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Accurate diagnosis of bipolar disorder (BPD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A depressive episode often precedes the first manic episode, making it difficult to distinguish BPD from unipolar major depressive disorder (MDD).
Aims
We use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores (PRS) that may aid early differential diagnosis.
Method
Based on individual genotypes from case–control cohorts of BPD and MDD shared through the Psychiatric Genomics Consortium, we compile case–case–control cohorts, applying a careful quality control procedure. In a resulting cohort of 51 149 individuals (15 532 BPD patients, 12 920 MDD patients and 22 697 controls), we perform a variety of GWAS and PRS analyses.
Results
Although our GWAS is not well powered to identify genome-wide significant loci, we find significant chip heritability and demonstrate the ability of the resulting PRS to distinguish BPD from MDD, including BPD cases with depressive onset (BPD-D). We replicate our PRS findings in an independent Danish cohort (iPSYCH 2015, N = 25 966). We observe strong genetic correlation between our case–case GWAS and that of case–control BPD.
Conclusions
We find that MDD and BPD, including BPD-D are genetically distinct. Our findings support that controls, MDD and BPD patients primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BPD and, importantly, BPD-D from MDD.
This study reveals the usefulness of multiple correlation techniques in estimating the relative importance of different aspects of a tracking task in the operator's tracking behavior. The technique is applied to a compensatory tracking task with a position control.
Pottery vessels played a central role in the processing, storage and transport of animal and plant products by prehistoric and historic peoples with their chemical residues surviving for thousands of years. Accurate radiocarbon dating of archaeological pottery vessels by isolating reliable sources of carbon relating to the use of pots has long been a major challenge, but is now possible using compound-specific radiocarbon analysis of absorbed organic residues preserved in the ceramic fabric of the vessel wall. This method involves the radiocarbon dating of single fatty acids most commonly derived from degraded animal fats. These compounds are extracted from the ceramic matrix and isolated from potentially interfering compounds using preparative capillary gas chromatography. When coupled with lipid biomarker and compound-specific stable carbon isotope analyses, this method enables the palaeodietary and chronological information contained in archaeological lipids preserved in ceramic vessels to be interpreted together. From a practical perspective the methodology is challenging and for successful application must adhere to rigorous protocols. We present here guidelines which include (i) consideration of pottery selection, (ii) technical parameters for the isolation of fatty acids then their 14C dating and calibration, and (iii) case studies selected to illustrate the best use of this method.
In the early stages of Thomas Rowlandson’s printmaking career, at least ninety of his prints are known to have been issued by women publishers, including Elizabeth Jackson, Hannah Humphrey, Elizabeth d’Achery, and Eleanor Lay. Of these, Jackson in particular had an important role in establishing his printmaking. The full extent of her production, for a long time obscured by the later sale of her plates to Samuel Fores, is only just emerging; several recent new discoveries suggest an even wider involvement by her in Rowlandson’s early non-satirical prints. While there is relatively little to be found in the historical record about these enterprising women, evidence from the prints shows the women were successful entrepreneurs, commissioning their own caricature output and collaborating commercially with other printsellers. Another figure of particular interest is Rowlandson’s younger sister Elizabeth, who, after her separation from her husband, the artist Samuel Howitt, also operated as a printseller for over twenty years. She was also an artist and even made a few caricature prints herself after her brother’s drawings, some of which are identified here for the first time.
