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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.
Pain, fatigue and anxiety are common features of fibromyalgia and ME/CFS and significantly impact quality of life. Aetiology is poorly defined but dysfunctional inflammatory, autonomic and interoceptive (sensing of internal bodily signals) processes are implicated.
To investigate how altered interoception relates to baseline expression of pain, fatigue and anxiety symptoms in fibromyalgia and ME/CFS and in response to an inflammatory challenge.
Sixty-five patients with fibromyalgia and/or ME/CFS diagnosis and 26 matched controls underwent baseline assessment: pressure-pain thresholds and self-report questionnaires assessing pain, fatigue and anxiety severity. Participants received injections of typhoid (inflammatory challenge) or saline (placebo) in a randomised, double-blind, crossover design, before completing heartbeat tracking tasks. Three interoception dimensions were examined: subjective sensibility, objective accuracy and metacognitive awareness. Interoceptive trait prediction error was calculated as discrepancy between accuracy and sensibility.
Patients with fibromyalgia and ME/CFS had significantly higher interoceptive sensibility and trait prediction error, despite no differences in interoceptive accuracy. Interoceptive sensibility and trait prediction error correlated with all self-report pain, fatigue and anxiety measures, and with lower pain thresholds. Anxiety mediated the positive-predictive relationships between pain (Visual Analogue Scale and Widespread Pain Index), fatigue impact and interoceptive sensibility. After inflammatory challenge, metacognitive awareness correlated with baseline self-reported symptom measures and lower pain thresholds.
This is the first study investigating interoceptive dimensions in patients with fibromyalgia and ME/CFS, which were found to be dysregulated and differentially influenced by inflammatory mechanisms. Interoceptive processes may represent a new potential target for diagnostic and therapeutic investigation in these poorly understood conditions.
This chapter comprises the following sections: names, taxonomy, subspecies and distribution, descriptive notes, habitat, movements and home range, activity patterns, feeding ecology, reproduction and growth, behavior, parasites and diseases, status in the wild, and status in captivity.
Attitudes, and in some cases legislation, make it decreasingly acceptable to admit people younger than 18 years to adult psychiatric inpatient units. One strategy to reduce the number of under 18s admitted to adult psychiatric units is the commissioning of specialist Child and Adolescent Mental Health (CAMHS) inpatient units.
Map the flow of admissions toacute adult psychiatric inpatient units and paediatric medical units in the years before and after the opening of specialist CAMHS inpatient units.
Determine if opening CAMHS inpatient increases or decreases the flow of admissions to acute adult psychiatric inpatient units and paediatric medical units
Analysis of statewide admission data for under 18s to specialist CAMHS inpatient units, acute adult psychiatric inpatient units, and paediatric medical units for the period January 2001 to December 2013 in New South Wales, Australia.
Five of 8 health districts experienced an increase in juvenile admissions to adult units in the year of opening a CAMHS unit. Admissions to related paediatric medical units increased in 3 of 7 health districts. Admissions to adult and paediatric units rose with time but there was no interaction between time and health district type (with/without CAMHS unit).
Opening CAMHS units may temporarily increase the number of juveniles admitted to adult units, but does not influence the flow of patients to non-CAMHS facilities in the longer term. CAMHS units appear to fulfil an additional as opposed to replacement role in the care pathway for young people with mental illness.
Self-screening using an electronic version of the Malnutrition Universal Screening Tool (‘MUST’) has been developed but its implementation requires investigation. A total of 100 outpatients (mean age 50 (sd 16) years; 57 % male) self-screened with an electronic version of ‘MUST’ and were then screened by a healthcare professional (HCP) to assess concurrent validity. Ease of use, time to self-screen and prevalence of malnutrition were also assessed. A further twenty outpatients (mean age 54 (sd 15) years; 55 % male) examined preference between self- screening with paper and electronic versions of ‘MUST’. For the three-category classification of ‘MUST’ (low, medium and high risk), agreement between electronic self-screening and HCP screening was 94 % (κ=0·74, se 0·092; P<0·001). For the two-category classification (low risk; medium+high risk) agreement was 96 % (κ=0·82, se 0·085; P<0·001), comparable with the previously reported paper-based self-screening. In all, 15 % of patients categorised themselves ‘at risk’ of malnutrition (5 % medium, 10 % high). Electronic self-screening took 3 min (sd 1·2 min), 40 % faster than previously reported for the paper-based version. Patients found the tool easy or very easy to understand (99 %) and complete (98 %). Patients that assessed both tools found the electronic tool easier to complete (65 %) and preferred it (55 %) to the paper version. Electronic self-screening using ‘MUST’ in a heterogeneous group of hospital outpatients is acceptable, user-friendly and has ‘substantial to almost-perfect’ agreement with HCP screening. The electronic format appears to be as agreeable and often the preferred format when compared with the validated paper-based ‘MUST’ self-screening tool.
