cumulative sibling years by age 6 (e.g. >=3 y exposure vs no exposure, adjusted OR = 0.49, 95% CI 0.30-0.79, p = 0.003). There was no association between birth order and JIA. We also compared cases to a second control sample (n = 341, mean age 8.1 y +/- 3.6 SD; 45% female) collected from the community and weighted to represent the Victorian child population. ORs were found to be similar in magnitude by this approach. Conclusion(s): Sibling exposure is associated with a reduced risk of disease in our sample. This is consistent with a role for the 'hygiene hypothesis' in the development of JIA.

PURPOSE: For a community cohort of children confirmed to have stuttered by the age of 4 years, we report (a) the recovery rate from stuttering, (b) predictors of recovery, and (c) comorbidities at the age of 7 years. METHOD: This study was nested in the Early Language in Victoria Study. Predictors of stuttering recovery included child, family, and environmental measures and first-degree relative history of stuttering. Comorbidities examined at 7 years included temperament, language, nonverbal cognition, and health-related quality of life. RESULTS: The recovery rate by the age of 7 years was 65%. Girls with stronger communication skills at the age of 2 years had higher odds of recovery (adjusted OR = 7.1, 95% CI [1.3, 37.9], p = .02), but similar effects were not evident for boys (adjusted OR = 0.5, 95% CI [0.3, 1.1], p = .10). At the age of 7 years, children who had recovered from stuttering were more likely to have stronger language skills than children whose stuttering persisted (p = .05). No evident differences were identified on other outcomes including nonverbal cognition, temperament, and parent-reported quality of life. CONCLUSION: Overall, findings suggested that there may be associations between language ability and recovery from stuttering. Subsequent research is needed to explore the directionality of this relationship.

Purpose: For a community cohort of children confirmed to have stuttered by the age of 4 years, we report (a) the recovery rate from stuttering, (b) predictors of recovery, and (c) comorbidities at the age of 7 years. Method: This study was nested in the Early Language in Victoria Study. Predictors of stuttering recovery included child, family, and environmental measures and first-degree relative history of stuttering. Comorbidities examined at 7 years included temperament, language, nonverbal cognition, and health-related quality of life. Results: The recovery rate by the age of 7 years was 65%. Girls with stronger communication skills at the age of 2 years had higher odds of recovery (adjusted OR = 7.1, 95% CI [1.3, 37.9], p =.02), but similar effects were not evident for boys (adjusted OR = 0.5, 95% CI [0.3, 1.1], p =.10). At the age of 7 years, children who had recovered from stuttering were more likely to have stronger language skills than children whose stuttering persisted (p =.05). No evident differences were identified on other outcomes including nonverbal cognition, temperament, and parent-reported quality of life. Conclusion: Overall, findings suggested that there may be associations between language ability and recovery from stuttering. Subsequent research is needed to explore the directionality of this relationship.

An Organic Foundation: Sound Composition in Titus AndronicusbyEmily Jankowski PezicMaster of Fine Arts in Theatre and Dance (Design)University of California, San Diego, 2013Professor Shahrokh Yadegari, ChairAs an artist and sound designer, I have always tended to start my work from an external, digital base point. As I incessantly dig through libraries of sound and synthesized textures, there is a moment of connection when I hear the tones, the layers, or the rhythm that makes sense for any given project. This moment is the point at which I begin. As a collaborator within the realm of theatre, however, I have realized the moment of artistic departure can come from any given interaction- not just from an ongoing search for a point of departure within the bounds of the technology I can afford. Titus Andronicus was a production where dramaturgical, emotional, and musical communication was free flowing from pre production to opening night. This steady conversational flow of ideas prepared me to generously extend design concepts to our musical cohorts. Collaborating with such verbose musicians for Titus Andronicus has introduced me to a language that has freed me from the bounds of a laptop and whatever software I have. I was enthralled with the extraordinary range of timbre generated by my musicians Judith Hamann and Samuel Dunscombe; suddenly my artistic process shifted. It became a personal exchange of ability, ideas, and inspiration. To me, this flux between designers, director, and musicians provided a thread upon which our form solidified. The movement of the play in the rehearsal room affected the form of my compositions, and in turn, my compositions influenced the movement of the play in the theatre.

