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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.
As the Global Financial Crisis has demonstrated, any complex system is vulnerable to fragility without purpose and vigilance. The tentacles of the finance industry traverse state boundaries. They create moral and economic hazards as well as opportunities. Each poses legitimacy and authority implications. Failure to address those threats have contributed to a populist turn, which poses the risk of further policy uncertainty and instability. Responding to this crisis through resilience as either metaphor or organising framework is, however, problematic. This chapter argues that notwithstanding its increasing usage by international bodies such as the G20, resilience is not a neutral concept. Privileging resilience as an end in itself may prove counterproductive unless underpinned by a normative reset of the purpose of the corporation and the market, and the duties and responsibilities each owe to society. It concludes that without clear definition of purpose, and accountability, regulatory structural form is irrelevant, as demonstrated by the failure and ineffectiveness of the Twin Peaks model in Australia.
This chapter explores the Twin Peaks legal and regulatory framework in Australia, the challenges that have arisen in areas such as coordination and functional separation between the Twin Peaks regulators and the outcomes from numerous reviews in which the model has been subject to scrutiny. It explores the evolution of the Twin Peaks model in Australia and certain challenges that have arisen in governance, information-sharing and coordination, and funding arrangements. It then surveys the terrain in Australia by outlining the recommendations from a review of the financial system in 2014, the Financial System Inquiry (FSI), and subsequent recommendations and reforms, including those proposed by or arising out of the Royal Commission into Misconduct in the Banking, Superannuation and Financial Services Industry.
Ethnohistoric accounts indicate that the people of Australia's Channel Country engaged in activities rarely recorded elsewhere on the continent, including food storage, aquaculture and possible cultivation, yet there has been little archaeological fieldwork to verify these accounts. Here, the authors report on a collaborative research project initiated by the Mithaka people addressing this lack of archaeological investigation. The results show that Mithaka Country has a substantial and diverse archaeological record, including numerous large stone quarries, multiple ritual structures and substantial dwellings. Our archaeological research revealed unknown aspects, such as the scale of Mithaka quarrying, which could stimulate re-evaluation of Aboriginal socio-economic systems in parts of ancient Australia.
Approved treatments for bipolar depression are limited and associated with a spectrum of undesirable side effects. Lumateperone (lumateperone tosylate, ITI−007), a mechanistically novel antipsychotic that simultaneously modulates serotonin, dopamine, and glutamate neurotransmission, is FDA-approved for the treatment of schizophrenia. Lumateperone is currently being investigated for the treatment of bipolar depression (major depressive episodes [MDE] associated with bipolar I and bipolar II disorder). This Phase 3 randomized, double-blind, parallel-group, placebo-controlled multinational study (NCT03249376) investigated the efficacy and safety of lumateperone in patients with bipolar I or bipolar II disorder experiencing a MDE.
Patients (18 75 years) with a clinical diagnosis of bipolar I or bipolar II disorder who were experiencing a MDE (Montgomery-Åsberg Depression Rating Scale [MADRS] Total score =20 and a Clinical Global Impression Scale-Bipolar Version-Severity [CGI-BP-S] score =4 at screening and baseline) were randomized to lumateperone 42mg or placebo for 6 weeks. The primary and key secondary efficacy endpoints were change from baseline to Day 43 in MADRS total score and CGI-BP-S scores, respectively. Secondary efficacy outcomes included response (MADRS improvement = 50%) and remission (MADRS total score =12) at Day 43. Safety assessments included treatment emergent adverse events, laboratory parameters, vital signs, extrapyramidal symptoms (EPS), and suicidality.
