Protocol for a randomised controlled trial evaluating the effect of a CBT-I smartphone application (Sleep Ninja®) on insomnia symptoms in children.

BACKGROUND: Sleep is necessary for healthy development and mental wellbeing. Despite this, many children do not get the recommended duration of sleep each night, and many experience sleep problems. Although treatable, existing interventions for sleep disturbance are time-consuming, burdensome for families, and focus on providing behavioural strategies to parents rather than upskilling children directly. To address this gap, we modified Sleep Ninja®, an evidence-based cognitive behavioural therapy for insomnia (CBT-I) smartphone app for adolescent sleep disturbance, to be appropriate for 10 to 12 year olds. Here, we describe the protocol for a randomised controlled trial to evaluate the effect of Sleep Ninja on insomnia and other outcomes, including depression, anxiety, sleep quality, and daytime sleepiness, and explore effects on the emergence of Major Depressive Disorder (MDD), compared to an active control group. METHODS: We aim to recruit 214 children aged 10 to 12 years old experiencing disturbed sleep. Participants will be screened for inclusion, complete the baseline assessment, and then be randomly allocated to receive Sleep Ninja, or digital psychoeducation flyers (active control) for 6-weeks. The primary outcome, insomnia symptoms, along with depression, anxiety, sleep quality, and daytime sleepiness will be assessed at 6-weeks (primary endpoint), 3-months, and 9-months post-baseline (secondary and tertiary endpoints, respectively). A mixed model repeated measures analytic approach will be used to conduct intention-to-treat analyses to determine whether reductions in insomnia and secondary outcomes are greater for those receiving Sleep Ninja relative to the control condition at the primary and secondary endpoints. The difference in relative risk for MDD onset will be explored at 9-months and compared between conditions. DISCUSSION: This is the first clinical trial examining the effects of a CBT-I smartphone app in children experiencing sleep disturbance. Results will provide empirical evidence about the effects of Sleep Ninja on insomnia and other mental health outcomes. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12623000587606). UNIVERSAL TRIAL NUMBER: U1111-1294-4167.

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10-6), and rs7700147, an intergenic variant (P=2.93 × 10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen.

Traditional plant functional groups explain variation in economic but not size-related traits across the tundra biome.

AIM: Plant functional groups are widely used in community ecology and earth system modelling to describe trait variation within and across plant communities. However, this approach rests on the assumption that functional groups explain a large proportion of trait variation among species. We test whether four commonly used plant functional groups represent variation in six ecologically important plant traits. LOCATION: Tundra biome. TIME PERIOD: Data collected between 1964 and 2016. MAJOR TAXA STUDIED: 295 tundra vascular plant species. METHODS: We compiled a database of six plant traits (plant height, leaf area, specific leaf area, leaf dry matter content, leaf nitrogen, seed mass) for tundra species. We examined the variation in species-level trait expression explained by four traditional functional groups (evergreen shrubs, deciduous shrubs, graminoids, forbs), and whether variation explained was dependent upon the traits included in analysis. We further compared the explanatory power and species composition of functional groups to alternative classifications generated using post hoc clustering of species-level traits. RESULTS: Traditional functional groups explained significant differences in trait expression, particularly amongst traits associated with resource economics, which were consistent across sites and at the biome scale. However, functional groups explained 19% of overall trait variation and poorly represented differences in traits associated with plant size. Post hoc classification of species did not correspond well with traditional functional groups, and explained twice as much variation in species-level trait expression. MAIN CONCLUSIONS: Traditional functional groups only coarsely represent variation in well-measured traits within tundra plant communities, and better explain resource economic traits than size-related traits. We recommend caution when using functional group approaches to predict tundra vegetation change, or ecosystem functions relating to plant size, such as albedo or carbon storage. We argue that alternative classifications or direct use of specific plant traits could provide new insights for ecological prediction and modelling.

Organizational uptake of NICE guidance in promoting employees' psychological health.

