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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
This study aimed to investigate general factors associated with prognosis regardless of the type of treatment received, for adults with depression in primary care.
We searched Medline, Embase, PsycINFO and Cochrane Central (inception to 12/01/2020) for RCTs that included the most commonly used comprehensive measure of depressive and anxiety disorder symptoms and diagnoses, in primary care depression RCTs (the Revised Clinical Interview Schedule: CIS-R). Two-stage random-effects meta-analyses were conducted.
Twelve (n = 6024) of thirteen eligible studies (n = 6175) provided individual patient data. There was a 31% (95%CI: 25 to 37) difference in depressive symptoms at 3–4 months per standard deviation increase in baseline depressive symptoms. Four additional factors: the duration of anxiety; duration of depression; comorbid panic disorder; and a history of antidepressant treatment were also independently associated with poorer prognosis. There was evidence that the difference in prognosis when these factors were combined could be of clinical importance. Adding these variables improved the amount of variance explained in 3–4 month depressive symptoms from 16% using depressive symptom severity alone to 27%. Risk of bias (assessed with QUIPS) was low in all studies and quality (assessed with GRADE) was high. Sensitivity analyses did not alter our conclusions.
When adults seek treatment for depression clinicians should routinely assess for the duration of anxiety, duration of depression, comorbid panic disorder, and a history of antidepressant treatment alongside depressive symptom severity. This could provide clinicians and patients with useful and desired information to elucidate prognosis and aid the clinical management of depression.
Psychotic experiences (PE) are highly prevalent in childhood and are known to be associated with co-morbid mental health disorders and functional difficulties in adolescence. However, little is known about the long-term outcomes of young people who report PE.
As part of the Adolescent Brain Development Study, 211 young people were recruited in childhood (mean age 11.7 years) and underwent detailed clinical interviews, with 25% reporting PE. A 10 year follow-up study was completed and 103 participants returned (mean age 20.9 years). Structured clinical interviews for DSM-5 (SCID-5) and interviewer-rated assessments of functioning were conducted. A detailed neuropsychological battery was also administered. Analyses investigated group differences between those who had ever reported PE and controls in early adulthood.
The PE group was at a significantly higher risk of meeting DSM-5 criteria for a current (OR 4.08, CI 1.16–14.29, p = 0.03) and lifetime psychiatric disorder (OR 3.27, CI 1.43–7.47, p = 0.005). They were also at a significantly higher risk of multi-morbid lifetime psychiatric disorders. Significantly lower scores on current social and global functioning measures were observed for the PE group. Overall, there were no differences in neuropsychological performance between groups apart from significantly lower scores on the Stroop Word task and the Purdue Pegboard task for the PE group.
Our findings suggest that reports of PE are associated with poorer mental health and functional outcomes in early adulthood, with some persisting cognitive and motor deficits. Young people who report such symptoms could be considered a target group for interventions to aid functional outcomes.
Major depressive disorder and neuroticism (Neu) share a large genetic basis. We sought to determine whether this shared basis could be decomposed to identify genetic factors that are specific to depression.
We analysed summary statistics from genome-wide association studies (GWAS) of depression (from the Psychiatric Genomics Consortium, 23andMe and UK Biobank) and compared them with GWAS of Neu (from UK Biobank). First, we used a pairwise GWAS analysis to classify variants as associated with only depression, with only Neu or with both. Second, we estimated partial genetic correlations to test whether the depression's genetic link with other phenotypes was explained by shared overlap with Neu.
We found evidence that most genomic regions (25/37) associated with depression are likely to be shared with Neu. The overlapping common genetic variance of depression and Neu was genetically correlated primarily with psychiatric disorders. We found that the genetic contributions to depression, that were not shared with Neu, were positively correlated with metabolic phenotypes and cardiovascular disease, and negatively correlated with the personality trait conscientiousness. After removing shared genetic overlap with Neu, depression still had a specific association with schizophrenia, bipolar disorder, coronary artery disease and age of first birth. Independent of depression, Neu had specific genetic correlates in ulcerative colitis, pubertal growth, anorexia and education.
Our findings demonstrate that, while genetic risk factors for depression are largely shared with Neu, there are also non-Neu-related features of depression that may be useful for further patient or phenotypic stratification.
The most frequently asked questions about Chlamydia trachomatis, commonly known as “chlamydia,” are (1) what is it? and (2) where did it come from? The capricious and cryptic nature of genital infections caused by C. trachomatis and the difficulties in isolating the pathogen have led to many misconceptions about its origins and how infection occurs. The first question is now easy to answer. There is no doubt: chlamydiae are not viruses, nor are they protozoan parasites; they are bacteria. However, they are not free-living bacteria and so cannot be cultivated on conventional media such as agar plates. Chlamydiae are highly specialized bacteria, which can be grown only within living cells; thus they are obligate intracellular pathogens.
