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Anxiety disorders are common, debilitating, and begin early in life. Early intervention to prevent anxiety disorders in children who are at risk could have long-term impact. The ‘Cool Little Kids’ parenting group program has previously been shown to be efficacious in preventing anxiety disorders in temperamentally inhibited young children. Wider dissemination of the program could be achieved with an internet-based delivery platform, affording greater accessibility and convenience for parents. The aim of this study was to evaluate ‘Cool Little Kids Online’, a newly developed online version of the existing parenting group program. Fifty-one parents of children aged 3–6 years were recruited to evaluate the online program's acceptability and preliminary efficacy in reducing inhibited young children's anxiety problems. Parents were randomized to receive either a clinician-supported version or an unsupported version of the program. Parents had 10 weeks to access the program and completed questionnaires at baseline and post-intervention. Both groups showed medium-to-large reductions in children's anxiety symptoms, emotional symptoms, number of child anxiety diagnoses, and improvements in life interference from anxiety. The effect of clinician support was inconsistent and difficult to interpret. Parents reported high levels of satisfaction with the program. These encouraging results indicate that the online version is acceptable and useful for parents with temperamentally inhibited young children. Cool Little Kids Online may be a promising direction for improving access to an evidence-based prevention and early intervention program for child anxiety problems. A large randomized trial is warranted to further evaluate efficacy., Highlights • An online version of an existing parenting program for child anxiety was developed. • Most parents found the program useful, user-friendly, and would recommend it. • A clinician-supported format was not clearly superior to a self-guided format.

Objectives Interventions to prevent postpartum common mental disorders (PCMD) among unselected populations of women have had limited success. The aim was to determine whether What Were We Thinking (WWWT) a gender-informed, psychoeducational programme for couples and babies can prevent PCMD among primiparous women 6 months postpartum. Design Cluster-randomised controlled trial. Setting 48 Maternal and Child Health Centres (MCHCs) from 6 Local Government Areas in Melbourne, Australia were allocated randomly to usual care (24) or usual care plus WWWT (24). Participants English-speaking primiparous women receiving primary care at trial MCHCs were recruited to the intervention (204) and control (196) conditions. Of these, 187 (91.7%) and 177 (90.3%) provided complete data. Intervention WWWT is a manualised programme comprising primary care from a trained nurse, print materials and a face-to-face seminar. Main outcome measures Data sources were standardised and study-specific measures collected in blinded computer-assisted telephone interviews at 6 and 26 weeks postpartum. The primary outcome was PCMD assessed by Composite International Diagnostic Interviews and Patient Health Questionnaire (PHQ) Depression and Generalised Anxiety Disorder modules. Results In intention-to-treat analyses the adjusted OR (AOR) of PCMD in the intervention compared to the usual care group was 0.78 (95% CI 0.38 to 1.63, ns), but mild to moderate anxiety symptoms (AOR 0.58, 95% CI 0.35 to 0.97) and poor self-rated health (AOR 0.46, 95% CI 0.22 to 0.97) were significantly lower. In a per protocol analysis, comparing the full (three component) intervention and usual care groups, the AOR of PCMD was 0.36, (95% CI 0.14 to 0.95). The WWWT seminar was appraised as salient, comprehensible and useful by >85% participants. No harms were detected. Conclusions WWWT is readily integrated into primary care, enables inclusion of fathers and addresses modifiable risks for PCMD directly. The full intervention appears a promising programme for preventing PCMD, optimising family functioning, and as the first component of a stepped approach to mental healthcare. Trial registration number ACTRN12613000506796; Results.

Shy/inhibited young children are at risk for internalising difficulties; however, for many, this temperamental style does not result in mental health problems. This study followed a population-based sample of temperamentally inhibited preschool children into mid childhood to explore the aetiology of clinical-level anxious and depressive problems. Amongst inhibited preschool children, we aimed to predict each of clinical child anxiety and depressive problems in mid childhood from a broad range of potential risks (demographics, traumatic events and broader recent stressors, parents’ well-being, and parenting practices). This study is based on data from a wider population trial of Cool Little Kids that recruited a representative sample of inhibited preschool children enrolled in their year before starting school. In 2011–2012, an inhibition screen was universally distributed to parents of children in their year before school (age 4 years) across eight diverse government areas in Melbourne, Australia. Participants were 545 parents of inhibited preschoolers (78% uptake, 545/703) who were followed to mid childhood (three annual waves 2015–2017, age 7–10 years) with 84% retention (456/545). Parents completed questionnaires spanning child ages 4–10 years, along with diagnostic interviews for child anxiety. Children also completed questionnaires in mid childhood. The questionnaires encompassed a variety of potential risks including sociodemographics, traumatic events, recent life stressors, parent wellbeing and parenting practices. In mid childhood, 57% (246/430) of inhibited preschoolers had a clinical level of anxiety problems while 22% (95/432) had depressive problems (by one or more sources). The aetiology analyses highlighted parent distress and parenting practices (overinvolved/protective, harsh discipline) as key predictors of inhibited preschoolers’ internalising problems by mid childhood. Some high-risk families may not have participated. Child depression was not assessed with a diagnostic interview. The measures did not include every possible risk factor. The findings lend support to parenting programs for shy/inhibited young children that aim to prevent the development of anxiety and depression as they grow.

Background This study explored whether temperamentally inhibited children who experience early trauma are vulnerable to developing internalizing problems in the face of later life-stressors. Methods A validated screen for temperamental inhibition was distributed to parents of young children attending preschools in six government regions of Melbourne, Australia. Screening identified 11% of children as inhibited (703 of 6347 screened) and eligible for a prevention study. Participants were 545 parents of inhibited preschoolers (78% uptake), of whom 84% were followed into mid childhood (age 7–10 years: wave 1, n = 446; wave 2, n = 427; wave 3, n = 426). Parents and children then completed questionnaires for child internalizing (anxious and depressive) symptoms, and parents received a diagnostic interview for child anxiety disorder. In mid-childhood parents also completed questionnaires annually to describe recent life-stressors experienced by their child, and any potentially traumatic events in the first four years of life. Results Only one in 14 temperamentally inhibited children had experienced a potentially traumatic event in early childhood. In mid childhood 56% experienced recent life-stressors. Inhibited children who had early life trauma experienced slightly more anxiety disorder and symptoms in mid childhood. Those children with more recent life-stressors in mid childhood also had slightly more symptoms of anxiety and depression. In contrast to stress sensitization, inhibited children with early trauma plus recent stressors did not show especially high mid-childhood internalizing difficulties. Conclusions Early life trauma and recent life-stressors each convey a small risk for children with an inhibited temperament to develop internalizing problems. Nevertheless, early life stress may not always result in negative sensitization for children in the general population.