An Organic Foundation: Sound Composition in Titus AndronicusbyEmily Jankowski PezicMaster of Fine Arts in Theatre and Dance (Design)University of California, San Diego, 2013Professor Shahrokh Yadegari, ChairAs an artist and sound designer, I have always tended to start my work from an external, digital base point. As I incessantly dig through libraries of sound and synthesized textures, there is a moment of connection when I hear the tones, the layers, or the rhythm that makes sense for any given project. This moment is the point at which I begin. As a collaborator within the realm of theatre, however, I have realized the moment of artistic departure can come from any given interaction- not just from an ongoing search for a point of departure within the bounds of the technology I can afford. Titus Andronicus was a production where dramaturgical, emotional, and musical communication was free flowing from pre production to opening night. This steady conversational flow of ideas prepared me to generously extend design concepts to our musical cohorts. Collaborating with such verbose musicians for Titus Andronicus has introduced me to a language that has freed me from the bounds of a laptop and whatever software I have. I was enthralled with the extraordinary range of timbre generated by my musicians Judith Hamann and Samuel Dunscombe; suddenly my artistic process shifted. It became a personal exchange of ability, ideas, and inspiration. To me, this flux between designers, director, and musicians provided a thread upon which our form solidified. The movement of the play in the rehearsal room affected the form of my compositions, and in turn, my compositions influenced the movement of the play in the theatre.

Background: A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this female bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. The JIA genetic risk variant, PTPN22 rs2476601, has been reported to show female-specific association in type 1 diabetes. Objective(s): We sought to determine whether PTPN22 rs2476601 exhibits a female-specific association with JIA. Method(s): The discovery sample was drawn from the Australian CLARITY JIA biobank. rs2476601 was genotyped in 413 cases (67% female, mean age 9.1 years) and 690 healthy controls (42% female, mean age 7.1 years). We used logistic regression to assess the association of rs2476601 with JIA in the total sample (males and females). We then explored the role of sex in this association: we adjusted the regression analysis for sex, stratified by sex, and performed a genotype x sex interaction analysis. Sensitivity analyses were performed by restricting to individuals of European descent, subtypes of oligoarticular and polyarticular RF negative disease course, and exclusion of systemic JIA. We sought to replicate the sex-specific associations in an independent JIA casecontrol sample collected from the USA and Norway and held at the Children's Hospital of Philadelphia. Analyses were performed using Stata or PLINK. Result(s): The outcomes of analyses are shown in the Table. rs2476601 was associated with all JIA in both the discovery and replication samples, and the association remained when adjusted for sex. When stratified by sex, a strong association was observed for females, but not for males. There was evidence for genotype-by-sex interaction (p=0.0087). Similar patterns were observed in all sensitivity analyses. In the replication sample, we also observed association of rs2476601 with JIA in females, but not in males. Conclusion(s):We have demonstrated, in both a discovery and replication sample, that the as

Background: A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this female bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. The JIA genetic risk variant, PTPN22 rs2476601, has been reported to show female-specific association in type 1 diabetes. Objective(s): We sought to determine whether PTPN22 rs2476601 exhibits a female-specific association with JIA. Method(s): The discovery sample was drawn from the Australian CLARITY JIA biobank. rs2476601 was genotyped in 413 cases (67% female, mean age 9.1 years) and 690 healthy controls (42% female, mean age 7.1 years). We used logistic regression to assess the association of rs2476601 with JIA in the total sample (males and females). We then explored the role of sex in this association: we adjusted the regression analysis for sex, stratified by sex, and performed a genotype x sex interaction analysis. Sensitivity analyses were performed by restricting to individuals of European descent, subtypes of oligoarticular and polyarticular RF negative disease course, and exclusion of systemic JIA. We sought to replicate the sex-specific associations in an independent JIA casecontrol sample collected from the USA and Norway and held at the Children's Hospital of Philadelphia. Analyses were performed using Stata or PLINK. Result(s): The outcomes of analyses are shown in the Table. rs2476601 was associated with all JIA in both the discovery and replication samples, and the association remained when adjusted for sex. When stratified by sex, a strong association was observed for females, but not for males. There was evidence for genotype-by-sex interaction (p=0.0087). Similar patterns were observed in all sensitivity analyses. In the replication sample, we also observed association of rs2476601 with JIA in females, but not in males. Conclusion(s):We have demonstrated, in both a discovery and replication sample, that the as

