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Attention-deficit/hyperactivity disorder (ADHD) is associated with self-harm during adolescence and young adulthood, especially among females. Yet little is known about the developmental trajectories or childhood predictors/moderators of self-harm in women with and without childhood histories of ADHD. We characterized lifetime risk for nonsuicidal self-injury (NSSI), suicidal ideation (SI), and suicide attempts (SA), comparing female participants with (n = 140) and without (n = 88) childhood ADHD. We examined theory-informed childhood predictors and moderators of lifetime risk via baseline measures from childhood. First, regarding developmental patterns, most females with positive histories of lifetime self-harm engaged in such behaviors in adolescence yet desisted by adulthood. Females with positive histories of self-harm by late adolescence emanated largely from the ADHD-C group. Second, we found that predictors of NSSI were early externalizing symptoms, overall executive functioning, and father's negative parenting; predictors of SI were adverse childhood experiences and low self-esteem; and predictors of SA were early externalizing symptoms, adverse childhood experiences, and low self-esteem. Third, receiver operating characteristics analyses helped to ascertain interactive sets of predictors. Findings indicate that pathways to self-harm are multifaceted for females with ADHD. Understanding early childhood predictors and moderators of self-harm can inform both risk assessment and intervention strategies.
Major depressive disorder (MDD) is associated with increased allostatic load (AL; a measure of physiological costs of repeated/chronic stress-responding) and metabolic dysregulation (MetD; a measure of metabolic health and precursor to many medical illnesses). Though AL and MetD are associated with poor somatic health outcomes, little is known regarding their relationship with antidepressant-treatment outcomes.
We determined pre-treatment AL and MetD in 67 healthy controls and 34 unmedicated, medically healthy MDD subjects. Following this, MDD subjects completed 8-weeks of open-label selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and were categorized as ‘Responders’ (⩾50% improvement in depression severity ratings) or ‘Non-responders’ (<50% improvement). Logistic and linear regressions were performed to determine if pre-treatment AL or MetD scores predicted SSRI-response. Secondary analyses examined cross-sectional differences between MDD and control groups.
Pre-treatment AL and MetD scores significantly predicted continuous antidepressant response (i.e. absolute decreases in depression severity ratings) (p = 0.012 and 0.014, respectively), as well as post-treatment status as a Responder or Non-responder (p = 0.022 and 0.040, respectively), such that higher pre-treatment AL and MetD were associated with poorer SSRI-treatment outcomes. Pre-treatment AL and MetD of Responders were similar to Controls, while those of Non-responders were significantly higher than both Responders (p = 0.025 and 0.033, respectively) and Controls (p = 0.039 and 0.001, respectively).
These preliminary findings suggest that indices of metabolic and hypothalamic-pituitary-adrenal-axis dysregulation are associated with poorer SSRI-treatment response. To our knowledge, this is the first study to demonstrate that these markers of medical disease risk also predict poorer antidepressant outcomes.
Catechol-O-methyltransferase (COMT) has a central role in brain dopamine, noradrenalin and adrenalin signaling, and has been suggested to be involved in the pathogenesis and pharmacological treatment of affective disorders. The functional single nucleotide polymorphism (SNP) in exon 4 (Val158Met, rs4680) influences the COMT enzyme activity. The Val158Met polymorphism is a commonly studied variant in psychiatric genetics, and initial studies in schizophrenia and bipolar disorder presented evidence for association with the Met allele. In unipolar depression, while some of the investigations point at an association between the Met/Met genotype and others have found a link between the Val/Val genotype and depression, most of the studies cannot detect any difference in Val158Met allele frequency between depressed individuals and controls.
In the present study, we further elucidated the impact of COMT polymorphisms including the Val158Met in MDD. We investigated 1,250 subjects with DSM-IV and/or ICD-10 diagnosis of major depression (MDD), and 1,589 control subjects from UK. A total of 24 SNPs spanning the COMT gene were successfully genotyped using the Illumina HumaHap610-Quad Beadchip (22 SNPs), SNPlex™ genotyping system (1 SNP), and Sequenom MassARRAY® iPLEX Gold (1 SNP). Statistical analyses were implemented using PASW Statistics18, FINETTI (http://ihg.gsf.de/cgi-bin/hw/hwa1.pl), UNPHASED version 3.0.10 program and Haploview 4.0 program.
Neither single-marker nor haplotypic association was found with the functional Val158Met polymorphism or with any of the other SNPs genotyped. Our findings do not provide evidence that COMT plays a role in MDD or that this gene explains part of the genetic overlap with bipolar disorder.