Immunodeficiència primària; Limfoproliferació; Inhibidor de mTOR Inmunodeficiencia primaria; Linfoproliferación; Inhibidor de mTOR Primary immunodeficiency; Lymphoproliferation; MTOR inhibitor Background Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). Objectives This study sought to characterize HCT outcomes in APDS. Methods Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. Results Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure–free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. Conclusions Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time. This research was funded in part from the Intramural Program of the National Cancer Institute, National Institutes of Health. The funding source had no involvement in study design; collection, analysis, and interpretation of data; writing of the report; or in the decision to submit the article for publication.

Contains fulltext : 291547.pdf (Publisher’s version ) (Open Access) OBJECTIVES: Genome-wide association studies have revealed over 200 genetic susceptibility loci for prostate cancer (PCa). By combining them, polygenic risk scores (PRS) can be generated to predict risk of PCa. We summarize the published evidence and conduct meta-analyses of PRS as a predictor of PCa risk in Caucasian men. PATIENTS AND METHODS: Data were extracted from 59 studies, with 16 studies including 17 separate analyses used in the main meta-analysis with a total of 20,786 cases and 69,106 controls identified through a systematic search of ten databases. Random effects meta-analysis was used to obtain pooled estimates of area under the receiver-operating characteristic curve (AUC). Meta-regression was used to assess the impact of number of single-nucleotide polymorphisms (SNPs) incorporated in PRS on AUC. Heterogeneity is expressed as I(2) scores. Publication bias was evaluated using funnel plots and Egger tests. RESULTS: The ability of PRS to identify men with PCa was modest (pooled AUC 0.63, 95% CI 0.62-0.64) with moderate consistency (I(2) 64%). Combining PRS with clinical variables increased the pooled AUC to 0.74 (0.68-0.81). Meta-regression showed only negligible increase in AUC for adding incremental SNPs. Despite moderate heterogeneity, publication bias was not evident. CONCLUSION: Typically, PRS accuracy is comparable to PSA or family history with a pooled AUC value 0.63 indicating mediocre performance for PRS alone. 01 april 2023

This feasibility study explored suitability of a preventive intervention for internalising problems in young children for culturally and linguistically diverse families in Australia. A subsample of 62 families whose main language at home was other than English was selected from a population-based randomised trial of the Cool Little Kids parenting program. The population trial recruited 545 inhibited preschool children. Measures included family demographics, feedback post-intervention and child internalising problems at longitudinal follow-up. Parents of children whose main language at home was not English gave feedback that Cool Little Kids was helpful for managing their inhibited child's emotional distress. Significantly fewer intervention than control children whose main language at home was not English had separation anxiety symptoms after 2 years (M (SD) = 3.00 (3.15) versus 5.95 (3.98), p = 0.041). Further work to expand accessibility of Cool Little Kids to recent immigrant parents who do not speak English could be worthwhile.

Objectives: There is evidence that diet quality is associated with mental health problems in adults and adolescents. Yet the extent to which overall diet quality (not individual nutrients or dietary patterns) may be associated with mental health problems in pre-adolescent children, a common time for first onset of symptoms, remains unclear. This study examined associations between overall diet quality, using a brief measure, and mental health problems during late childhood, in a large community sample. Methods: Participants were 787 eight and nine-year-old children taking part in the Childhood to Adolescence Transition Study. Parents reported on their child's mental health problems using the Strengths and Difficulties Questionnaire and on their child's diet quality, using a six-item screening tool. Results: Regression analyses were conducted, adjusting for child age, sex, body mass index, and family socioeconomic status. Overall diet quality was significantly associated with children's mental health before (beta = -0.11, 95% CI -0.18 to -0.04, p = 0.004) and after adjustments for age, sex, body mass index and family socioeconomic status (beta = -0.10, 95% CI -0.18 to -0.03, p = 0.007). Conclusion: Concordant with previous literature, results indicate that better overall diet quality is related to more positive mental health in pre-adolescent children. Additionally, these results support the utility and efficacy of a brief (six-item) parent-report questionnaire as an indicator of overall diet quality.

This pilot study aimed to explore the suitability of a preventative intervention for internalising problems in young children with chronic physical health conditions. The pilot study focused on a subsample of 27 children with chronic physical health conditions within a population-level randomised controlled trial of the Cool Little Kids parenting programme. The Cool Little Kids parenting programme aims to prevent the development of internalising problems in inhibited (shy/anxious) preschool children by educating parents to reduce young children’s avoidant coping styles and manage their anxiety/distress. The wider trial recruited 545 temperamentally inhibited preschool children. Measures included child health/development concerns and internalising symptoms at baseline, feedback on Cool Little Kids post-intervention and child internalising problems at one- and two-year longitudinal follow-up. At baseline, inhibited children with and without chronic physical health conditions had levels of internalising symptoms above the normative mean. At post-intervention, parents of children with chronic physical health conditions gave feedback that Cool Little Kids was helpful for managing their child’s emotional distress. At follow-up, significantly fewer intervention than control children with chronic physical health conditions had specific phobia after 1 year (25% vs 70%) and specific fear symptoms after 2 years (mean 9.57 vs 16.89). As the pilot findings are promising, a further trial of Cool Little Kids in a physical health treatment service with a larger sample of children with chronic physical illness diagnoses would be worthwhile.