Studies on the transport of deer (Cervidae), in the UK, were published > 15 years ago. A more recent study of deer transport is required to allow for assessments and improvements to the transport of farmed deer. Sixteen deer farmers participated in a survey describing their management practices related to transport. Their responses showed that most vehicles used to transport deer were designed for other livestock. Participating farmers estimated journey times to slaughter as 1–8 h, with an arithmetic mean of 4.8 (± 2.38) h. Specific concerns raised by the respondents, relating to the transport of deer, included a need for deer-specific vehicles, stop-off areas for long journeys, market locations and haulier experience. Furthermore, data were collected from two abattoirs between July 2019 and June 2020 comprising journey times, slaughter times, bruising, location of origin, vehicle type and the number of animals. In total, 4,922 deer were transported across 133 journeys (from farm to abattoir) from 61 farms. Median and range for journey length were 3.2 (0.4–9.8) h and 154.2 (7.1–462.2) km, whereas group size and time spent in the lairage were 24 (1–121) and 17.8 (10.2–68.9) h, respectively. Group size was found to be significantly associated with both the presence of bruising in a group and the amount of bruising per deer. This study provides a much-needed update on the transport of farmed deer in the UK and highlights key areas for future research including the welfare impact of transport in larger groups and for longer durations.
In Great Britain, more than eleven million animals are transported to or from livestock markets annually. Time spent at markets is considered by Defra (Department of Environment, Food and Rural Affairs) to be ‘neutral time’, ie potentially a rest period. However, sheep in markets are subject to many potential stressors, which may prevent them resting. Lying and ruminating behaviours were analysed from 1,638 behavioural scans of sheep in 279 pens in 23 markets across Great Britain. Likelihood of observing ≥ 1 animals lying down during a scan decreased as stocking density and activity outside the pen increased. Proportion of animals observed lying in a pen (when at least one animal was lying) increased as group size and stocking rate decreased. Likelihood of observing ≥ 1 animals ruminating increased when there was no activity around the pen, and as number of sheep in the pen increased. Proportion of animals observed ruminating in a pen (when at least one animal was ruminating) increased as stocking rate, number of sheep in the pen and activity outside the pen decreased. Proportion of sheep ruminating was greater where there was no activity, compared with where there was activity outside the pen. We suggest that in order to allow higher quality rest periods for sheep in markets, then markets should be organised so that activity around the pen is minimised, eg by filling the market from back to front so that, once penned, sheep are not passed repeatedly. Stocking densities should also be low enough to allow animals to lie if they wish, while groups sizes should not be so low as to increase fear responses.
The maintenance of head-only minimum stunning currents for sheep to ≥ 1.0 Amp as per current legislation was examined in two trials in a commercial abattoir. In the first trial, a Jetco MS100 stunner failed to maintain the current to > 1.0 Amp in 118 of the 228 sheep. In a second trial, a Jetco MS105 delivered sufficient current in all sheep (n = 275) to meet the legislative requirement, apart from a single animal. Recorded electrocardiograms showed a regular heartbeat, with no evidence of ventricular fibrillation, in all animals in both trials following stunning and neck-cut. Only one of the two stun units may therefore be considered to meet the statutory requirements but both may meet the requirements for halal slaughter where pre-stun is considered acceptable.
Malnutrition is common in the acute care setting. Despite the existence of a plethora of screening tools, many malnourished patients remain undiagnosed and untreated, in part due to competing responsibilities for screening staff, under- or over-referral to dietetics services, and inadequate dietetics resources. Better identification of patients at risk of malnutrition would enable optimised care provision and streamlined care pathways. This narrative review of reviews aimed to collate and synthesise literature documenting nutritional risk factors in adult hospital inpatients, to generate a comprehensive list of nutritional risk indicators from high methodological quality review articles. Six electronic databases were searched (Medline, Cumulative Index to Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, Joanna Briggs Institute Database, Embase and Scopus) using a systematic search strategy. Three researchers screened the resulting 5889 citations, identifying 59 reviews summarising original studies that investigated associations between indicators and measures of malnutrition, undernutrition or nutritional risk. After quality appraisal by two researchers, using the American Dietetic Association Quality Criteria Checklist for Review Articles, seven reviews were classified as high quality, identifying fifty-seven unique indicators of nutritional risk (disease status/condition – twenty-three; eating/appetite/digestion – twelve; type of diet – five; cognition/psychology/social factors – five; medication-related – two; miscellaneous – ten). This is the first comprehensive list of nutritional risk factors in adult hospital inpatients, derived from only the highest methodological quality reviews. This list contributes to the development of practice and evidence-informed systems-level approaches to the identification of nutritional risk in the acute care setting.