BACKGROUND: Annual costs to organizations of poor mental health are estimated to be between £33 billion and £42 billion. The UK's National Institute for Clinical Excellence (NICE) has produced evidence-based guidance on improving employees' psychological health, designed to encourage organizations to take preventative steps in tackling this high toll. However, the extent of implementation is not known outside the National Health Service. AIMS: To assess the awareness and implementation of NICE guidance on workplace psychological health. METHODS: A total of 163 organizations participated in a survey of UK-based private, public and third sector organizations employing an accumulated minimum of 322 033 workers. RESULTS: Seventy-seven per cent of organizations were aware of the NICE guidance for improving mental well-being in the workplace, but only 37% were familiar with its recommendations. Less than half were aware of systems in place for monitoring employees' mental well-being and only 12% confirmed that this NICE guidance had been implemented in their workplace. Where employee health and well-being featured as a regular board agenda item, awareness and implementation of NICE guidance were more likely. Significant associations were found between organizational sector and size and uptake of many specific features of NICE guidance. CONCLUSIONS: The majority of organizations are aware of NICE guidance in general, but there is a wide gap between this and possession of detailed knowledge and implementation. The role of sector and size of organization is relevant to uptake of some features of NICE guidance, although organizational leadership is important where raised awareness and implementation are concerned.

Graduated Compression Stockings as an Adjunct to Low Dose Low Molecular Weight Heparin in Venous Thromboembolism Prevention in Surgery: A Multicentre Randomised Controlled Trial.

BACKGROUND: The evidence base upon which current global venous thromboembolism (VTE) prevention recommendations have been made is not optimal. The cost of purchasing and applying graduated compression stockings (GCS) in surgical patients is considerable and has been estimated at £63.1 million per year in England alone. OBJECTIVE: The aim was to determine whether low dose low molecular weight heparin (LMWH) alone is non-inferior to a combination of GCS and low dose LMWH for the prevention of VTE. METHODS: The randomised controlled Graduated compression as an Adjunct to Pharmacoprophylaxis in Surgery (GAPS) Trial (ISRCTN 13911492) will randomise adult elective surgical patients identified as being at moderate and high risk of VTE to receive either the current "standard" combined thromboprophylactic LMWH with GCS mechanical thromboprophylaxis, or thromboprophylactic LMWH pharmacoprophylaxis alone. To show non-inferiority (3.5% non-inferiority margin) for the primary endpoint of all VTE within 90 days, 2236 patients are required. Recruitment will be from seven UK centres. Secondary outcomes include quality of life, compliance with stockings and LMWH, overall mortality, and GCS or LMWH related complications (including bleeding). Recruitment commenced in April 2016 with the seven UK centres coming "on-line" in a staggered fashion. Recruitment will be over a total of 18 months. The GAPS trial is funded by the National Institute for Health Research Health Technology Assessment in the UK (14/140/61).

Improved measurement of the shape of the electron.

The electron is predicted to be slightly aspheric, with a distortion characterized by the electric dipole moment (EDM), d(e). No experiment has ever detected this deviation. The standard model of particle physics predicts that d(e) is far too small to detect, being some eleven orders of magnitude smaller than the current experimental sensitivity. However, many extensions to the standard model naturally predict much larger values of d(e) that should be detectable. This makes the search for the electron EDM a powerful way to search for new physics and constrain the possible extensions. In particular, the popular idea that new supersymmetric particles may exist at masses of a few hundred GeV/c(2) (where c is the speed of light) is difficult to reconcile with the absence of an electron EDM at the present limit of sensitivity. The size of the EDM is also intimately related to the question of why the Universe has so little antimatter. If the reason is that some undiscovered particle interaction breaks the symmetry between matter and antimatter, this should result in a measurable EDM in most models of particle physics. Here we use cold polar molecules to measure the electron EDM at the highest level of precision reported so far, providing a constraint on any possible new interactions. We obtain d(e) = (-2.4 ± 5.7(stat) ± 1.5(syst)) × 10(-28)e cm, where e is the charge on the electron, which sets a new upper limit of |d(e)| < 10.5 × 10(-28)e cm with 90 per cent confidence. This result, consistent with zero, indicates that the electron is spherical at this improved level of precision. Our measurement of atto-electronvolt energy shifts in a molecule probes new physics at the tera-electronvolt energy scale.

The Role 2 Afloat custodian.

The Role 2 Afloat (R2A) capability is now firmly established on several maritime platforms using the 370 Module (afloat) equipment. This year has seen the appointment on board ships that support R2A of a new full-time role, the Medical Module Manager (MMM), who is responsible for the equipment on board. This article outlines the new role.

Muscle hypertrophy as the presenting sign in a patient with a complete FHL1 deletion.