Public health advocates have highlighted internalising problems as a leading cause of global burden of disease. Internalising problems (anxiety/depression) affect up to 20% of school-age children and can impact peer relations, school engagement and later employment and mortality. This translational trial aimed to determine whether a selective/indicated parenting group programme to prevent internalising distress in shy/inhibited preschool children had sustained effects in middle childhood. Translational design aspects were a brief parent-report screening tool for child inhibition offered universally across the population via preschools in the year before school, followed by an invitation to parents of all inhibited children to attend the parenting programme at venues in their local community.Design of the study was a randomised controlled trial. The setting was 307 preschool services across eight socioeconomically diverse government areas in Melbourne, Australia. Participants were 545 parents of inhibited four-year-old children of which 456 (84%) were retained during middle childhood (age of seven to 10 years). Early intervention was the Cool Little Kids parenting group programme, and control was 'usual care' access to available support services in the community. Primary outcomes were child anxiety and depression symptoms (parent and child report) and DSM-IV anxiety disorders (assessor masked). Secondary outcomes were parenting practices and parent mental health.There was no significant difference in anxiety disorders between the intervention and control group during the three annual follow-ups of the cohort in middle childhood (2015 43% vs. 41%, 2016 40% vs. 36%, 2017 27% vs. 30%, respectively; p's .05). There were also no significant differences in child anxiety or depression symptoms (by child or parent report), parenting practices or parent mental health, between the intervention and control group during middle childhood. However, a priori interaction tests suggested that for children with anxious parents, early intervention attenuated risk for middle childhood internalising problems.An issue for population translation is low levels of parent engagement in preventive interventions. Initial effects of the Cool Little Kids parenting group programme in reducing shy/inhibited preschool children's internalising distress at school entry dissipated over time, perhaps due to low engagement. Future translational research on early prevention of internalising problems could benefit from screening preschool children in the population at higher risk (combining temperamental inhibition and parent distress) and incorporating motivational techniques to facilitate family engagement. Trial registration ISRCTN30996662 http://www.isrctn.com/ISRCTN30996662.

Overinvolved/protective parenting has emerged in child development literature as part of the etiology of internalizing problems (anxiety/depression). This review aimed to explore overinvolved/protective parenting questionnaires that exist in the internalizing literature for different childhood periods and their psychometric properties (reliability, validity, norms). A systematic review was conducted through seven databases and Google Scholar. Extraction and evaluation of psychometric properties were double coded. Four hundred and sixty publications were screened for eligibility, with 20 of these further assessed. Ten overinvolved/protective parenting questionnaires were described in the literature (between 1993 and 2019) six starting as young as preschool age, two at primary school age and two in adolescence. Some questionnaires at each age stood out in terms of psychometric development: at preschool age, the Overinvolved/protective Parenting Scale, and at primary and high school age the Modified My Memories of Upbringing for Children. The Parental Bonding Instrument is also recommended in late adolescence. Clinicians and researchers can select from the questionnaires reviewed, to assist in clinical practice with children and families, along with etiology, treatment and prevention research.

Background The aim was to determine outcomes in the first year of school of a population-delivered parenting program to prevent internalising problems in temperamentally inhibited preschool children and predictors of engagement in parenting groups. Method Design: Randomised controlled trial. Setting 307 preschool services across eight socio-economically diverse government areas in Melbourne, Australia. Participants 545 parents of inhibited 4-year-old children; 469 (86%) retained at two-year follow-up. Intervention Cool Little Kids program. Primary outcomes were child internalising symptoms and anxiety disorders. Secondary outcomes were parenting, parent well-being and engagement. Trial registration ISRCTN30996662 http://www.isrctn.com/ISRCTN30996662. Results In the first year of school (M (SD) age 6.7 (0.4) years), child anxiety symptoms were reduced in the intervention versus control arm (PAS-R M (SD): total 36.2 (17.2) versus 39.4 (18.5); adjusted difference -3.26, 95% CI -6.46 to -0.05, p = .047; specific fears 9.1 (6.2) versus 10.7 (6.8), adjusted difference -1.53; 95% CI -2.69 to -0.38, p = .009). However, there was little difference in broader child internalising (CMFWQ M (SD): 2.2 (0.5) versus 2.3 (0.6); adjusted difference -0.03, 95% CI -0.13 to 0.06, p = .489) or anxiety disorders (37.6% vs. 42.6%; adjusted OR 0.79, 95% CI 0.53 to 1.18, p = .242). Lower income, younger mothers, less educated and more culturally diverse fathers engaged less with the intervention. Continued skills practice was less frequent for parents of girls and in advantaged neighbourhoods. Conclusions There were population effects of Cool Little Kids in the first year of school for anxiety symptoms but not disorders. Considering motivation techniques to engage subgroups of families would be helpful in translation research.

Shy/inhibited young children are at risk for internalising difficulties; however, for many, this temperamental style does not result in mental health problems. This study followed a population-based sample of temperamentally inhibited preschool children into mid childhood to explore the aetiology of clinical-level anxious and depressive problems. Amongst inhibited preschool children, we aimed to predict each of clinical child anxiety and depressive problems in mid childhood from a broad range of potential risks (demographics, traumatic events and broader recent stressors, parents' well-being, and parenting practices). This study is based on data from a wider population trial of Cool Little Kids that recruited a representative sample of inhibited preschool children enrolled in their year before starting school. In 2011-2012, an inhibition screen was universally distributed to parents of children in their year before school (age 4 years) across eight diverse government areas in Melbourne, Australia. Participants were 545 parents of inhibited preschoolers (78% uptake, 545/703) who were followed to mid childhood (three annual waves 2015-2017, age 7-10 years) with 84% retention (456/545). Parents completed questionnaires spanning child ages 4-10 years, along with diagnostic interviews for child anxiety. Children also completed questionnaires in mid childhood. The questionnaires encompassed a variety of potential risks including sociodemographics, traumatic events, recent life stressors, parent wellbeing and parenting practices. In mid childhood, 57% (246/430) of inhibited preschoolers had a clinical level of anxiety problems while 22% (95/432) had depressive problems (by one or more sources). The aetiology analyses highlighted parent distress and parenting practices (overinvolved/protective, harsh discipline) as key predictors of inhibited preschoolers' internalising problems by mid childhood. Some high-risk families may not have participated. Child depression was not assessed with a diagnostic interview. The measures did not include every possible risk factor. The findings lend support to parenting programs for shy/inhibited young children that aim to prevent the development of anxiety and depression as they grow.

Aim To examine, in a community cohort of healthy one-month-old infants, (i) the prevalence of early infant sleeping, crying and feeding problems; (ii) the extent to which they co-exist; and (iii) infant and mother characteristics associated with each problem alone and with comorbid problems. Methods A survey at 4 weeks of infant age examined the presence of infant sleeping, crying and feeding problems (yes/no); parenting self-efficacy; rating of self as a tense person; and doubts about parenting at bedtime. Results A total of 770 mothers (39% of those approached) with a total of 781 infants (11 twins) took part. Infant sleeping, crying and feeding problems were reported by 38.5, 27.4 and 25.2% of mothers, respectively. On comorbidity, 25.5% reported one problem, 20.5% reported two and 7.3% reported all three problems. Mothers of first-born infants reported more crying problems and comorbid problems. Mothers who described themselves as a 'tense person' reported more infant feeding problems. Maternal doubt and low self-efficacy were consistently associated with each type of infant problem and comorbid problems (adjusting for other factors). Conclusion Mothers expressing doubt and low parenting self-efficacy may benefit from additional support and guidance on normal infant behaviour.