In this study, 377 patients received treatment (placebo, n=189; lumateperone 42mg, n=188) and 333 completed treatment. Patients in the lumateperone 42-mg group had significantly greater mean improvement on MADRS total score change from baseline to Day 43 compared with placebo (least squares mean difference [LSMD]=-4.6; 95% confidence interval [CI]=-6.34, −2.83; effect size vs placebo [ES]=-0.56; P<.0001). Lumateperone treatment was associated with significant MADRS improvement in both patients with bipolar I (LSMD=-4.0; 95% CI=-5.92, −1.99; ES=-0.49; P<.0001) and bipolar II (LSMD=-7.0; 95% CI=-10.92, −3.16; ES=-0.81; P=.0004). The lumateperone 42-mg group also had significantly greater mean improvement in CGI-BP-S total score compared with placebo (LSMD=-0.9; 95% CI=-1.37, −0.51; ES=-0.46; P<.001). Lumateperone compared with placebo had significantly greater MADRS response rate (51.1% vs 36.7%; odds ratio=2.98; P<.001) and remission rates (P=.02) at Day 43. Lumateperone treatment was well tolerated, with minimal risk of EPS, metabolic, and prolactin side effects.
Lumateperone 42 mg significantly improved depression symptoms in both patients with bipolar I and bipolar II depression. Lumateperone was generally well tolerated. These results suggest that lumateperone 42 mg may be a promising new treatment for bipolar depression associated with bipolar I or bipolar II disorder.
Previous results have been mixed regarding the role of the apolipoprotein E e4 (APOE e4) allele in later-life depression: some studies note that carriers experience greater symptoms and increased risk while others find no such association. However, there are few prospective, population-based studies of the APOE e4-depression association and fewer that examine depressive symptom trajectory and depression risk longitudinally. We examined the association between APOE e4 allele status and longitudinal change in depressive symptoms and depression risk in later-life, over a 12-year follow-up period.
We used data from 690 participants of the Lothian Birth Cohort 1936 who took part in the Scottish Mental Survey 1947 (aged 11) and were followed-up in later-life over five waves from 2004 to 2019 (aged 70–82). We used APOE e4 allele status to predict longitudinal change in depressive symptom scores and risk of depression (defined by a symptom score threshold or use of depression-related medication). Models were adjusted for sex, childhood cognitive ability, childhood social class, education, adult social class, smoking status and functional limitations at baseline.
Depressive symptom scores increased with age. Once adjusted for covariates, APOE e4 allele status did not significantly predict symptom score trajectories or depression risk. Greater functional limitations at baseline significantly predicted poorer symptom score trajectories and increased depression risk (defined by medications). APOE e4 allele status did not significantly moderate the contribution of sex, education or functional limitations.
There was no evidence that APOE e4 carriers experience an increased risk for later-life depression.
The National Institute for Health and Care Excellence (NICE) informs us that the first-line treatments for behavioural and psychological symptoms of dementia (BPSD) are non-pharmacological. Although psychotropics used to be the main strategy in the management of behaviours that challenge, there has been an increase in the use of biopsychosocial formulations since 2010, and there are now over a dozen to choose from. However, many are overly focused on obtaining information about the agitation, and less specific about providing details of the actions required to manage the behaviours. The NICE guidelines too fail to provide specific guidance on which non-pharmacological approaches to use. This article argues for giving equal weight to both the collection of meaningful information and the development of ‘informed actions’, because it is the actions that lead to change. The article outlines a management programme providing a framework for the assessment, formulation and treatment of agitation in dementia. The work draws on theory, evidence-based practice and practice-based evidence to provide a model with sufficient structure and flexibility to be useful for clinicians across a range of settings and professional groups.
The First World War led to the largest boom in published American war books since the Civil War. War memoirs were popular with both publishers and readers alike. Hundreds of returning doughboys took to their pens and published accounts of fighting in France. Joining them were books by nurses and canteen workers who also told stories of their experiences at the front supporting the Allied war effort. This chapter examines war memoirs published both during and after the war. It considers trends in martial publishing and argues that the wealth of war-relating writing created a cultural footprint of American war books that rested somewhat uneasily as feelings about the First World War changed in the 1920s. Moreover, the variety of war memoirs released further complicates notions of a uniform American experience in print. Rather, there is tension between books celebrating American and Allied victory with those that emphasize the hard-fought realities of combat on the western front.