Alcohol induced liver disease (ALD) is the predominant cause of alcohol-related mortality in the UK. Therefore helping patients with ALD to quit is a primary treatment goal.
The primary aim of this study was to measure the effectiveness and tolerability of Baclofen in maintaining abstinence, and to determine if this resulted in a reduction in standard measures of liver damage.
An observational prospective clinical audit was performed. Patients with ALD were commenced on Baclofen titrated according to tolerability and response up to 30 mg TDS. Primary outcome measures were severity of physical dependence (SADQ score) and biochemical markers of liver damage GGT, ALT, Bilirubin fibroelastography. These were compared at baseline, and 1 year.
Of the 243 patients commenced on Baclofen, 151 (85 female 66 male) have completed 1 year follow-up (F/U) of which 130 (86%) have remained engaged. 10 have died. Comparison of baseline (B/L) and 1 year biochemical markers showed a reduction in GGT (c2= 66.8 P < 0.0001) and Bil (c2= 82.6 P < 0.0001). There was a significant reduction in alcohol consumption (P < 0.0001 95% CI = 10 to 22). And the presence of physical dependence (c<sup>2</sup> = 77.4 P < 0.0001) as categorised by SADQ.
Baclofen is well tolerated in this very difficult to treat, high risk patient group. It has a positive impact on alcohol consumption, and overall measures of liver function and harm. A RCT is needed to confirm the benefit of Baclofen in this patient group.</div>
Integrating mental health care into HIV services is critical to addressing the high unmet treatment needs for people living with HIV and comorbid major depressive disorder. Introducing routine mental health screening at the primary health care level is a much needed diagonal approach to enhancing HIV care. In low-resource settings with a shortage of mental health care providers, eMental Health may provide a novel opportunity to attenuate this treatment gap and strengthen the health system.
To conduct formative health systems research on the implementation of routine depression screening using a digital tool – Mood in Retroviral Positive Individuals Application Monitoring (MIR + IAM) – in an HIV primary care setting in South Africa.
A Theory of Change (ToC) approach was utilised through individual and group session interviews to design an intervention that is embedded in the local context. Ten experts and local stakeholders were selected from the UK and South Africa. Data were analysed thematically using Atlas.ti to identify interventions, assumptions, barriers and facilitators of implementation.
The participants considered digital depression screening in HIV care services relevant for the improvement of mental health in this population. The six main themes identified from the ToC process were: (1) user experience including acceptability by patients, issues of patient privacy and digital literacy, and the need for a patient-centred tool; (2) benefits of the digital tool for data collection and health promotion; (3) availability of treatment after diagnosis; (4) human and physical resource capacity of primary health care; (5) training for lay health care workers; and (6) demonstration of the intervention's usefulness to generate interest from decision-makers.
Digital depression screening coupled with routine mental health data collection and analysis in HIV care is an applicable service that could improve the mental and physical health outcomes of this population. Careful consideration of the local health system capacity, including both workers and patients, is required. Future research to refine this intervention should focus on service users, government stakeholders and funders.
BACKGROUND: IGTS is a rare phenomenon of paradoxical germ cell tumor (GCT) growth during or following treatment despite normalization of tumor markers. We sought to evaluate the frequency, clinical characteristics and outcome of IGTS in patients in 21 North-American and Australian institutions. METHODS: Patients with IGTS diagnosed from 2000-2017 were retrospectively evaluated. RESULTS: Out of 739 GCT diagnoses, IGTS was identified in 33 patients (4.5%). IGTS occurred in 9/191 (4.7%) mixed-malignant GCTs, 4/22 (18.2%) immature teratomas (ITs), 3/472 (0.6%) germinomas/germinomas with mature teratoma, and in 17 secreting non-biopsied tumours. Median age at GCT diagnosis was 10.9 years (range 1.8-19.4). Male gender (84%) and pineal location (88%) predominated. Of 27 patients with elevated markers, median serum AFP and Beta-HCG were 70 ng/mL (range 9.2-932) and 44 IU/L (range 4.2-493), respectively. IGTS occurred at a median time of 2 months (range 0.5-32) from diagnosis, during chemotherapy in 85%, radiation in 3%, and after treatment completion in 12%. Surgical resection was attempted in all, leading to gross total resection in 76%. Most patients (79%) resumed GCT chemotherapy/radiation after surgery. At a median follow-up of 5.3 years (range 0.3-12), all but 2 patients are alive (1 succumbed to progressive disease, 1 to malignant transformation of GCT). CONCLUSION: IGTS occurred in less than 5% of patients with GCT and most commonly after initiation of chemotherapy. IGTS was more common in patients with IT-only on biopsy than with mixed-malignant GCT. Surgical resection is a principal treatment modality. Survival outcomes for patients who developed IGTS are favourable.