The aim of this study was to explore how some temperamentally inhibited young children and not others in the general population develop anxiety disorders and broader clinical-level internalizing (anxious/depressive) problems, with a focus on the family. A brief screening tool for inhibition was universally distributed to parents of children in their year before starting school across eight socioeconomically diverse government areas in Melbourne, Australia (307 preschool services). Screening identified 11% of all children as inhibited. We invited all parents of inhibited children to participate in a longitudinal prevention study. Participants were 545 parents of inhibited pre-schoolers (78% uptake) of whom 498 (91%) completed assessment one year later and 469 (86%) two years later. Parents completed questionnaires to assess parenting practices, parent wellbeing, and child internalizing problems. Parents also engaged in structured diagnostic interviews to assess child anxiety disorders. During the follow up period close to half of the inhibited young children had anxiety disorders and one in seven had clinical-level internalizing problems, with girls perhaps at higher risk. The family variables significantly predicted inhibited children's anxiety disorders and broader internalizing problems. For child anxiety disorders, overinvolved/protective parenting was particularly important for girls and boys, and poorer parent wellbeing contributed. For child anxious/depressive problems, harsh discipline was a consistent predictor for girls and boys, and poorer parent wellbeing again contributed. These etiological findings support early intervention for temperamentally inhibited young children that focuses on the family environment to prevent the development of mental health problems.

This pilot study explored acceptability to parents and outcomes for children of a preventive intervention for anxiety problems in pre-schoolers with autism spectrum disorder (ASD) who were an identified sub-group within a population-based randomised trial of the Cool Little Kids parenting group programme. The population trial included 545 temperamentally inhibited pre-schoolers recruited across eight economically diverse areas of Melbourne, Australia. Within this sample, 26 parents reported that their child had received an ASD diagnosis. Trial measures included baseline inhibited temperament and developmental problems, post-intervention feedback on the programme, and caregiver-reported child mental health outcomes (anxiety diagnoses and internalising symptoms) at 1- and 2-year follow-up. Sample retention for the children with ASD over 2 years was strong (92%). At follow-up, fewer intervention than control children with ASD had anxiety disorders after 1 year (% (n): 25 (3) vs. 77 (10), P = .028) and separation anxiety symptoms after 2 years (M (SD): 4.22 (2.68) vs. 9.38 (5.91), P = .017). Similar effects favouring the intervention group were apparent across other child emotional outcome measures but without statistical significance in this small sample. Parents of the children with ASD reported that Cool Little Kids was "quite useful" in relation to their child's anxiety but also gave feedback that they would appreciate some tailoring of programme content to the context of ASD. These pilot findings suggest Cool Little Kids may be helpful for reducing comorbid anxiety in pre-schoolers with ASD. Further research is warranted to develop an ASD-specific adaptation which can be trialled with a larger sample of children with confirmed ASD diagnosis. Trial registration ISRCTN30996662 http://www.isrctn.com/ISRCTN30996662. Autism Res 2018, 11: 1166-1174. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Many children with autism spectrum disorder (ASD) also have anxiety. This pilot study explored acceptability to parents and outcomes for pre-schoolers with ASD of a parenting group programme to prevent anxiety problems. Among the sample of 26 pre-schoolers with ASD, we found reduced anxiety disorders and separation symptoms when their parents had received the intervention, as reported by caregivers in checklists and clinical interviews. Parents gave feedback that the programme was useful but suggested content be adapted to the context of ASD.

Sphingosine-1-phosphate (S1P) signaling influences bone metabolism, but its therapeutic potential in bone disorders has remained unexplored. We show that raising S1P levels in adult mice through conditionally deleting or pharmacologically inhibiting S1P lyase, the sole enzyme responsible for irreversibly degrading S1P, markedly increased bone formation, mass and strength and substantially decreased white adipose tissue. S1P signaling through S1P2 potently stimulated osteoblastogenesis at the expense of adipogenesis by inversely regulating osterix and PPAR-γ, and it simultaneously inhibited osteoclastogenesis by inducing osteoprotegerin through newly discovered p38–GSK3β–β-catenin and WNT5A–LRP5 pathways. Accordingly, S1P2-deficient mice were osteopenic and obese. In ovariectomy-induced osteopenia, S1P lyase inhibition was as effective as intermittent parathyroid hormone (iPTH) treatment in increasing bone mass and was superior to iPTH in enhancing bone strength. Furthermore, lyase inhibition in mice successfully corrected severe genetic osteoporosis caused by osteoprotegerin deficiency. Human data from 4,091 participants of the SHIP-Trend population-based study revealed a positive association between serum levels of S1P and bone formation markers, but not resorption markers. Furthermore, serum S1P levels were positively associated with serum calcium , negatively with PTH , and curvilinearly with body mass index. Bone stiffness, as determined through quantitative ultrasound, was inversely related to levels of both S1P and the bone formation marker PINP, suggesting that S1P stimulates osteoanabolic activity to counteract decreasing bone quality. S1P-based drugs should be considered as a promising therapeutic avenue for the treatment of osteoporotic diseases. Promoting more bone growth is of keen interest in the treatment of osteoporosis, and preventing the degradation of S1P offers a new therapeutic avenue for this approach.

Previous research has identified factors related to outcome in child anxiety treatment and parent training programs for child behavior problems. However, it is unclear what factors predict outcomes in interventions delivered online to parents of young children at risk of anxiety. This study investigated predictors of child anxiety outcomes among 433 families with young children (3-6 years) who participated in a randomized controlled trial of Cool Little Kids Online, an eight-module early intervention program for child anxiety based on cognitive-behavioral therapy (CBT). Potential predictors included baseline demographic factors, child and parent mental health factors, and indicators of program use, including number of online modules completed and frequency of homework practice. Results showed that only access to a printer moderated intervention effectiveness. Printer access predicted lower child anxiety in the Cool Little Kids Online group, but had no effect on outcomes in the wait-list group. In both groups, higher levels of child anxiety symptoms, child-inhibited temperament, and poorer parent mental health at baseline predicted higher levels of child anxiety symptoms at 6-month follow-up. The amount of online program use was not related to improvements in child anxiety symptoms. However, parents who reported practicing the program skills more frequently showed greater reductions in child anxiety, and access to a printer was related to frequency of program skills practice. These findings provide empirical support for the important role of skills practice in online CBT interventions, and suggest that practicing program skills may be more important than completing the online modules.