Transposable elements (TEs) have the capacity to replicate and insert into new genomic locations. This contributs significantly to evolution of genomes, but can also result in DNA breaks and illegitimate recombination, and therefore poses a significant threat to genomic integrity. Excess damage to the germ cell genome results in sterility. A specific RNA silencing pathway, termed the piRNA pathway operates in germ cells of animals to control TE activity. At the core of the piRNA pathway is a ribonucleoprotein complex consisting of a small RNA, called piRNA, and a protein from the PIWI subfamily of Argonaute nucleases. The piRNA pathway relies on the specificity provided by the piRNA sequence to recognize complementary TE targets, while effector functions are provided by the PIWI protein. PIWI-piRNA complexes silence TEs both at the transcriptional level – by attracting repressive chromatin modifications to genomic targets – and at the posttranscriptional level – by cleaving TE transcripts in the cytoplasm. Impairment of the piRNA pathway leads to overexpression of TEs, significantly compromised genome structure and, invariably, germ cell death and sterility. The piRNA pathway is best understood in the fruit fly, Drosophila melanogaster, and in mouse. This Chapter gives an overview of current knowledge on piRNA biogenesis, and mechanistic details of both transcriptional and posttranscriptional TE silencing by the piRNA pathway. It further focuses on the importance of post-translational modifications and subcellular localization of the piRNA machinery. Finally, it provides a brief description of analogous pathways in other systems.

Background: Our understanding of the genetic factors underlying juvenile idiopathic arthritis (JIA) is growing, but remains incomplete. Recently, a number of novel genetic loci were reported to be associated with JIA at (or near) genome-wide significance in a large case-control discovery sample using the Immunochip genotyping array. However, independent replication of findings has yet to be performed. We therefore attempted to replicate these newly identified loci in the Australian CLARITY JIA case-control sample. Finding(s): Genotyping was successfully performed on a total of 404 JIA cases (mean age 6.4 years, 68% female) and 676 healthy child controls (mean age 7.1 years, 42% female) across 19 SNPs previously associated with JIA. We replicated a significant association (p < 0.05, odds ratio (OR) in a direction consistent with the previous report) for seven loci, six replicated for the first time - C5orf56-IRF1 (rs4705862), ERAP2-LNPEP (rs27290), PRR5L (rs4755450), RUNX1 (rs9979383), RUNX3 (rs4648881), and UBE2L3 (rs2266959). Conclusion(s): We have carried out the first independent replication of association for six genes implicated in JIA susceptibility. Our data significantly strengthens the evidence that these loci harbor true disease associated variants. Thus, this study makes an important contribution to the growing body of international data that is revealing the genetic risk landscape of JIA.Copyright © 2014 Chiaroni-Clarke et al.

Objective Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by both genes and environment. However, the environmental factors remain largely unknown. The hygiene hypothesis suggests that exposure to siblings, as a marker of exposure to microbes in early life, may protect against the development of later immune disorders. Some prior evidence suggests this may also be true for JIA. The present study was undertaken to test this hypothesis in detail. Methods We conducted a comprehensive analysis of the role of sibling exposure in JIA risk within the Childhood Arthritis Risk Factor Identification Study JIA case-hospital control sample (302 cases and 676 controls) from Victoria, Australia. Results We found that, compared to being an only child, having any siblings was protective against JIA, with an adjusted odds ratio (OR) of 0.46 (95% confidence interval [95% CI] 0.28-0.74) (P=0.001). The protective association appeared to increase with increasing number of siblings (e.g., for >=3 siblings, adjusted OR 0.25 [95% CI 0.13-0.48], P<0.001). A protective association of siblings was also observed when we considered cumulative sibling years by age 6 (e.g., for >=3 years of exposure versus no exposure, adjusted OR 0.49 [95% CI 0.30-0.79], P=0.003). We also compared cases to a second control sample (n=341) collected from the community and weighted to represent the child population of Victoria. Data remained supportive of an association between sibling exposure and protection against JIA, particularly for exposure to younger siblings. Conclusion Increased exposure to siblings is associated with a reduced risk of disease in our sample. This suggests that increased microbial exposure in childhood may confer protection against the development of JIA.Copyright © 2015, American College of Rheumatology.

A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (P interaction =0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.Copyright © 2015 Macmillan Publishers Limited All rights reserved.

Background: Our understanding of the genetic factors underlying juvenile idiopathic arthritis (JIA) is growing, but remains incomplete. Recently, a number of novel genetic loci were reported to be associated with JIA at (or near) genome-wide significance in a large case-control discovery sample using the Immunochip genotyping array. However, independent replication of findings has yet to be performed. We therefore attempted to replicate these newly identified loci in the Australian CLARITY JIA case-control sample. Finding(s): Genotyping was successfully performed on a total of 404 JIA cases (mean age 6.4 years, 68% female) and 676 healthy child controls (mean age 7.1 years, 42% female) across 19 SNPs previously associated with JIA. We replicated a significant association (p < 0.05, odds ratio (OR) in a direction consistent with the previous report) for seven loci, six replicated for the first time - C5orf56-IRF1 (rs4705862), ERAP2-LNPEP (rs27290), PRR5L (rs4755450), RUNX1 (rs9979383), RUNX3 (rs4648881), and UBE2L3 (rs2266959). Conclusion(s): We have carried out the first independent replication of association for six genes implicated in JIA susceptibility. Our data significantly strengthens the evidence that these loci harbor true disease associated variants. Thus, this study makes an important contribution to the growing body of international data that is revealing the genetic risk landscape of JIA.Copyright © 2014 Chiaroni-Clarke et al.