Chlamydiae also have a complex developmental cycle. The name is derived from Chlamydozoa, which means “cloaked organisms,” because they develop within an inclusion membrane within the cytoplasm of the cell and initially in the infection process are not visible. These gram-negative bacteria have a unique development cycle that includes the repeated division of a replicating stage, called an RB, or reticulate body. RBs increase in number to a point where they can be seen under the microscope as moving specks within a defined membrane structure known as an inclusion in the host cell's cytoplasm. With time the inclusion ruptures out of the cell and releases the smaller nonreplicating infectious forms called “elementary bodies.”
The genus is also known as Chlamydia; it is a proper noun written in italics, with no plural. The genus Chlamydia currently contains nine species and no doubt, more will be added. The species C. trachomatis, the focus of our discussion, is made up of a number of serovars, differentiated by surface antigens that induce specific antibodies. It has four ocular serovars that cause blinding endemic trachoma, A, B, Ba, and C and at least eight serovars, D to K, which typically cause genital tract infections. There are additionally the three L serovars that cause the condition known as lymphogranuloma venerum. Closely related species are C. muridarum, which infects mice and hamsters, and C. suis, which is endemic in pigs.
Refractory depression is a major contributor to the economic burden of depression. Radically open dialectical behaviour therapy (RO DBT) is an unevaluated new treatment targeting overcontrolled personality, common in refractory depression, but it is not yet known whether the additional expense of RO DBT is good value for money.
To estimate the cost-effectiveness of RO DBT plus treatment as usual (TAU) compared with TAU alone in people with refractory depression (trial registration: ISRCTN85784627).
We undertook a cost-effectiveness analysis alongside a randomised trial evaluating RO DBT plus TAU versus TAU alone for refractory depression in three UK secondary care centres. Our economic evaluation, 12 months after randomisation, adopted the perspective of the UK National Health Service (NHS) and personal social services. It evaluated cost-effectiveness by comparing the net cost of RO DBT with the net gain in quality-adjusted life-years (QALYs), estimated using the EQ-5D-3L measure of health-related quality of life.
The additional cost of RO DBT plus TAU compared with TAU alone was £7048 and was associated with a difference of 0.032 QALYs, yielding an incremental cost-effectiveness ratio (ICER) of £220 250 per QALY. This ICER was well above the National Institute for Health and Care Excellence (NICE) upper threshold of £30 000 per QALY. A cost-effectiveness acceptability curve indicated that RO DBT had a zero probability of being cost-effective compared with TAU at the NICE £30 000 threshold.
In its current resource-intensive form, RO DBT is not a cost-effective use of resources in the UK NHS.
Declaration of interest
R.H. is co-owner and director of Radically Open Ltd, the RO DBT training and dissemination company. D.K. reports grants outside the submitted work from the National Institute for Health Research (NIHR). T.L. receives royalties from New Harbinger Publishing for sales of RO DBT treatment manuals, speaking fees from Radically Open Ltd, and a grant outside the submitted work from the Medical Research Council. He was co-director of Radically Open Ltd between November 2014 and May 2015 and is married to Erica Smith-Lynch, the principal shareholder and one of two directors of Radically Open Ltd. H.O'M. reports personal fees outside the submitted work from the Charlie Waller Institute and Improving Access to Psychological Therapy. S.R. provides RO DBT supervision through her company S C Rushbrook Ltd. I.R. reports grants outside the submitted work from NIHR and Health & Care Research Wales. M. Stanton reports personal fees outside the submitted work from British Isles DBT Training, Stanton Psychological Services Ltd and Taylor & Francis. M. Swales reports personal fees outside the submitted work from British Isles DBT Training, Guilford Press, Oxford University Press and Taylor & Francis. B.W. was co-director of Radically Open Ltd between November 2014 and February 2015.
Individuals with depression often do not respond to medication or psychotherapy. Radically open dialectical behaviour therapy (RO DBT) is a new treatment targeting overcontrolled personality, common in refractory depression.
To compare RO DBT plus treatment as usual (TAU) for refractory depression with TAU alone (trial registration: ISRCTN 85784627).
RO DBT comprised 29 therapy sessions and 27 skills classes over 6 months. Our completed randomised trial evaluated RO DBT for refractory depression over 18 months in three British secondary care centres. Of 250 adult participants, we randomised 162 (65%) to RO DBT. The primary outcome was the Hamilton Rating Scale for Depression (HRSD), assessed masked and analysed by treatment allocated.
After 7 months, immediately following therapy, RO DBT had significantly reduced depressive symptoms by 5.40 points on the HRSD relative to TAU (95% CI 0.94–9.85). After 12 months (primary end-point), the difference of 2.15 points on the HRSD in favour of RO DBT was not significant (95% CI –2.28 to 6.59); nor was that of 1.69 points on the HRSD at 18 months (95% CI –2.84 to 6.22). Throughout RO DBT participants reported significantly better psychological flexibility and emotional coping than controls. However, they reported eight possible serious adverse reactions compared with none in the control group.