BACKGROUND: Frequent bullying predicts adolescent mental health problems, particularly depression. This population-based study with young Australian primary school children aimed to determine the frequency and mental health correlates of bullying, and whether friendship could be protective. METHOD: Participants were a population-based sample of 1221 children aged 8-9 years attending 43 primary schools in metropolitan Melbourne, Australia. Children were taking part in the Childhood to Adolescence Transition Study. Children completed online questionnaires at school to measure peer relations and emotional well-being. Parents reported on their child's mental health in questionnaires sent to the home. RESULTS: One in three children (29.2%) reported experiencing frequent bullying, defined as at least once a week. This included physical bullying alone (13.8%), verbal bullying alone (22.7%) and the combination (7.4%). Children who reported being frequently bullied self-reported higher internalising symptoms compared with children who did not report frequent bullying (M (SD) 1.6 (0.9) vs. 1.1 (0.8), p

Objective: In university-based randomised trials the Cool Little Kids parenting group program for temperamentally inhibited preschool children reduced the risk for anxiety disorders. The present st...

Despite growing recognition of childhood anxiety as a common and often debilitating clinical concern, we have limited knowledge of the particular ways in which anxiety interferes with daily life for young children who have not yet entered formal schooling. The present study evaluated the psychometric properties of the Child Anxiety Life Interference Scale - Preschool Version (CALIS-PV). The CALIS-PV is a brief (18 item) parent-report measure of the impacts of a young child's anxiety on their own life and that of her or his parent. Participants were 784 parents of a child aged 3-7 years, who completed the CALIS-PV as a part of the follow-up assessment battery for two anxiety prevention trials targeted at preschool children with temperamental inhibition. Confirmatory factor analysis supported three CALIS-PV factors reflecting anxiety-related life interference at home, outside home and on parent life. The three factors showed good internal consistency and good convergent and divergent validity, and successfully differentiated children with and without an anxiety diagnosis. Findings provide initial support for the CALIS-PV as a reliable and valid measure of the daily life impacts of childhood anxiety for preschool-aged children and their parents.

BACKGROUND Many emotional and behavioral problems first emerge in primary school and are the forerunners of mental health problems occurring in adolescence. However, the extent that these problems may be associated with academic failure has been explored less. We aimed to quantify the association between emotional and behavioral problems with academic performance. METHODS A stratified random sample of 8- to 9-year-olds (N = 1239) were recruited from schools in Australia. Data linkage was performed with a national assessment of academic performance to assess reading and numeracy. Parent report assessed emotional and behavioral problems with students dichotomized into “borderline/abnormal” and “normal” categories. RESULTS One in 5 grade 3 students fell in the “borderline/abnormal” category. Boys with total difficulties (β = -47.8, 95% CI: -62.8 to -32.8), conduct problems, and peer problems scored lower on reading. Numeracy scores were lower in boys with total difficulties (β = -37.7, 95% CI: -53.9 to -21.5) and emotional symptoms. Children with hyperactivity/inattention scored lower in numeracy. Girls with peer problems scored lower in numeracy. CONCLUSIONS Boys with emotional and behavioral problems in mid-primary school were 12 months behind their peers. Children with emotional and behavioral problems are at high risk for academic failure, and this risk is evident in mid-primary school.

Background: Prior anxiety and depression have been identified as risk factors for maternal perinatal mental health problems, but other preconception mental disorders have not been prospectively examined. This study investigated prospectively whether women with preconception personality disorder have increased rates of antenatal anxiety and/or depressive symptoms.Methods: 244 women in a population cohort were assessed for personality disorder at age 24 using the Standardised Assessment of Personality. Five to twelve years later, women were screened with the Clinical Interview Schedule, Revised Anxiety Subscale and the Edinburgh Postnatal Depression Scale during the third trimester of 328 pregnancies.Results: Preconception personality disorder was associated with a three-fold increase in the odds of antenatal anxiety symptoms, which remained with adjustment for preconception background factors and preconception common mental disorder (adjusted OR 2.84, 95% CI 1.31-6.15). Preconception personality disorder was associated with doubled odds of antenatal depressive symptoms, however this was attenuated with adjustment for preconception background factors and preconception common mental disorder (adjusted OR 1.98, 95% CI 0.81-4.81).Limitations: Our findings are restricted to pregnant women aged 29-35 years. Anxiety and depression may have been under-identified because they were assessed at a single antenatal time point. Residual confounding of the associations by preconception common mental disorder at other time points may have occurred. Conclusions: Women with personality disorder are at heightened risk of anxiety symptoms in pregnancy, over and above risks associated with prior common mental disorder. This raises a possibility that pregnancy brings particular emotional challenges for women with personality disorders.

One in five school-age children has mental health problems, yet less than a quarter access professional help. Early childhood presents a window for prevention. This study implemented the ‘Theory of Planned Behaviour’ to explore parents’ intentions to seek professional help for young children’s behaviour and emotional problems. Participants were 442 parents of 6-year-old children, recruited as a population sample in infancy. The ‘Theory of Planned Behaviour’ measured parents’ personal intentions, attitudes and beliefs about seeking professional help for young children’s mental health. Although many parents (84%) had positive intentions to seek help if their young child were in need, a proportion (16%) was ambivalent/unlikely to do so. Specific beliefs distinguishing parents with positive intentions were that professionals would provide expert strategies with empathy and understanding, with appointments providing value for time and money. Community mental health initiatives could target these belief...