Objective Susceptibility to juvenile idiopathic arthritis (JIA) is presumed to be determined by both genes and environment. However, the environmental factors remain largely unknown. The hygiene hypothesis suggests that exposure to siblings, as a marker of exposure to microbes in early life, may protect against the development of later immune disorders. Some prior evidence suggests this may also be true for JIA. The present study was undertaken to test this hypothesis in detail. Methods We conducted a comprehensive analysis of the role of sibling exposure in JIA risk within the Childhood Arthritis Risk Factor Identification Study JIA case-hospital control sample (302 cases and 676 controls) from Victoria, Australia. Results We found that, compared to being an only child, having any siblings was protective against JIA, with an adjusted odds ratio (OR) of 0.46 (95% confidence interval [95% CI] 0.28-0.74) (P=0.001). The protective association appeared to increase with increasing number of siblings (e.g., for >=3 siblings, adjusted OR 0.25 [95% CI 0.13-0.48], P<0.001). A protective association of siblings was also observed when we considered cumulative sibling years by age 6 (e.g., for >=3 years of exposure versus no exposure, adjusted OR 0.49 [95% CI 0.30-0.79], P=0.003). We also compared cases to a second control sample (n=341) collected from the community and weighted to represent the child population of Victoria. Data remained supportive of an association between sibling exposure and protection against JIA, particularly for exposure to younger siblings. Conclusion Increased exposure to siblings is associated with a reduced risk of disease in our sample. This suggests that increased microbial exposure in childhood may confer protection against the development of JIA.Copyright © 2015, American College of Rheumatology.

A preponderance of females develop autoimmune disease, including juvenile idiopathic arthritis (JIA), yet the reason for this bias remains elusive. Evidence suggests that genetic risk of disease may be influenced by sex. PTPN22 rs2476601 is associated with JIA and numerous other autoimmune diseases, and has been reported to show female-specific association with type 1 diabetes. We performed main effect and sex-stratified association analyses to determine whether a sex-specific association exists in JIA. As expected, rs2476601 was associated with JIA in our discovery (413 cases and 690 controls) and replication (1008 cases and 9284 controls) samples. Discovery sample sex-stratified analyses demonstrated an association specifically in females (odds ratio (OR)=2.35, 95% confidence interval (CI)=1.52-3.63, P=0.00011) but not males (OR=0.91, 95% CI=0.52-1.60, P=0.75). This was similarly observed in the replication sample. There was evidence for genotype-by-sex interaction (P interaction =0.009). The association between rs2476601 and JIA appears restricted to females, partly accounting for the predominance of females with this disease.Copyright © 2015 Macmillan Publishers Limited All rights reserved.

BACKGROUND: Self-reported physical activity has been inversely associated with mortality but the effect of objectively measured step activity on mortality has never been evaluated. The objective is to determine the prospective association of daily step activity on mortality among free-living adults. METHODS AND FINDINGS: Cohort study of free-living adults residing in Tasmania, Australia between 2000 and 2005 who participated in one of three cohort studies (n = 2 576 total participants). Daily step activity by pedometer at baseline at a mean of 58.8 years of age, and for a subset, repeated monitoring was available 3.7 (SD 1.3) years later (n = 1 679). All-cause mortality (n = 219 deaths) was ascertained by record-linkage to the Australian National Death Index; 90% of participants were followed-up over ten years, until June 2011. Higher daily step count at baseline was linearly associated with lower all-cause mortality (adjusted hazard ratio AHR, 0.94; 95% CI, 0.90 to 0.98 per 1 000 steps; P = 0.004). Risk was altered little by removing deaths occurring in the first two years. Increasing baseline daily steps from sedentary to 10 000 steps a day was associated with a 46% (95% CI, 18% to 65%; P = 0.004) lower risk of mortality in the decade of follow-up. In addition, those who increased their daily steps over the monitoring period had a substantial reduction in mortality risk, after adjusting for baseline daily step count (AHR, 0.39; 95% CI, 0.22 to 0.72; P = 0.002), or other factors (AHR, 0.38; 95% CI, 0.21-0.70; P = 0.002). CONCLUSIONS: Higher daily step count was linearly associated with subsequent long term mortality among free living adults. These data are the first to quantify mortality reductions using an objective measure of physical activity in a free living population. They strongly underscore the importance of physical inactivity as a major public health problem.