The RO DBT group reported significantly lower HRSD scores than the control group after 7 months, but not thereafter. The imbalance in serious adverse reactions was probably because of the controls' limited opportunities to report these.
Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.
The present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2370 male and 2574 female UK Biobank participants.
There was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β = 0.191, q = 0.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β = 0.098, p = 0.026), compared to a negative association among controls (β = −0.087, p = 0.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.
Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.
Psychotic experiences (PEs) are common in childhood and adolescence and their association with mental disorders is well-established. We aim to conduct a quantitative synthesis the literature on the relationship between childhood and adolescent PEs and (i) any mental disorder; and (ii) specific categories of mental disorder, while stratifying by study design.
Three electronic databases (PUBMED, PsycINFO and EMBASE) were searched from inception to August 2017 for all the published literature on childhood and adolescent PEs and mental disorder (outcome) in non-help-seeking community samples. Study quality was assessed using a recognised quality assessment tool for observational studies. Two authors conducted independent data extraction. Pooled odds ratios were calculated for mental disorders using random-effects models. Additional analyses were conducted investigating different categories of mental disorder while stratifying by study design.
Fourteen studies from 13 community samples (n = 29 517) were identified with 9.8% of participants reporting PEs. PEs were associated with a three-fold increased risk of any mental disorder [odds ratio (OR) 3.08, confidence interval (CI) 2.26–4.21, k = 12]. PEs were associated with four-fold increase risk of psychotic disorder (OR 3.96, CI 2.03–7.73, population-attributable-fraction: 23.2%, k = 5). In addition, PEs were associated with an increased risk of affective disorders, anxiety disorders, behavioural disorders and substance-use disorders. Few longitudinal studies have investigated childhood and adolescent PEs and subsequent non-psychotic disorders which limited a meaningful synthesis and interpretation of these results.
This meta-analysis confirms that PEs are prevalent in childhood and adolescent community samples and are associated with a variety of mental disorders beyond psychotic disorders. Further longitudinal research is necessary to fully determine the longitudinal relationship between PEs and non-psychotic disorders.
Sample preparation techniques for radiocarbon analysis of dissolved inorganic carbon (DIC) and dissolved organic carbon (DOC) in freshwater, as well as CO2 and CH4 in gas mixtures are presented. Focused efforts have been on developing a robust and low-background wet oxidation extraction method for DOC in freshwater, following routine methods developed for stable carbon isotope analysis and adapted for radiocarbon (14C) analysis. DIC (by acidification) and DOC (by wet oxidation) are converted to CO2 in pre-baked septum-fitted borosilicate bottles, where the resulting CO2 is extracted from the dissolved and headspace portions on a low-flow He-carrier flow-through system interfaced to a vacuum extraction line. A peripheral CH4 extraction line interfaces to the flow line to separate CH4 from environmental samples following the methods of Pack et al. 2015. High sample throughput and low blanks are achievable with this method. DIC and DOC blanks are consistently <0.7 pMC, while CO2 and CH4 blanks are typically <0.1 pMC.
Objectives: This study examined the effects of anodal transcranial direct current stimulation (a-tDCS) on sentence and word comprehension in healthy adults. Methods: Healthy adult participants, aged between 19 and 30 years, received either a-tDCS over the left inferior frontal gyrus (n=18) or sham stimulation (n=18). Participants completed sentence comprehension and word comprehension tasks before and during stimulation. Accuracy and reaction times (RTs) were recorded as participants completed both tasks. Results: a-tDCS was found to significantly decrease RT on the sentence comprehension task compared to baseline. There was no change in RT following sham stimulation. a-tDCS was not found to have a significant effect on accuracy. Also, a-tDCS did not affect accuracy or RTs on the word comprehension task. Conclusions: The study provides evidence that non-invasive anodal electrical stimulation can modulate sentence comprehension in healthy adults, at least compared to their baseline performance. (JINS, 2019, 25, 331–335)
The Norfolk Youth Service was created in 2012 in response to calls to redesign mental health services to better meet the needs of young people. The new service model transcends traditional boundaries by creating a single, ‘youth friendly’ service for young people aged 14–25 years. The aim of this study was to investigate the effect of the transition to this new model on patterns of referral, acceptance and service use. We analysed routinely collected data on young people aged 14–25 years referred for secondary mental healthcare in Norfolk before and after implementation of the youth mental health service. The number of referrals, their age and gender, proportion of referrals accepted and average number of service contacts per referral by age pre- and post-implementation were compared.