This paper reviews some of the research that has been carried out at the University of Liverpool where the Flight Science and Technology Research Group has developed its Heliflight-R full-motion research simulator to create a simulation environment for the launch and recovery of maritime helicopters to ships. HELIFLIGHT-R has been used to conduct flight trials to produce simulated Ship-Helicopter Operating Limits (SHOLs). This virtual engineering approach has led to a much greater understanding of how the dynamic interface between the ship and the helicopter contributes to the pilot's workload and the aircraft's handling qualities and will inform the conduct of future real-world SHOL trials. The paper also describes how modelling and simulation has been applied to the design of a ship's superstructure to improve the aerodynamic flow field in which the helicopter has to operate. The superstructure aerodynamics also affects the placement of the ship's anemometers and the dispersion of the ship's hot exhaust gases, both of which affect the operational envelope of the helicopter, and both of which can be investigated through simulation.
Depression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.
To confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.
The sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.
In the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β=0.12, P = 2.7 × 10−4) and with the Han/Eskin random effects method (P = 1.4 × 10−7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10−8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTO.
This meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression.
The brain has a high metabolic rate and its metabolism is almost entirely restricted to oxidative utilisation of glucose. These factors emphasise the extreme dependence of neural tissue on a stable and adequate supply of glucose. Whereas initially it was thought that only glucose deprivation (i.e. under hypoglycaemic conditions) can affect brain function, it has become apparent that low-level fluctuations in central availability can affect neural and consequently, cognitive performance. In the present paper the impact of diet-based glycaemic response and glucose regulation on cognitive processes across the lifespan will be reviewed. The data suggest that although an acute rise in blood glucose levels has some short-term improvements of cognitive function, a more stable blood glucose profile, which avoids greater peaks and troughs in circulating glucose is associated with better cognitive function and a lower risk of cognitive impairments in the longer term. Therefore, a habitual diet that secures optimal glucose delivery to the brain in the fed and fasting states should be most advantageous for the maintenance of cognitive function. Although the evidence to date is promising, it is insufficient to allow firm and evidence-based nutritional recommendations. The rise in obesity, diabetes and metabolic syndrome in recent years highlights the need for targeted dietary and lifestyle strategies to promote healthy lifestyle and brain function across the lifespan and for future generations. Consequently, there is an urgent need for hypothesis-driven, randomised controlled trials that evaluate the role of different glycaemic manipulations on cognition.
The unsteady air flow over and around the helicopter landing deck of a naval vessel is known to cause high pilot workload and to limit the helicopter's operational envelope for launch and recovery. Previous research has suggested that modifications to the ship's hangar edges can beneficially modify the flow over the deck. This paper examines the effectiveness of five hangar-edge modifications using computational fluid dynamics–generated airwakes and flight mechanics modelling, as well as piloted flight trials in a motion-base simulator. Results are presented, in terms of unsteady helicopter loads and pilot workload ratings, for modifications to the windward vertical rear edge of the hangar and with an oblique wind. The results demonstrate that while the airwake can be altered by superstructure modifications, the integrated effect of the altered airwake on the entire helicopter does not necessarily give the desired result; indeed of the five modifications tested, two were seen to be beneficial while three caused an increase in pilot workload compared with the unmodified hangar. Overall, the paper shows that the airwake can be modified by superstructure design changes, and that the effect on the helicopter can be measured through modelling and simulation. It is also demonstrated that making judgements on the severity of the airwake based on the aerodynamic flow field alone can be misleading. The benefit of these simulation tools is that they can be used during the ship design process to evaluate the effect of the superstructure aerodynamics, rather than wait until after the ship is built.