Recent findings highlight that there are prenatal risks for affective disorders that are mediated by glucocorticoid mechanisms, and may be specific to females. There is also evidence of sex differences in prenatal programming mechanisms and developmental psychopathology, whereby effects are in opposite directions in males and females. As birth weight is a risk for affective disorders, we sought to investigate whether maternal prenatal cortisol may have sex-specific effects on fetal growth. Participants were 241 mothers selected from the Wirral Child Health and Development Study (WCHADS) cohort (n=1233) using a psychosocial risk stratifier, so that responses could be weighted back to the general population. Mothers provided saliva samples, which were assayed for cortisol, at home over 2 days at 32 weeks gestation (on waking, 30-min post-waking and during the evening). Measures of infant birth weight (corrected for gestational age) were taken from hospital records. General population estimates of associations between variables were obtained using inverse probability weights. Maternal log of the area under the curve cortisol predicted infant birth weight in a sex-dependent manner (interaction term P=0.029). There was a positive and statistically significant association between prenatal cortisol in males, and a negative association in females that was not statistically significant. A sex interaction in the same direction was evident when using the waking (P=0.015), and 30-min post-waking (P=0.013) cortisol, but not the evening measure. There was no interaction between prenatal cortisol and sex to predict gestational age. Our findings add to an emerging literature that suggests that there may be sex-specific mechanisms that underpin fetal programming.
Arbitration has long been the default mechanism for resolving international investment disputes. The traditional consensus favoring arbitration, however, has now given way, and reform proposals abound. The articles by Sergio Puig and Gregory Shaffer, on institutional choice and investment law reform, and by Anthea Roberts, on incremental, systemic, and paradigmatic reform of investor-state arbitration, helpfully situate the current controversies, debates, and reform options for states. Both articles reveal just how far and fast the debate has shifted in recent years. They also confirm states’ desire to exercise greater control over the regime for resolving international investment disputes. Many states continue to struggle to fully comply with their investment treaty obligations, to efficiently defend against investor claims, and to properly keep abreast of and shape developments in international investment law. Puig and Shaffer provide a useful framework for comparatively assessing possible institutional alternatives in light of their relative trade-offs. But any reform recommendations should draw lessons from states’ experience with the existing regime, including states’ significant problems of capacity. The merits of any reform proposals, therefore, should be measured in part by their ability to improve states’ capacity to cope with the existing investment protection regime and rapidly changing developments.
The discovery of the first electromagnetic counterpart to a gravitational wave signal has generated follow-up observations by over 50 facilities world-wide, ushering in the new era of multi-messenger astronomy. In this paper, we present follow-up observations of the gravitational wave event GW170817 and its electromagnetic counterpart SSS17a/DLT17ck (IAU label AT2017gfo) by 14 Australian telescopes and partner observatories as part of Australian-based and Australian-led research programs. We report early- to late-time multi-wavelength observations, including optical imaging and spectroscopy, mid-infrared imaging, radio imaging, and searches for fast radio bursts. Our optical spectra reveal that the transient source emission cooled from approximately 6 400 K to 2 100 K over a 7-d period and produced no significant optical emission lines. The spectral profiles, cooling rate, and photometric light curves are consistent with the expected outburst and subsequent processes of a binary neutron star merger. Star formation in the host galaxy probably ceased at least a Gyr ago, although there is evidence for a galaxy merger. Binary pulsars with short (100 Myr) decay times are therefore unlikely progenitors, but pulsars like PSR B1534+12 with its 2.7 Gyr coalescence time could produce such a merger. The displacement (~2.2 kpc) of the binary star system from the centre of the main galaxy is not unusual for stars in the host galaxy or stars originating in the merging galaxy, and therefore any constraints on the kick velocity imparted to the progenitor are poor.
I want to consider the European Commission's proposed multilateral investment court as an international claims tribunal. The commission is not promoting its investment court as a claims tribunal, but that is essentially what it is. The commission seeks to establish a mechanism to allow foreign investors to submit future disputes under international law to binding dispute resolution before a standing tribunal. The proposed court differs from most claims tribunals, as it is intended to be multilateral and to apply to future disputes. But that is what makes the proposal so interesting and potentially useful.
Postnatal depression affects about 10–15% of women in the year after giving birth. Many women and healthcare professionals would like an effective and accessible non-pharmacological treatment for postnatal depression.