Mutations resulting in increased PI3K signaling confer increased risk of B cell lymphoma, recurrent infections, poor viral control, and autoimmunity. Allogeneic HCT is curative, but the optimal approach to HCT for these patients is still evolving as experience grows. Herein, we present the clinical outcomes of 27 patients transplanted for activating PI3K mutations. Required approvals were obtained by contributing centers. Nineteen PIK3CD patients and 8 PIK3R1 patients received 22 and 10 HCTs respectively, at median age 12 years (range 2-66) at time of first HCT. Significant pre-HCT comorbidities were common, Fig 1. Conditioning platforms varied in intensity; most included serotherapy (84%). With median survivor follow up of 26.3 months from first HCT (range 2.4-71.8), overall survival was 85% (3 infectious deaths and 1 due to organ toxicity); graft failure (GF)-free survival (GFFS) was estimated at 80% at 1 year but declined to 68% by 2 years, Fig 2. Neutrophil engraftment occurred at median 15.5 days (range 11-33) with autologous recovery in 1 patient at day +14 and another deceased prior to engraftment. Four engrafted patients are alive and well despite mixed donor chimerism ( Grade 2-4 acute graft versus host disease (GVHD) occurred in 27% patients, with Grade 3-4 acute GVHD and limited self-resolved chronic GVHD in 1 (4%). Organ toxicities and infectious complications are summarized in Fig 3; CMV infection requiring treatment occurred in 11 (41%) patients with disease in 3 (11%). Serotherapy use, conditioning intensity, and degree of donor human leukocyte antigen (HLA) match were not significantly associated with cumulative incidence of GF or subsequent unplanned DCI (with death as a competing risk), while mTOR inhibitor use post-HCT was associated with subsequent unplanned DCI for graft augmentation or GF (p=0.006). An mTOR inhibitor was used within the year following 12 HCTs, for primary GVHD prophylaxis (n=7) or to treat disease manifestations or GVHD; loss of chimerism and/or need for subsequent DCI occurred in 9 of these. Patients with activating PI3K mutations are at overall significant risk of GF or need for subsequent DCI. While we found no association with GF or DCI for discrete elements such as serotherapy use, donor source, or conditioning intensity, small numbers preclude conclusions regarding the optimal HCT approach, and more HCTs with longer follow up are needed to refine these preliminary findings. Post-HCT mTOR inhibitor exposure was associated with need for subsequent unplanned DCI, perhaps by providing a survival advantage to host lymphocytes, and may thus be detrimental in these patients during the early post-HCT timeframe.

Objective A translational trial evaluated the effectiveness of screening for inhibited childhood temperament, followed by a preventive parenting program -Cool Little Kids. This study determined the cost-effectiveness from societal and health sector perspectives using trial data. Method Resources to deliver the screening and parenting sessions were determined from study records. Parents completed a questionnaire reporting resources used at one-year follow-up. Standard Australian unit costs were applied. Clinical outcomes for children and parental quality adjusted life-years (QALYs) were used to calculate incremental cost-effectiveness ratios (ICERs). Results Total societal costs were lower, but non-significant for the intervention compared to the control group (mean difference -$500 p = 0.937). Total health sector costs were significantly greater (mean difference $1,956; p = 0.015). The intervention led to significantly fewer internalising symptoms (Strengths and Difficulties Questionnaire (SDQ)-emotional difficulties adjusted mean difference −0.5; p = 0.006), fewer children with SDQ-emotional symptoms in the abnormal range (24.2 % vs. 33.0 % p = .014) and fewer with diagnosed anxiety (44.2 % vs. 50.2 % p = 0.427). From the societal perspective, the intervention would likely be cost-effective. Health sector ICERs were $1,171/SDQ-emotional symptom decrease, $51/abnormal SDQ avoided and $77/anxiety case avoided. Conclusions This economic analysis alongside an implementation study provides an early indication that Cool Little Kids may be cost-effective.

Background The Online Assessment of Preschool Anxiety (OAPA) is a newly developed measure that assesses anxiety disorders in preschool children aged 3-6 years. This study aimed to explore the OAPA's initial psychometric properties with a particular focus on examining its construct validity, both convergent and discriminant. Method The OAPA was completed online by a community sample of 319 Australian parents of temperamentally inhibited preschool children (M: 5.3 years). Preliminary diagnoses were automatically generated before assessment reports were reviewed by a psychologist. Construct validity was examined by assessing the degree of agreement between the OAPA and existing valid questionnaire measures that were simultaneously administered online. Results Nearly half of participants met criteria for a child anxiety disorder according to the OAPA, most commonly social phobia. Findings supported convergent validity with the Revised Preschool Anxiety Scale (an anxiety symptom measure), the Children's Anxiety Life Interference Scale - Preschool Version (a measure of life interference from anxiety), the Emotional Symptoms scale of the Strengths and Difficulties Questionnaire-Parent Version (a measure of broader internalizing symptoms), as well as an over-involved/protective parenting scale. Findings also supported initial discriminant validity with the Conduct Problems scale of the Strengths and Difficulties Questionnaire-Parent Version. Conclusions Results of this study provide evidence for the OAPA's preliminary construct validity. With further research into the OAPA's reliability (test-retest and interrater) and confirming construct validity, the OAPA may be a useful instrument for use in research settings and clinical practice.

We would like to acknowledge Professor Daniel Shaw, Bibi Gerner, Amelia Hicks, Daisy Grinter, Amy Loughman and Kate Lycett for their help to commence this study in 2010, and their contribution to data collection and intervention delivery. We would also like to thank all the maternal child health nurses from the nine participating LGAs (City of Casey, Bayside City Council, Darebin City Council, Hobsons Bay City Council, City of Port Phillip, Mornington Peninsula Shire, Manningham City Council, Knox City Council and Yarra Ranges Shire Council) and the families taking part. We would like to thank the parenting experts at the Parenting Research Centre who co-facilitate the Toddlers Without Tears parenting groups. Murdoch Childrens Research Institute research is supported by the Victorian Government's Operational Infrastructure Support Programme and funded by Australian National Health and Medical Research Council (NHMRC) Partnership 46525 and community partners: Victorian Department of Education and Early Childhood, Victorian Department of Health and the Municipal Associations of Victoria. The researchers acknowledge support of the Australian NHMRC for salary support through Early Career Fellowship 1035100 (LG), Career Development Awards 607351 (HH) and 546405 (MW) and Capacity Building Grants 425855 (LG) and 436914 (HH, JB and OU). OU is supported by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula at the Royal Devon and Exeter NHS Foundation Trust. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health in England.