Referrals increased by 68% following implementation of the new service model, but the proportion of referrals accepted fell by 27 percentage points. Before implementation of the youth service, there was a clear discrepancy between the peak age of referral and the age of those seen by services. Following implementation, service contacts were more equitable across ages, with no marked discontinuity at age 18 years.
Our findings suggest that the transformation of services may have succeeded in reducing the ‘cliff edge’ in access to mental health services at the transition to adulthood. However, the sharp rise in referrals and reduction in the proportion of referrals accepted highlights the importance of considering possible unintended consequences of new service models.
Ice-wedge activity can be used to reconstruct past environmental conditions. We investigated the moisture source and timing of ice-wedge formation on the Blackstone Plateau. A section of permafrost exposed ice wedges that developed at two distinct depths: the first set formed syngenetically and penetrated alluvial silts from the top of permafrost; the second set, truncated by an erosional or thaw contact, was found solely in icy muddy gravels (>3.1 m depth). The δ18O and D-excess records of the ice wedges suggest that they formed from freezing of snow meltwater whose isotopic composition evolved during meltout. The 14CDOC results suggest that climate was favorable to ice-wedge growth between 32,000–30,000 and 14,000–12,500 cal yr BP, but there was likely a hiatus during the last glacial maximum due to climate being too dry. During the early to mid-Holocene, ice wedges were inactive as a result of warmer and wetter climate. Ice wedge re-initiated around 6360 cal yr BP, with a peak in activity between 3980 and 920 cal yr BP, a period characterized by cool and moist climate. Overall, timing of ice-wedge activity was broadly consistent with the climate and vegetation evolution in the western Arctic.
Current policy emphasises the importance of ‘living well’ with dementia, but there has been no comprehensive synthesis of the factors related to quality of life (QoL), subjective well-being or life satisfaction in people with dementia. We examined the available evidence in a systematic review and meta-analysis. We searched electronic databases until 7 January 2016 for observational studies investigating factors associated with QoL, well-being and life satisfaction in people with dementia. Articles had to provide quantitative data and include ⩾75% people with dementia of any type or severity. We included 198 QoL studies taken from 272 articles in the meta-analysis. The analysis focused on 43 factors with sufficient data, relating to 37639 people with dementia. Generally, these factors were significantly associated with QoL, but effect sizes were often small (0.1–0.29) or negligible (<0.09). Factors reflecting relationships, social engagement and functional ability were associated with better QoL. Factors indicative of poorer physical and mental health (including depression and other neuropsychiatric symptoms) and poorer carer well-being were associated with poorer QoL. Longitudinal evidence about predictors of QoL was limited. There was a considerable between-study heterogeneity. The pattern of numerous predominantly small associations with QoL suggests a need to reconsider approaches to understanding and assessing living well with dementia.
The A.E. Lalonde accelerator mass spectrometer (3MV, HVEE) was commissioned in early 2014 at the University of Ottawa (Canada). The radiocarbon sample preparation laboratory spent the better part of 2014 undertaking a quality control program, establishing pretreatment protocols, and streamlining sample processing. In the fall of 2014, the first unknown samples were accepted and in the first year of operation well over 1000 targets (~60% unknowns) were analyzed. Here, we present an overview of sample processing protocols and results from routinely measured standards, reference, and blank materials.
Argon, krypton and xenon have different solubilities in water, meaning their ratios in water are different from those in atmospheric air. This characteristic is used in a novel method to distinguish between ice bodies which originate from the compaction of snow (i.e. buried snow banks, glacial ice) vs. ice which forms from the freezing of groundwater (i.e. pingo ice). Ice which forms from the compaction of snow has gas ratios similar to atmospheric air, while ice which forms from the freezing of liquid water is expected to have gas ratios similar to air-equilibrated water. This analysis has been conducted using a spike dilution noble gas line with gas extraction conducted on-line. Samples were mixed with an aliquot of rare noble gases while being melted, then extracted gases are purified and cryogenically separated. Samples have been analysed from glacial ice, buried snow bank ice, intrusive ice, wedge ice, cave ice and two unknown ice bodies. Ice bodies which have formed from different processes have different gas ratios relative to their formation processes.
The use of underground geological repositories, such as in radioactive waste disposal (RWD) and in carbon capture (widely known as Carbon Capture and Storage; CCS), constitutes a key environmental priority for the 21st century. Based on the identification of key scientific questions relating to the geophysics, geochemistry and geobiology of geodisposal of wastes, this paper describes the possibility of technology transfer from high-technology areas of the space exploration sector, including astrobiology, planetary sciences, astronomy, and also particle and nuclear physics, into geodisposal. Synergies exist between high technology used in the space sector and in the characterization of underground environments such as repositories, because of common objectives with respect to instrument miniaturization, low power requirements, durability under extreme conditions (in temperature and mechanical loads) and operation in remote or otherwise difficult to access environments.