Women who fulfilled the International Classification of Diseases (ICD)-10 criteria for major depression in the first 6 months postnatally were randomized to receive usual care plus a facilitated exercise intervention or usual care only. The intervention involved two face-to-face consultations and two telephone support calls with a physical activity facilitator over 6 months to support participants to engage in regular exercise. The primary outcome was symptoms of depression using the Edinburgh Postnatal Depression Scale (EPDS) at 6 months post-randomization. Secondary outcomes included EPDS score as a binary variable (recovered and improved) at 6 and 12 months post-randomization.
A total of 146 women were potentially eligible and 94 were randomized. Of these, 34% reported thoughts of self-harming at baseline. After adjusting for baseline EPDS, analyses revealed a −2.04 mean difference in EPDS score, favouring the exercise group [95% confidence interval (CI) −4.11 to 0.03, p = 0.05]. When also adjusting for pre-specified demographic variables the effect was larger and statistically significant (mean difference = −2.26, 95% CI −4.36 to −0.16, p = 0.03). Based on EPDS score a larger proportion of the intervention group was recovered (46.5% v. 23.8%, p = 0.03) compared with usual care at 6 months follow-up.
This trial shows that an exercise intervention that involved encouragement to exercise and to seek out social support to exercise may be an effective treatment for women with postnatal depression, including those with thoughts of self-harming.
Cellular networks are ubiquitous in nature. Most engineered materials are polycrystalline microstructures composed of a myriad of small grains separated by grain boundaries, thus comprising cellular networks. The recently discovered grain boundary character distribution (GBCD) is an empirical distribution of the relative length (in 2D) or area (in 3D) of interface with a given lattice misorientation and normal. During the coarsening, or growth, process, an initially random grain boundary arrangement reaches a steady state that is strongly correlated to the interfacial energy density. In simulation, if the given energy density depends only on lattice misorientation, then the steady state GBCD and the energy are related by a Boltzmann distribution. This is among the simplest non-random distributions, corresponding to independent trials with respect to the energy. Why does such simplicity emerge from such complexity? Here we describe an entropy based theory which suggests that the evolution of the GBCD satisfies a Fokker-Planck Equation, an equation whose stationary state is a Boltzmann distribution.
In North America, terrestrial records of biodiversity and climate change that span Marine Oxygen Isotope Stage (MIS) 5 are rare. Where found, they provide insight into how the coupling of the ocean–atmosphere system is manifested in biotic and environmental records and how the biosphere responds to climate change. In 2010–2011, construction at Ziegler Reservoir near Snowmass Village, Colorado (USA) revealed a nearly continuous, lacustrine/wetland sedimentary sequence that preserved evidence of past plant communities between ~140 and 55 ka, including all of MIS 5. At an elevation of 2705 m, the Ziegler Reservoir fossil site also contained thousands of well-preserved bones of late Pleistocene megafauna, including mastodons, mammoths, ground sloths, horses, camels, deer, bison, black bear, coyotes, and bighorn sheep. In addition, the site contained more than 26,000 bones from at least 30 species of small animals including salamanders, otters, muskrats, minks, rabbits, beavers, frogs, lizards, snakes, fish, and birds. The combination of macro- and micro-vertebrates, invertebrates, terrestrial and aquatic plant macrofossils, a detailed pollen record, and a robust, directly dated stratigraphic framework shows that high-elevation ecosystems in the Rocky Mountains of Colorado are climatically sensitive and varied dramatically throughout MIS 5.
During catastrophic disasters, government leaders must decide how to efficiently and effectively allocate scarce public health and medical resources. The literature about triage decision making at the individual patient level is substantial, and the National Response Framework provides guidance about the distribution of responsibilities between federal and state governments. However, little has been written about the decision-making process of federal leaders in disaster situations when resources are not sufficient to meet the needs of several states simultaneously. We offer an ethical framework and logic model for decision making in such circumstances. We adapted medical triage and the federalism principle to the decision-making process for allocating scarce federal public health and medical resources. We believe that the logic model provides a values-based framework that can inform the gestalt during the iterative decision process used by federal leaders as they allocate scarce resources to states during catastrophic disasters. (Disaster Med Public Health Preparedness. 2014;0:1–10)
A primary goal of the International Law Commission’s work on the identification of customary international law is to offer “guidance to those called upon to identify the existence of a rule of customary international law,” particularly national court judges. The ILC report, however, should be no less useful to participants in international adjudication. The report’s impact might be particularly significant in investment arbitration, which, given the field’s growing importance and impact, could greatly facilitate the ILC’s principal mandate of promoting the “progressive development of international law.”
Investment arbitration is proving hugely significant for the development of international law. The United Nations Conference on Trade and Development reported that, at the end of last year, there were 568 known cases brought under international investment agreements, including 57 cases brought in 2013 alone. There have been 98 different State respondents, including the United States, which reportedly is the ninth most frequent respondent State.