Predicting trajectories of symptom change during and following treatment in adolescents with Unipolar Major Depression.

Objective: Definitions of treatment response used in randomised controlled trials for unipolar major depression are non-standardised and arbitrary. Proportion of non-responders has been estimated as ranging from 20%-40% across such trials. I aimed to classify depressed adolescents recruited to the UK IMPACT trial into different trajectories of depression symptom response using a longitudinal data-driven approach: growth mixture modelling (GMM) and investigate potential predictors of trajectory classes in this cohort. Method: 465 depressed adolescents received manualised psychological therapies in the IMPACT trial. GMM was used to plot the trajectories of self-reported depressive symptoms measured at 6 nominal time points over 86 weeks from randomisation, and categorise patients into their most likely trajectory class. Chapters 2-4 investigated the prognostic value of a number of variables. Chapter 2 investigated a battery of demographic and clinical variables including subclinical psychotic symptoms. Chapter 3 focused on a subsample of patients: 109 of the 465 with structural magnetic resonance imaging (MRI) data. FreeSurfer was used to extract cortical thickness (CT) and surface area (SA) measures from 4 regions of interest (ROI; rostral anterior cingulate, dorsolateral prefrontal cortex, orbitofrontal cortex, and insular cortex). Chapter 4 focused on another subsample of patients: 166 of the 465 with salivary basal cortisol data at both waking and evening. Logistic regressions were used in Chapters 2-4 to investigate whether these variables were associated with increased likelihood of membership to a certain GMM class. Results: A piecewise GMM categorised patients into two classes with initially similar and subsequently distinct trajectories. Both groups had a significant decline in depressive symptoms over the first 18 weeks. Eighty-four per cent of patients were classed as “continued-improvers” through reporting an improvement in symptoms over the full duration of the study. A further class of 15.9% of patients were termed “halted-improvers” who had higher depression scores at baseline, faster recovery but no further improvement after 18 weeks. This data-driven method of classification showed only moderate agreement with a priori classification methods, and suggested misclassification rate could be as great as 31%. Co-morbid psychiatric disorders at baseline moderately increased the liability of being a member of the halted-improvers class (OR = 1.40, CI 1.00-1.96). No other clinical, neurological or cortisol variable reached statistical significance for predicting trajectory class. Conclusion: A fast reduction in depressive symptoms in the first few weeks of treatment may not indicate a good prognosis. Further, halted-improvement may not be apparent until after 18 weeks of treatment. Capitalizing on repeated symptom assessments with longitudinal data driven modelling may improve the precision of revealing patient groups with differential responses to treatment. Further work should seek to validate these trajectories in a separate sample of adolescents.The IMPACT study was funded by the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme (project number 06/05/01). MR-IMPACT was funded by the Medical Research Council (grant: G0802226) and IMPACT-GH was funded by the Evelyn Trust. My doctoral studentship was awarded by the Neuroscience in Psychiatry (NSPN.Org) Consortium itself funded by a strategic award from the Wellcome Trust (095844/Z/11/Z) awarded to Professor Ian Goodyer and Professor Peter Fonagy

Paramedic views regarding clinical research in out of hospital cardiac arrest

Background: The success of pre-hospital research relies on positive engagement from paramedics. Without adequate participation and protocol compliance trials will not succeed. Aims: To seek feedback from paramedics about trial participation and determine their preferences regarding a future large-scale research study. Methods: Paramedics participating in REVIVE-Airways were sent a feedback questionnaire according to their study allocation. Findings: 99% of respondents were willing to participate in a further large-scale trial. Participants offered recommendations for future pre-hospital trials. Conclusion: There was strong support for further clinical trials of alternative airway management strategies during OHCA. Paramedics welcome opportunities to participate in research and receive feedback about trial progress and patient outcomes

Circadian rhythms in the plant host influence rhythmicity of rhizosphere microbiota

Background Recent studies demonstrated that microbiota inhabiting the plant rhizosphere exhibit diel changes in abundance. To investigate the impact of plant circadian rhythms on bacterial and fungal rhythms in the rhizosphere, we analysed temporal changes in fungal and bacterial communities in the rhizosphere of Arabidopsis plants overexpressing or lacking function of the circadian clock gene LATE ELONGATED HYPOCOTYL (LHY). Results Under diel light–dark cycles, the knock-out mutant lhy-11 and the gain-of-function mutant lhy-ox both exhibited gene expression rhythms with altered timing and amplitude compared to wild-type plants. Distinct sets of bacteria and fungi were found to display rhythmic changes in abundance in the rhizosphere of both of these mutants, suggesting that abnormal patterns of rhythmicity in the plant host caused temporal reprogramming of the rhizosphere microbiome. This was associated with changes in microbial community structure, including changes in the abundance of fungal guilds known to impact on plant health. Under constant environmental conditions, microbial rhythmicity persisted in the rhizosphere of wild-type plants, indicating control by a circadian oscillator. In contrast, loss of rhythmicity in lhy-ox plants was associated with disrupted rhythms for the majority of rhizosphere microbiota. Conclusions These results show that aberrant function of the plant circadian clock is associated with altered rhythmicity of rhizosphere bacteria and fungi. In the long term, this leads to changes in composition of the rhizosphere microbiome, with potential consequences for plant health. Further research will be required to understand the functional implications of these changes and how they impact on plant health and productivity