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.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
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.
Results
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.
Conclusions
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.
The analysis of processing standards alongside samples for quality assurance in radiocarbon (14C) analyses is critical. Ideally, these standards should be similar both in nature and age to unknown samples. A new compound-specific approach was developed at the University of Bristol for dating pottery vessels using palmitic and stearic fatty acids extracted from within the clay matrix and isolated by preparative capillary gas chromatography. Obtaining suitable potsherds for use as processing standards in such analyses is not feasible, so we suggest that bog butter represents an ideal material for such purposes. We sampled ca. 450 g from two bog butter specimens and homogenized them by melting. We verified the homogeneity of both specimens by characterization of their lipid composition, δ13C values of individual lipids, and both bulk- and compound-specific radiocarbon analyses on 10 sub-samples of each bog butter specimen. The weighted means of all 14C measurements on the bog butter standards are 3777 ± 4 BP (IB33) and 338 ± 3 BP (IB38), thereby providing age-relevant standards for archaeological and historical fatty acids and ensuring the accuracy of radiocarbon determinations of lipids using a compound-specific approach. These new secondary standards will be subjected to an intercomparison exercise to provide robust consensus values.
The first demonstration of laser action in ruby was made in 1960 by T. H. Maiman of Hughes Research Laboratories, USA. Many laboratories worldwide began the search for lasers using different materials, operating at different wavelengths. In the UK, academia, industry and the central laboratories took up the challenge from the earliest days to develop these systems for a broad range of applications. This historical review looks at the contribution the UK has made to the advancement of the technology, the development of systems and components and their exploitation over the last 60 years.
Questions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation.
Methods
Using data from 9,421 individuals aged 8–21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation.
Results
Externalizing was heritable (h2 = 0.46, p = 1 × 10−6), but not anxious-misery (h2 = 0.09, p = 0.183), fear (h2 = 0.04, p = 0.337), psychosis-spectrum (h2 = 0.00, p = 0.494), or general psychopathology (h2 = 0.21, p = 0.040). Externalizing showed genetic overlap with face memory (ρg = −0.412, p = 0.004), verbal reasoning (ρg = −0.485, p = 0.001), spatial reasoning (ρg = −0.426, p = 0.010), motor speed (ρg = 0.659, p = 1x10−4), verbal knowledge (ρg = −0.314, p = 0.002), and general cognitive ability (g)(ρg = −0.394, p = 0.002). Gene × Age analyses revealed decreasing genetic variance (γg = −0.146, p = 0.004) and increasing environmental variance (γe = 0.059, p = 0.009) on externalizing.
Conclusions
Cognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.
Chaperones protect other proteins against misfolding and aggregation, a key requirement for maintaining biological function. Experimental observations of changes in solubility of amyloid proteins in the presence of certain chaperones are discussed here in terms of thermodynamic driving forces. We outline how chaperones can enhance amyloid solubility through the formation of heteromolecular aggregates (co-aggregates) based on the second law of thermodynamics and the flux towards equal chemical potential of each compound in all phases of the system. Higher effective solubility of an amyloid peptide in the presence of chaperone implies that the chemical potential of the peptide is higher in the aggregates formed under these conditions compared to peptide-only aggregates. This must be compensated by a larger reduction in chemical potential of the chaperone in the presence of peptide compared to chaperone alone. The driving force thus relies on the chaperone being very unhappy on its own (high chemical potential), thus gaining more free energy than the amyloid peptide loses upon forming the co-aggregate. The formation of heteromolecular aggregates also involves the kinetic suppression of the formation of homomolecular aggregates. The unhappiness of the chaperone can explain the ability of chaperones to favour an increased population of monomeric client protein even in the absence of external energy input, and with broad client specificity. This perspective opens for a new direction of chaperone research and outlines a set of outstanding questions that aim to provide additional cues for therapeutic development in this area.