AIM: We aim to describe health service (HS) use in the first 6 months post-partum and to examine the associations between service costs, infant behaviour and maternal depressive symptoms. METHODS: Participants were 781 infants and mothers in Melbourne, Australia. Mothers reported infant feeding, sleeping and crying problems, depressive symptoms and health service use. Costs were valued in 2012 Australian dollars. RESULTS: The most common services used were maternal child health nurses, general practitioners (GP) and allied health. Infant feeding problems were associated with increased costs for services relevant to infant behaviour including maternal child health nurses (P = 0.007), GP (P = 0.008) and paediatricians (P = 0.03). Maternal depressive symptoms were associated with increased costs for services relevant to depressive symptoms including parenting centres (P = 0.04), GP (P = 0.004), psychiatrists (P = 0.02) and psychologists (P = 0.001). Mothers who completed high school had higher service costs for infant problems than those with lower education (P = 0.02). Single mothers had higher costs for services used for their depressive symptoms than partnered mothers (P

The effects of climate change on lake ecosystems are often complex. We examined how phytoplankton in two neighbouring, pre-alpine, large oligotrophic lakes with similar catchments and land uses are likely to respond to climate change. We hypothesised that (i) while their climates and landscape filters were relatively similar, differences in in-lake biological, physical and chemical filters would influence the phytoplankton responses to climate and (ii) direct effects of warming on phytoplankton dynamics and productivity would be relatively minor compared to indirect effects, especially those influencing the lakes’ mixing regimes. We combined (i) dynamic modelling of the physical forcing of the lakes under climate change, (ii) multi-year field sampling of relevant biological, physical and chemical variables and (iii) bioassay experiments, to test our hypotheses. Water temperatures have warmed over recent decades in one lake, but not in the other. The warming lake showed evidence of incomplete mixing and phytoplankton layering in winter 2009, while the other lake did not. Such changes influenced the phytoplankton phenology, and incomplete winter mixing is common in similar deep, temperate lakes. Inhibited winter mixing and related indirect effects of climate warming appear to be key early drivers of climate change effects on the phytoplankton of deep, temperate lakes.

An inhibited temperamental style has been identified as one of the core risks for the later development of anxiety and related disorders. Several additional risks are believed to interact with child inhibition, including parent emotionality, parental rearing style, and poor social skills. These factors lend themselves to modification, opening the door to prevention of emotional disorders. To date there has been surprisingly little focus on the prevention of emotional disorder through identification of early child inhibition. The current chapter briefly summarises the current literature. It then moves on to consider several relevant issues including the best target for intervention, the most relevant population, and novel intervention strategies. Finally, the chapter describes some attempts to apply prevention at a population level and discusses barriers and future directions.

Objective:Up to 22% of school age children have mental health problems. However, less than one quarter at risk of mental health problems access professional services. This study explored help seeking rates for early childhood mental health problems, as measured by the Child Behaviour Checkli

Natural feed additives are used to maintain health and to promote performance of pigs without antibiotics. Effects of a probiotic, inulin, and their combination (synbiotic), on the microbial diversity and composition at different intestinal locations were analysed using denaturing gradient gel electrophoresis (DGGE), real-time PCR, and 16S rRNA gene pyrosequencing. Bacterial diversity assessed by DGGE and/or pyrosequencing was increased by inulin in all three gut locations and by the synbiotic in the caecum and colon. In contrast, the probiotic did only affect the microbiota diversity in the ileum. Shifts in the DGGE microbiota profiles of the caecum and colon were detected for the pro- and synbiotic fed animals, whereas inulin profiles were more similar to the ones of the control. 16S rRNA gene pyrosequencing revealed that all three additives could reduce Escherichia species in each gut location, indicating a potential beneficial effect on the gut microbiota. An increase of relative abundance of Clostridiaceae in the large intestine was found in the inulin group and of Enterococcaceae in the ileum of probiotic fed pigs. Furthermore, real-time PCR results showed that the probiotic and synbiotic increased bifidobacterial numbers in the ileum, which was supported by sequencing results. The probiotic and inulin, to different extents, changed the diversity, relative abundance of phylotypes, and community profiles of the porcine microbiota. However, alterations of the bacterial community were not uniformly between gut locations, demonstrating that functionality of feed additives is site specific. Therefore, gut sampling from various locations is crucial when investigations aim to identify the composition of a healthy gut microbiota after its manipulation through feed additives.

Knowledge is scarce about how to promote mental health in children when they have started life facing various risks. This study investigated whether parents' interactions with their young children can facilitate mental health resiliency after starting life ‘at risk’ in infancy. Data were sourced from a longitudinal population-based study in Victoria, Australia. An ‘at-risk’ infant sample (N = 283) was identified, with difficult temperament, maternal mental health problems, substance misuse, home violence and social isolation (one or more risks). Parenting practices were measured throughout early childhood. The Child Behaviour Checklist assessed resilience at school-entry. Discriminant function analysis differentiated at-risk infants who became resilient versus non-resilient. Findings highlighted parenting interactions with young children characterised by low levels of harsh discipline promoting resiliency over time. A third of babies in the population may face significant stressors. Parents facing early r...

OBJECTIVE Prevention of child behavior problems may reduce later mental health problems. We compared the effectiveness, at the population level, of an efficacious targeted prevention program alone or following a universal parenting program. METHODS Three-arm, cluster randomized controlled trial. One thousand three hundred fifty-three primary caregivers and healthy 8-month-old babies recruited from July 2010 to January 2011 from well-child centers (randomization unit). PRIMARY OUTCOME Child Behavior Checklist (CBCL) externalizing and internalizing scales* at child ages 3 and 4.5 years. SECONDARY OUTCOMES Parenting Behavior Checklist* and over-involved/protective parenting (primary caregiver report). Secondary caregivers completed starred measures at age 3. RESULTS Retention was 76% and 77% at ages 3 and 4.5 years, respectively. At 3 years, intention-to-treat analyses found no statistically significant differences (adjusted mean difference [95% confidence interval (CI); p-value]) for externalizing (targeted vs usual care -0.2 [-1.7 to 1.2; p = .76]; combined vs usual care 0.4 [-1.1 to 1.9; p = .60]) or internalizing behavior problems (targeted vs usual care 0.2 [-1.2 to 1.6; p = .76]; combined vs usual care 0.4 [-1.1 to 2.0; p = .58]). Primary outcomes were similar at 4.5 years. At 3 years, primary and secondary caregivers reported less over-involved/protective parenting in both the combined and targeted versus usual care arm; secondary caregivers also reported less harsh discipline in the combined and targeted versus usual care arm. Mean program costs per family were A$218 (targeted arm) and A$682 (combined arm). CONCLUSION When translated to the population level by existing staff, pre-existing programs seemed ineffective in improving child behavior, alone or in combination, but improved parenting.