Four and a half LIM protein 1 (FHL1/SLIM1) has recently been identified as the causative gene mutated in four distinct diseases affecting skeletal muscle that have overlapping features, including reducing body myopathy, X-linked myopathy, X-linked dominant scapuloperoneal myopathy and Emery-Dreifuss muscular dystrophy. FHL1 localises to the sarcomere and the sarcolemma and is believed to participate in muscle growth and differentiation as well as in sarcomere assembly. We describe in this case report a boy with a deletion of the entire FHL1 gene who is now 15 years of age and presented with muscle hypertrophy, reduced subcutaneous fat, rigid spine and short stature. This case is the first, to our knowledge, with a complete loss of the FHL1 protein and MAP7D3 in combination. It supports the theory that dominant negative effects (accumulation of cytotoxic-mutated FHL1 protein) worsen the pathogenesis. It extends the phenotype of FHL1-related myopathies and should prompt future testing in undiagnosed patients who present with unexplained muscle hypertrophy, contractures and rigid spine, particularly if male.

Relationships between soft tissues in a posed smile and vertical cephalometric skeletal measurements.

INTRODUCTION: The purposes of this study were to measure the 3-dimensional parameters of the posed smile and to see whether there are any correlations with vertical cephalometric skeletal measurements. METHODS: Pretreatment records from a sample of 110 white girls between the ages of 12 and 18 years were gathered. The measurements of SN-GoGn, anterior facial height, and lower and upper facial height percentages were obtained from tracing lateral cephalograms. Superimposing the repose and the posed smile facial scans allowed for measurements to be obtained showing the movements in the x, y, and z dimensions of the upper and lower lips, the commissures, and the Cupid's bows. Correlations and multiple linear regression analyses were run to check for associations and predictive relationships between the cephalometric skeletal measurements and soft tissue changes. RESULTS: We found significant moderate correlations and weak correlations. Significant multiple regression models were found for intercommissural width, smile index, and lower lip in the y and z dimensions. CONCLUSIONS: There were moderate correlations showing that as SN-GoGn and anterior facial height increased, the interlabial gap increased as the smile index decreased. Significant relationships were found between certain hard tissue cephalometric measurements and the width of the smile as well as the movements of the lower lip.

A genome-wide association study of anorexia nervosa.

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge-purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10(-7)) in SOX2OT and rs17030795 (P=5.84 × 10(-6)) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10(-)(6)) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10(-)(6)) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10(-6)), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Estimated glomerular filtration rate leads to higher drug dose recommendations in the elderly compared with creatinine clearance.

PURPOSE: The elderly are at risk for adverse drug events because of inappropriate dosing of renally eliminated medications. The purpose of this study was to evaluate differences in estimates of kidney function and recommended doses of select medications in the elderly using the Modification of Diet in Renal Disease (MDRD) or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations compared with the Cockcroft-Gault (CG) equation. METHODS: Patients 65 years of age and older were included in this retrospective, observational analysis. Kidney function was estimated by CG, MDRD and CKD-EPI equations for all patients and by age category (65-69, 70-79, 80-89 and 90-100 years). Differences in estimates and dosing of allopurinol, enoxaparin, gabapentin, piperacillin/tazobactam and sulfamethoxazole/trimethoprim using the MDRD and CKD-EPI compared with the CG were assessed. RESULTS: In the 4160 patients (98% male, mean age 74 ± 7 years), the MDRD and CKD-EPI estimates were significantly higher than CG estimates for all patients and by age category (p < 0.001). Dosing discordance was predominantly because of a higher dose recommended by MDRD and CKD-EPI estimates compared with CG. Discordance was highest with gabapentin (27%), the medication with the greatest number of dosing stratifications by estimated kidney function, and increased by 66% from the youngest to the oldest age category. CONCLUSIONS: Until newer equations are used uniformly to develop dosing nomograms, it is prudent to adopt a process for drug dosing in the elderly that is more conservative than eGFR based dosing, but that considers the potential for underestimating kidney function with the CG equation.

Metabolic enrichment of omega-3 polyunsaturated fatty acids does not reduce the onset of idiopathic knee osteoarthritis in mice.