The devastating toll of gun violence has given rise to hundreds of lawsuits seeking justice on behalf of victims and their families. A significant number of challenges against gun companies, however, are blocked by courts' broad reading of the Protection of Lawful Commerce in Arms Act (PLCAA) — a federal statute often interpreted to shield the gun industry from civil liability. This article reexamines PLCAA in light of the Supreme Court's recent federalism caselaw, which counsels courts to narrowly construe federal laws that could otherwise upset the balance of power between states and the federal government. Since PLCAA infringes on traditional areas of state authority, the Supreme Court's federalism jurisprudence requires lower courts to interpret PLCAA narrowly, to not bar states from imposing negligence, nuisance, product liability, or other common law liability on gun companies. Reading PLCAA in line with federalism principles would preserve states' traditional authority over their civil justice laws, and enable gun violence victims, and their families, to hold gun companies responsible for wrongdoing.
The Rapid ASKAP Continuum Survey (RACS) is the first large-area survey to be conducted with the full 36-antenna Australian Square Kilometre Array Pathfinder (ASKAP) telescope. RACS will provide a shallow model of the ASKAP sky that will aid the calibration of future deep ASKAP surveys. RACS will cover the whole sky visible from the ASKAP site in Western Australia and will cover the full ASKAP band of 700–1800 MHz. The RACS images are generally deeper than the existing NRAO VLA Sky Survey and Sydney University Molonglo Sky Survey radio surveys and have better spatial resolution. All RACS survey products will be public, including radio images (with
15 arcsec resolution) and catalogues of about three million source components with spectral index and polarisation information. In this paper, we present a description of the RACS survey and the first data release of 903 images covering the sky south of declination
made over a 288-MHz band centred at 887.5 MHz.
Fast pixelated detectors incorporating direct electron detection (DED) technology are increasingly being regarded as universal detectors for scanning transmission electron microscopy (STEM), capable of imaging under multiple modes of operation. However, several issues remain around the post-acquisition processing and visualization of the often very large multidimensional STEM datasets produced by them. We discuss these issues and present open source software libraries to enable efficient processing and visualization of such datasets. Throughout, we provide examples of the analysis methodologies presented, utilizing data from a 256 × 256 pixel Medipix3 hybrid DED detector, with a particular focus on the STEM characterization of the structural properties of materials. These include the techniques of virtual detector imaging; higher-order Laue zone analysis; nanobeam electron diffraction; and scanning precession electron diffraction. In the latter, we demonstrate a nanoscale lattice parameter mapping with a fractional precision ≤6 × 10−4 (0.06%).
Dialysis patients may not have access to conventional renal replacement therapy (RRT) following disasters. We hypothesized that improvised renal replacement therapy (ImpRRT) would be comparable to continuous renal replacement therapy (CRRT) in a porcine acute kidney injury model.
Following bilateral nephrectomies and 2 hours of caudal aortic occlusion, 12 pigs were randomized to 4 hours of ImpRRT or CRRT. In the ImpRRT group, blood was circulated through a dialysis filter using a rapid infuser to collect the ultrafiltrate. Improvised replacement fluid, made with stock solutions, was infused pre-pump. In the CRRT group, commercial replacement fluid was used. During RRT, animals received isotonic crystalloids and norepinephrine.
There were no differences in serum creatinine, calcium, magnesium, or phosphorus concentrations. While there was a difference between groups in serum potassium concentration over time (P < 0.001), significance was lost in pairwise comparison at specific time points. Replacement fluids or ultrafiltrate flows did not differ between groups. There were no differences in lactate concentration, isotonic crystalloid requirement, or norepinephrine doses. No difference was found in electrolyte concentrations between the commercial and improvised replacement solutions.
The ImpRRT system achieved similar performance to CRRT and may represent a potential option for temporary RRT following disasters.