An exploration of the views of paramedics regarding airway management

© 2016 Brandling et al. Background: Paramedics are a skilled group of clinicians with expertise in airway management. Our research group has completed a trial comparing supraglottic airway devices with tracheal intubation during out of hospital cardiac arrest. This is a contentious topic amongst paramedics in the United Kingdom (UK). We explored the customs and beliefs of UK paramedics in relation to airway management, and whether tracheal intubation contributes to and sustains paramedic professional identity. Methods: The study took place within South Western Ambulance Service NHS Foundation Trust. We used a qualitative approach, conducting interviews and focus groups with paramedics. The themes arising from interviews were discussed in focus groups, developing a deeper understanding and providing insight and recommendations for future research and policy. Purposive sampling accounted for differing training and for participation in the main trial. There were 17interviews and five focus groups with a further 17 participants. Data saturation was achieved. Results: Four domains were identified. Pride - The ability to use a life-saving skill in austere conditions. Utility - Different training routes and experience have led to different attitudes towards airway management. Inconsistent expectations - Paramedics felt that there were different perceptions of their abilities amongst hospital staff and the general public. Professionalization - Debate over airway management is not founded on good evidence. Conclusion: We have demonstrated that UK paramedics have a wide range of views regarding airway management, and that these are based on evidence and experience rather than dogma. Airway management contributes to paramedics' professional identity, but is not reliant on this

Contemporary accuracy of death certificates for coding prostate cancer as a cause of death : Is reliance on death certification good enough? A comparison with blinded review by an independent cause of death evaluation committee

BACKGROUND: Accurate cause of death assignment is crucial for prostate cancer epidemiology and trials reporting prostate cancer-specific mortality outcomes. METHODS: We compared death certificate information with independent cause of death evaluation by an expert committee within a prostate cancer trial (2002-2015). RESULTS: Of 1236 deaths assessed, expert committee evaluation attributed 523 (42%) to prostate cancer, agreeing with death certificate cause of death in 1134 cases (92%, 95% CI: 90%, 93%). The sensitivity of death certificates in identifying prostate cancer deaths as classified by the committee was 91% (95% CI: 89%, 94%); specificity was 92% (95% CI: 90%, 94%). Sensitivity and specificity were lower where death occurred within 1 year of diagnosis, and where there was another primary cancer diagnosis. CONCLUSIONS: UK death certificates accurately identify cause of death in men with prostate cancer, supporting their use in routine statistics. Possible differential misattribution by trial arm supports independent evaluation in randomised trials

Effect of a Low-Intensity PSA-Based Screening Intervention on Prostate Cancer Mortality:The CAP Randomized Clinical Trial

Importance Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment. Objective To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer–specific mortality. Design, Setting, and Participants The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016. Intervention An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. Main Outcomes and Measures Primary outcome: prostate cancer–specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic. Results Among 415 357 randomized men (mean [SD] age, 59.0 [5.6] years), 189 386 in the intervention group and 219 439 in the control group were included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%) attended the PSA testing clinic and 67 313 (36%) underwent PSA testing. Of 64 436 with a valid PSA test result, 6857 (11%) had a PSA level between 3 ng/mL and 19.9 ng/mL, of whom 5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, −0.013 per 1000 person-years [95% CI, −0.047 to 0.022]; rate ratio [RR], 0.96 [95% CI, 0.85 to 1.08]; P = .50). The number diagnosed with prostate cancer was higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95% CI, 1.14 to 1.25]; P

Börjeson–Forssman–Lehmann syndrome: Delineating the clinical and allelic spectrum in 14 new families

Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS

Pathogenic copy number variants and SCN1A mutations in patients with intellectual disability and childhood-onset epilepsy

Background Copy number variants (CNVs) have been linked to neurodevelopmental disorders such as intellectual disability (ID), autism, epilepsy and psychiatric disease. There are few studies of CNVs in patients with both ID and epilepsy. Methods We evaluated the range of rare CNVs found in 80 Welsh patients with ID or developmental delay (DD), and childhood-onset epilepsy. We performed molecular cytogenetic testing by single nucleotide polymorphism array or microarray-based comparative genome hybridisation. Results 8.8 % (7/80) of the patients had at least one rare CNVs that was considered to be pathogenic or likely pathogenic. The CNVs involved known disease genes (EHMT1, MBD5 and SCN1A) and imbalances in genomic regions associated with neurodevelopmental disorders (16p11.2, 16p13.11 and 2q13). Prompted by the observation of two deletions disrupting SCN1A we undertook further testing of this gene in selected patients. This led to the identification of four pathogenic SCN1A mutations in our cohort. Conclusions We identified five rare de novo deletions and confirmed the clinical utility of array analysis in patients with ID/DD and childhood-onset epilepsy. This report adds to our clinical understanding of these rare genomic disorders and highlights SCN1A mutations as a cause of ID and epilepsy, which can easily be overlooked in adults

Brain-behaviour modes of covariation in healthy and clinically depressed young people

Abstract: Understanding how variations in dimensions of psychometrics, IQ and demographics relate to changes in brain connectivity during the critical developmental period of adolescence and early adulthood is a major challenge. This has particular relevance for mental health disorders where a failure to understand these links might hinder the development of better diagnostic approaches and therapeutics. Here, we investigated this question in 306 adolescents and young adults (14–24 y, 25 clinically depressed) using a multivariate statistical framework, based on canonical correlation analysis (CCA). By linking individual functional brain connectivity profiles to self-report questionnaires, IQ and demographic data we identified two distinct modes of covariation. The first mode mapped onto an externalization/internalization axis and showed a strong association with sex. The second mode mapped onto a well-being/distress axis independent of sex. Interestingly, both modes showed an association with age. Crucially, the changes in functional brain connectivity associated with changes in these phenotypes showed marked developmental effects. The findings point to a role for the default mode, frontoparietal and limbic networks in psychopathology and depression