Objectives: Visuospatial processing deficits have been reported in Huntington’s disease (HD). To date, no study has examined associations between visuospatial cognition and posterior brain findings in HD. Methods: We compared 119 premanifest (55> and 64<10.8 years to expected disease onset) and 104 early symptomatic (59 stage-1 and 45 stage-2) gene carriers, with 110 controls on visual search and mental rotation performance at baseline and 12 months. In the disease groups, we also examined associations between task performance and disease severity, functional capacity and structural brain measures. Results: Cross-sectionally, there were strong differences between all disease groups and controls on visual search, and between diagnosed groups and controls on mental rotation accuracy. Only the premanifest participants close to onset took longer than controls to respond correctly to mental rotation. Visual search negatively correlated with disease burden and motor symptoms in diagnosed individuals, and positively correlated with functional capacity. Mental rotation (“same”) was negatively correlated with motor symptoms in stage-2 individuals, and positively correlated with functional capacity. Visual search and mental rotation were associated with parieto-occipital (pre-/cuneus, calcarine, lingual) and temporal (posterior fusiform) volume and cortical thickness. Longitudinally, visual search deteriorated over 12 months in stage-2 individuals, with no evidence of declines in mental rotation. Conclusions: Our findings provide evidence linking early visuospatial deficits to functioning and posterior cortical dysfunction in HD. The findings are important since large research efforts have focused on fronto-striatal mediated cognitive changes, with little attention given to aspects of cognition outside of these areas. (JINS, 2016, 22, 595–608)
Our review highlights research during the past century focussed on the population ecology of outbreak-prone insect defoliators in Canadian forests. Based on reports from national and provincial surveys that began in the 1930s, there have been at least 106 insect defoliators reported to outbreak, most of which are native Lepidoptera, Hymenoptera (sawflies), or Coleoptera (in order of frequency from most to least). Studies comparing life-history traits of outbreak versus non-outbreak species to better understand why certain species are more outbreak-prone indicate several traits especially common among outbreak species, including egg clustering and aggregative larval feeding. There have been at least 50 time-series studies examining the spatiotemporal population behaviour of 12 major defoliator species. These studies provide evidence for both regular periodicity and spatial synchrony of outbreaks for most major species. Life-table studies seeking to understand the agents causing populations to fluctuate have been carried out for at least seven outbreak species, with the majority identifying natural enemies (usually parasitoids) as the major driver of outbreak collapse. Our review concludes with several case studies highlighting the impact and historical underpinnings of population studies for major defoliator species and a discussion of potential avenues for future research.
Major depressive disorder (MDD) is a common and disabling condition with well-established heritability and environmental risk factors. Gene–environment interaction studies in MDD have typically investigated candidate genes, though the disorder is known to be highly polygenic. This study aims to test for interaction between polygenic risk and stressful life events (SLEs) or childhood trauma (CT) in the aetiology of MDD.
The RADIANT UK sample consists of 1605 MDD cases and 1064 controls with SLE data, and a subset of 240 cases and 272 controls with CT data. Polygenic risk scores (PRS) were constructed using results from a mega-analysis on MDD by the Psychiatric Genomics Consortium. PRS and environmental factors were tested for association with case/control status and for interaction between them.
PRS significantly predicted depression, explaining 1.1% of variance in phenotype (p = 1.9 × 10−6). SLEs and CT were also associated with MDD status (p = 2.19 × 10−4 and p = 5.12 × 10−20, respectively). No interactions were found between PRS and SLEs. Significant PRSxCT interactions were found (p = 0.002), but showed an inverse association with MDD status, as cases who experienced more severe CT tended to have a lower PRS than other cases or controls. This relationship between PRS and CT was not observed in independent replication samples.
CT is a strong risk factor for MDD but may have greater effect in individuals with lower genetic liability for the disorder. Including environmental risk along with genetics is important in studying the aetiology of MDD and PRS provide a useful approach to investigating gene–environment interactions in complex traits.
Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).
For investigating familiality, we used 691 families with 2–5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.
Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.
AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
This paper describes a simulation technique that has been developed to quantify the unsteady forces and moments that are imposed onto a maritime helicopter by a ship’s airwake during a deck landing. An unsteady CFD-generated airwake, created using a CAD model of the ship, is integrated with a flight dynamics model of a helicopter. By holding the helicopter at a fixed position in the airwake it is possible to quantify the unsteady forces and moments imposed on the aircraft. The technique is therefore a software-based airwake dynamometer, and has been called the virtual AirDyn. As well as determining the mean loads, from consideration of the unsteady loads in the closed-loop pilot response frequency range of 0·2-2Hz it is also possible to quantify the magnitude of the unsteady disturbance in each axis. The loads are also indicators of the control activity the pilot would have to exert to maintain aircraft position and attitude. By placing the virtual AirDyn at different positions around the landing deck in different wind conditions, it is able to quantify the effect of the airwake on the mean and unsteady loads. The quantified loads can be explained by examining the CFD-generated flow field, and the geometric features on the ship’s superstructure that gave rise to them can be identified. The virtual AirDyn is therefore a tool that can be used to evaluate and inform ship design for maritime helicopter operations.