Marine-terminating glaciers, such as those along the coastline of Greenland, often release meltwater into the ocean in the form of subglacial discharge plumes. Though these plumes can dramatically alter the mass loss along the front of a glacier, the conditions surrounding their genesis remain poorly constrained. In particular, little is known about the geometry of subglacial outlets and the extent to which seawater may intrude into them. Here, the latter is addressed by exploring the dynamics of an arrested salt wedge – a steady-state, two-layer flow system where salty water partially intrudes a channel carrying fresh water. Building on existing theory, we formulate a model that predicts the length of a non-entraining salt wedge as a function of the Froude number, the slope of the channel and coefficients for interfacial and wall drag. In conjunction, a series of laboratory experiments were conducted to observe a salt wedge within a rectangular channel. For experiments conducted with laminar flow (Reynolds number $Re<800$), good agreement with theoretical predictions are obtained when the drag coefficients are modelled as being inversely proportional to $Re$. However, for fully turbulent flows on geophysical scales, these drag coefficients are expected to asymptote toward finite values. Adopting reasonable drag coefficient estimates for this flow regime, our theoretical model suggests that typical subglacial channels may permit seawater intrusions of the order of several kilometres. While crude, these results indicate that the ocean has a strong tendency to penetrate subglacial channels and potentially undercut the face of marine-terminating glaciers.
Here, the authors report a detailed method of growing LaAlGe, a nonmagnetic Weyl semimetal, thin film on silicon(100) substrates by molecular beam epitaxy and their structural and electrical characterizations. About 50-nm-thick LaAlGe films were deposited and annealed for 16 h in situ at a temperature of 793 K. As-grown high-quality films showed uniform surface topography and near ideal stoichiometry with a body-centered tetragonal crystal structure. Temperature-dependent longitudinal resistivity can be understood with dominant interband s–d electron–phonon scattering in the temperature range of 5–40 K. Hall measurements confirmed the semimetallic nature of the films with an electron-dominated charge carrier density of ~7.15 × 1021 cm−3 at 5 K.
The Antarctic Impulsive Transient Antenna (ANITA) balloon experiment was designed to detect radio signals initiated by high-energy neutrinos and cosmic ray (CR) air showers. These signals are typically discriminated by the polarization and phase inversions of the radio signal. The reflected signal from CRs suffer phase inversion compared to a direct ‘tau neutrino’ event. In this paper, we study subsurface reflection, which can occur without phase inversion, in the context of the two anomalous up-going events reported by ANITA. It is found that subsurface layers and firn density inversions may plausibly account for the events, while ice fabric layers and wind ablation crusts could also play a role. This hypothesis can be tested with radar surveying of the Antarctic region in the vicinity of the anomalous ANITA events. Future experiments should not use phase inversion as a sole criterion to discriminate between down-going and up-going events, unless the subsurface reflection properties are well understood.
Theoretical calculations and experimental observations show MoTe2 is a type II Weyl semimetal, along with many members of transition metal dichalcogenides family. We have grown highly crystalline large-area MoTe2 thin films on Si/SiO2 substrates by chemical vapor deposition. Very uniform, continuous, and smooth films were obtained as confirmed by scanning electron microscopy and atomic force microscopy analyses. Measurements of the temperature dependence of longitudinal resistivity and current–voltage characteristics at different temperature are discussed. Unsaturated, positive quadratic magnetoresistance of the as-grown thin films has been observed from 10 to 200 K. Hall resistivity measurements confirm the majority charge carriers are hole.
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 authors report on pulsed laser powder bed fusion fabrication of nitinol (NiTi) shape memory materials. The authors first performed single-track laser parameter sweeps to assess melt pool stability and determine energy parameters and hatch spacing for larger builds. The authors then assessed the melt pool chemistry as a function of laser energy density and build plate composition. Brittle intermetallics were found to form at the part/build plate interface for both N200 and Ti-6-4 substrates. The intermetallic formation was reduced by building on a 50Ni–50Ti substrate, but delamination still occurred due to thermal stresses upon cooling. The authors were able to overcome delamination on all substrates and fabricate macroscopic parts by building a lattice support structure, which is both compliant and controls heat transfer into the build plate. This approach will enable scalable fabrication of complex NiTi parts.