OBJECTIVE: We evaluated the effect of a reduction in the systemic ratio of n-6:n-3 polyunsaturated fatty acids (PUFAs) on changes in inflammation, glucose metabolism, and the idiopathic development of knee osteoarthritis (OA) in mice. We hypothesized that a lower ratio of n-6:n-3 PUFAs would protect against OA markers in cartilage and synovium, but not bone. DESIGN: Male and female fat-1 transgenic mice (Fat-1), which convert dietary n-6 to n-3 PUFAs endogenously, and their wild-type (WT) littermates were fed an n-6 PUFA enriched diet for 9-14 months. The effect of gender and genotype on serum PUFAs, interleukin (IL)-6, tumor necrosis factor (TNF)-α, and glucose tolerance was tested by 2-factor analysis of variance (ANOVA). Cortical and trabecular subchondral bone changes were documented by micro-focal computed tomography (CT), and knee OA was assessed by semi-quantitative histomorphometry grading. RESULTS: The n-6:n-3 ratio was reduced 12-fold and 7-fold in male and female Fat-1 mice, respectively, compared to WT littermates. IL-6 and TNF-α levels were reduced modestly in Fat-1 mice. However, these systemic changes did not reduce osteophyte development, synovial hyperplasia, or cartilage degeneration. Also the fat-1 transgene did not alter subchondral cortical or trabecular bone morphology or bone mineral density. CONCLUSIONS: Reducing the systemic n-6:n-3 ratio does not slow idiopathic changes in cartilage, synovium, or bone associated with early-stage knee OA in mice. The anti-inflammatory and anti-catabolic effects of n-3 PUFAs previously reported for cartilage may be more evident at later stages of disease or in post-traumatic and other inflammatory models of OA.

The contribution of familial internalizing and externalizing liability factors to borderline personality disorder.

BACKGROUND: Individuals with borderline personality disorder (BPD) frequently display co-morbid mental disorders. These disorders include 'internalizing' disorders (such as major depressive disorder and anxiety disorders) and 'externalizing' disorders (such as substance use disorders and antisocial personality disorder). It is hypothesized that these disorders may arise from latent 'internalizing' and 'externalizing' liability factors. Factor analytic studies suggest that internalizing and externalizing factors both contribute to BPD, but the extent to which such contributions are familial is unknown. METHOD: Participants were 368 probands (132 with BPD; 134 without BPD; and 102 with major depressive disorder) and 885 siblings and parents of probands. Participants were administered the Diagnostic Interview for DSM-IV Personality Disorders, the Revised Diagnostic Interview for Borderlines, and the Structured Clinical Interview for DSM-IV. RESULTS: On confirmatory factor analysis of within-person associations of disorders, BPD loaded moderately on internalizing (factor loading 0.53, S.E. = 0.10, p < 0.001) and externalizing latent variables (0.48, S.E. = 0.10, p < 0.001). Within-family associations were assessed using structural equation models of familial and non-familial factors for BPD, internalizing disorders, and externalizing disorders. In a Cholesky decomposition model, 84% (S.E. = 17%, p < 0.001) of the association of BPD with internalizing and externalizing factors was accounted for by familial contributions. CONCLUSIONS: Familial internalizing and externalizing liability factors are both associated with, and therefore may mutually contribute to, BPD. These familial contributions account largely for the pattern of co-morbidity between BPD and internalizing and externalizing disorders.

Relationship between water quality parameters and bacterial indicators in a large prairie reservoir: Lake Diefenbaker, Saskatchewan, Canada.

Lake Diefenbaker (LD) is a large reservoir on the South Saskatchewan River used for agricultural irrigation, drinking water, and recreation. Our objectives were to determine the distribution and abundance of bacterial indicators in embayments and the main channel of LD and to relate these to environmental factors. Total coliforms (TCs), fecal coliforms (FCs), and fecal indicator bacteria (i.e., Escherichia coli) were measured concurrently with water quality parameters. Although TCs, FCs, and E. coli were present in LD, they rarely exceeded the TC and FC Canadian Council of Ministers of the Environment (CCME) water quality standards for agricultural use (1000 colony-forming units (CFU) per 100 mL and 100 CFU per 100 mL, respectively). The correlation between the bacterial indicators in the sediments and the water column indicates that higher embayment abundances may be related to sediment loading and (or) resuspension events in these frequently mixed embayments. With higher water temperatures and water levels, as well as higher microbial activity, CCME bacterial limits may be exceeded. The greatest contributor to bacterial indicator abundance was water temperature. We predict that water quality standards will be exceeded more frequently with climate warming.

Suppression of lipopolysaccharide-stimulated cytokine/chemokine production in skin cells by sandalwood oils and purified α-santalol and ß-santalol.