Objective: To determine whether a population-delivered parenting programme assists in preventing internalising problems at school entry for preschool children at-risk with temperamental inhibition. Methods: Design: a randomised controlled trial was used. Setting: the setting was 307 preschool services across eight socioeconomically diverse government areas in Melbourne, Australia. Participants: a total of 545 parents of inhibited 4-year-old children: 498 retained at 1-year follow up. Early intervention: Cool Little Kids parenting group programme was implemented. Primary outcomes: the primary outcomes were child DSM-IV anxiety disorders (assessor blind) and internalising problems. Secondary outcomes: the secondary outcomes were parenting practices and parent mental health. Results: At 1-year follow up (mean (standard deviation) age = 5.8 (0.4) years), there was little difference in anxiety disorders between the intervention and control arms (44.2% vs 50.2%; adjusted odds ratio = 0.86, 95% confidence interval = [0.60, 1.25], p = 0.427). Internalising problems were reduced in the intervention arm (Strengths and Difficulties Questionnaire: abnormal – 24.2% vs 33.0%; adjusted odds ratio = 0.56, 95% confidence interval = [0.35, 0.89], p = 0.014; symptoms – mean (standard deviation) = 2.5 (2.0) vs 2.9 (2.2); adjusted mean difference = –0.47, 95% confidence interval = [–0.81, –0.13], p = 0.006). Parents’ participation in the intervention was modest (29.4% attended most groups, 20.5% used skills most of the time during the year). A priori interaction tests suggested that for children with anxious parents, the intervention reduced anxiety disorders and internalising symptoms after 1 year. Conclusion: Offering Cool Little Kids across the population for inhibited preschoolers does not impact population outcomes after 1 year. Effects may be emerging for inhibited children at highest risk with parent anxiety. Trial outcomes will continue into mid-childhood.

This pilot study explored acceptability to parents and outcomes for children of a preventive intervention for anxiety problems in pre-schoolers with autism spectrum disorder (ASD) who were an identified sub-group within a population-based randomised trial of the Cool Little Kids parenting group programme. The population trial included 545 temperamentally inhibited pre-schoolers recruited across eight economically diverse areas of Melbourne, Australia. Within this sample, 26 parents reported that their child had received an ASD diagnosis. Trial measures included baseline inhibited temperament and developmental problems, post-intervention feedback on the programme, and caregiver-reported child mental health outcomes (anxiety diagnoses and internalising symptoms) at 1- and 2-year follow-up. Sample retention for the children with ASD over 2 years was strong (92%). At follow-up, fewer intervention than control children with ASD had anxiety disorders after 1 year (% (n): 25 (3) vs. 77 (10), P = .028) and separation anxiety symptoms after 2 years (M (SD): 4.22 (2.68) vs. 9.38 (5.91), P = .017). Similar effects favouring the intervention group were apparent across other child emotional outcome measures but without statistical significance in this small sample. Parents of the children with ASD reported that Cool Little Kids was "quite useful" in relation to their child's anxiety but also gave feedback that they would appreciate some tailoring of programme content to the context of ASD. These pilot findings suggest Cool Little Kids may be helpful for reducing comorbid anxiety in pre-schoolers with ASD. Further research is warranted to develop an ASD-specific adaptation which can be trialled with a larger sample of children with confirmed ASD diagnosis. Trial registration ISRCTN30996662 http://www.isrctn.com/ISRCTN30996662. Autism Res 2018, 11: 1166-1174. © 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Many children with autism spectrum disorder (ASD) also have anxiety. This pilot study explored acceptability to parents and outcomes for pre-schoolers with ASD of a parenting group programme to prevent anxiety problems. Among the sample of 26 pre-schoolers with ASD, we found reduced anxiety disorders and separation symptoms when their parents had received the intervention, as reported by caregivers in checklists and clinical interviews. Parents gave feedback that the programme was useful but suggested content be adapted to the context of ASD.

Background/aims Achieving a high response rate to follow-up questionnaires in randomized controlled trials of interventions is important for study validity. Few studies have tested the value of incentives in increasing response rates to online questionnaires in clinical trials of health interventions. This study evaluated the effect of a gift card prize-draw incentive on response rates to follow-up questionnaires within a trial of an online health intervention. Method The study was embedded in a host randomized controlled trial of an online parenting program for child anxiety. A total of 433 participants were randomly allocated to one of two groups: (1) being informed that they would enter a gift card prize-draw if they completed the final study questionnaire (24-week follow-up) and (2) not informed about the prize-draw. All participants had a 1 in 20 chance of winning an AUD50 gift card after they completed the online questionnaire. Results The odds of the informed group completing the follow-up questionnaire were significantly higher than the uninformed group, (79.6% vs 68.5%, odds ratio = 1.79, 95% confidence interval = 1.15–2.79). This response rate increase of 11.1% (95% confidence interval = 2.8–19.1) occurred in both intervention and control groups in the host randomized controlled trial. The incentive was also effective in increasing questionnaire commencement (84.6% vs 75.9%, odds ratio = 1.74, 95% confidence interval = 1.07–2.84) and reducing the delay in completing the questionnaire (19.9 vs 22.6 days, hazard ratio = 1.34, 95% confidence interval = 1.07–1.67). Conclusion This study adds to evidence for the effectiveness of incentives to increase response rates to follow-up questionnaires in health intervention trials.

WOS: 000393996800025, PubMed: 27577878, Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/ 110) and management was directly altered in nearly a quarter (26/ 110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes., South-Eastern Norway Health Authority; American Women's club of Oslo; National Human Genome Research InstituteUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Human Genome Research Institute (NHGRI); National Heart, Lung, and BloodUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Heart Lung & Blood Institute (NHLBI) [U54HG006542]; Jeffrey Modell Foundation; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [AI-120989], Funding for the work performed in Oslo was provided by the South-Eastern Norway Health Authority, and A. S.-P. received research scholarship from the American Women's club of Oslo. The BHCMG is supported by the National Human Genome Research Institute and the National Heart, Lung, and Blood (U54HG006542). Funding was also provided by the Jeffrey Modell Foundation and NIH AI-120989 (to J.S.O.).