Medicinally, sandalwood oil (SO) has been attributed with antiinflammatory properties; however, mechanism(s) for this activity have not been elucidated. To examine how SOs affect inflammation, cytokine antibody arrays and enzyme-linked immunosorbent assays were used to assess changes in production of cytokines and chemokines by co-cultured human dermal fibroblasts and neo-epidermal keratinocytes exposed to lipopolysaccharides and SOs from Western Australian and East Indian sandalwood trees or to the primary SO components, α-santalol and ß-santalol. Lipopolysaccharides stimulated the release of 26 cytokines and chemokines, 20 of which were substantially suppressed by simultaneous exposure to either of the two sandalwood essential oils and to ibuprofen. The increased activity of East Indian SO correlated with increased santalol concentrations. Purified α-santalol and ß-santalol equivalently suppressed production of five indicator cytokines/chemokines at concentrations proportional to the santalol concentrations of the oils. Purified α-santalol and ß-santalol also suppressed lipopolysaccharide-induced production of the arachidonic acid metabolites, prostaglandin E2, and thromboxane B2, by the skin cell co-cultures. The ability of SOs to mimic ibuprofen non-steroidal antiinflammatory drugs that act by inhibiting cyclooxygenases suggests a possible mechanism for the observed antiinflammatory properties of topically applied SOs and provides a rationale for use in products requiring antiinflammatory effects.

Friendship quality and social information processing in clinically anxious children.

The association between perceived friendship quality (FQ) and social information processing (SIP) was examined in three groups of children and their close friends aged 7-12 years: 16 anxiety disordered children with social phobia (SP); 12 anxiety disordered children without SP (No-SP); and 32 nonclinical children. Positive and negative FQ positively associated with target children's positive and negative responding on a vignette measure of SIP. SP children reported lower positive SIP than No-SP but not nonclinical children; and this was the only group difference in SIP. Target children and their friends were similar in negative but not positive SIP. Following discussion about the vignette with a close friend, all target children increased in positive SIP; negative SIP did not change. Lower FQ and a more socially anxious friend predicted higher negative target child SIP postdiscussion. Close friendships play an important role in the SIP of both clinical and nonclinical children.

Factors affecting medical students' sense of belonging in a longitudinal integrated clerkship.

BACKGROUND: Longitudinal integrated clerkships (LICs) have been shown to be effective educationally and may assist in promoting rural career choices when undertaken in rural communities. Despite these merits, some students find LICs challenging. METHODS: Students from a regional medical school undertaking a LIC participated in semi-structured interviews. A template approach was used for analysis of the transcripts. RESULTS: Thirteen students participated. Three major themes were identified: academic leadership, external (general practice) environment and intrinsic (student) factors. Optimally, a synergistic relationship between factors, facilitated by academic leadership, resulted in a sense of belonging. DISCUSSION: Our findings support the concept that there is a highly dynamic interaction between factors determining the experience of students in the LIC. The individual nature of learners and the learning contexts require multi-level academic leadership.

RESTORE: Once-nightly oxybate dosing preference and nocturnal experience with twice-nightly oxybates.

Objective/Background: Preference for extended-release, once-nightly sodium oxybate (ON-SXB, FT218) vs twice-nightly immediate-release (IR) oxybate was assessed in participants switching from IR oxybate to ON-SXB in an open-label/switch study, RESTORE (NCT04451668). Patients/Methods: Participants aged ≥16 years with narcolepsy who completed the phase 3 REST-ON trial, were oxybate-naive, or were on a stable IR oxybate dose (≥1 month) were eligible for RESTORE. For participants who switched from twice-nightly dosing to ON-SXB, initial doses were closest or equivalent to their previous nightly IR oxybate dose. These participants completed a questionnaire at baseline about nocturnal adverse events associated with the middle-of-the-night IR oxybate dose in the preceding 3 months, a preference questionnaire after 3 months of stable-dose ON-SXB, and an end-of-study (EOS) questionnaire. Results: There were 130 switch participants; 92/98 (93.9 %) who completed the preference questionnaire preferred ON-SXB. At baseline, 69.2 % reported missing their second IR oxybate dose at least once; in these cases, 80 % felt worse the next day. Approximately 39 % reported taking a second nightly IR oxybate dose >4 h after the first dose, 51 % of whom felt somewhat to extremely groggy/unsteady the next morning; 120 participants (92 %) reported getting out of bed after their second oxybate dose. Of those, 9 (8 %) reported falls and 5 (4 %) reported injuries. Of the switch participants who completed the EOS questionnaire, 91.2 % felt better able to follow the recommended ON-SXB dosing schedule. Conclusions: The second nightly IR oxybate dose presents significant treatment burdens and adherence concerns. Participants overwhelmingly preferred the once-nightly dosing regimen of ON-SXB.