The radiocarbon (14C) calibration curve so far contains annually resolved data only for a short period of time. With accelerator mass spectrometry (AMS) matching the precision of decay counting, it is now possible to efficiently produce large datasets of annual resolution for calibration purposes using small amounts of wood. The radiocarbon intercomparison on single-year tree-ring samples presented here is the first to investigate specifically possible offsets between AMS laboratories at high precision. The results show that AMS laboratories are capable of measuring samples of Holocene age with an accuracy and precision that is comparable or even goes beyond what is possible with decay counting, even though they require a thousand times less wood. It also shows that not all AMS laboratories always produce results that are consistent with their stated uncertainties. The long-term benefits of studies of this kind are more accurate radiocarbon measurements with, in the future, better quantified uncertainties.
Diet has a major influence on the composition and metabolic output of the gut microbiome. Higher-protein diets are often recommended for older consumers; however, the effect of high-protein diets on the gut microbiota and faecal volatile organic compounds (VOC) of elderly participants is unknown. The purpose of the study was to establish if the faecal microbiota composition and VOC in older men are different after a diet containing the recommended dietary intake (RDA) of protein compared with a diet containing twice the RDA (2RDA). Healthy males (74⋅2 (sd 3⋅6) years; n 28) were randomised to consume the RDA of protein (0⋅8 g protein/kg body weight per d) or 2RDA, for 10 weeks. Dietary protein was provided via whole foods rather than supplementation or fortification. The diets were matched for dietary fibre from fruit and vegetables. Faecal samples were collected pre- and post-intervention for microbiota profiling by 16S ribosomal RNA amplicon sequencing and VOC analysis by head space/solid-phase microextraction/GC-MS. After correcting for multiple comparisons, no significant differences in the abundance of faecal microbiota or VOC associated with protein fermentation were evident between the RDA and 2RDA diets. Therefore, in the present study, a twofold difference in dietary protein intake did not alter gut microbiota or VOC indicative of altered protein fermentation.
Bipolar disorder and alcohol use disorder (AUD) have a high rate of comorbidity, more than 50% of individuals with bipolar disorder also receive a diagnosis of AUD in their lifetimes. Although both disorders are heritable, it is unclear if the same genetic factors mediate risk for bipolar disorder and AUD. We examined 733 Costa Rican individuals from 61 bipolar pedigrees. Based on a best estimate process, 32% of the sample met criteria for bipolar disorder, 17% had a lifetime AUD diagnosis, 32% met criteria for lifetime nicotine dependence, and 21% had an anxiety disorder. AUD, nicotine dependence and anxiety disorders were relatively more common among individuals with bipolar disorder than in their non-bipolar relatives. All illnesses were shown to be heritable and bipolar disorder was genetically correlated with AUD, nicotine dependence and anxiety disorders. The genetic correlation between bipolar and AUD remained when controlling for anxiety, suggesting that unique genetic factors influence the risk for comorbid bipolar and AUD independent of anxiety. Our findings provide evidence for shared genetic effects on bipolar disorder and AUD risk. Demonstrating that common genetic factors influence these independent diagnostic constructs could help to refine our diagnostic nosology.
The lipidome is rapidly garnering interest in the field of psychiatry. Recent studies have implicated lipidomic changes across numerous psychiatric disorders. In particular, there is growing evidence that the concentrations of several classes of lipids are altered in those diagnosed with MDD. However, for lipidomic abnormalities to be considered potential treatment targets for MDD (rather than secondary manifestations of the disease), a shared etiology between lipid concentrations and MDD should be demonstrated.
Methods:
In a sample of 567 individuals from 37 extended pedigrees (average size 13.57 people, range = 3–80), we used mass spectrometry lipidomic measures to evaluate the genetic overlap between twenty-three biologically distinct lipid classes and a dimensional scale of MDD.
Results:
We found that the lipid class with the largest endophenotype ranking value (ERV, a standardized parametric measure of pleiotropy) were ether-phosphodatidylcholines (alkylphosphatidylcholine, PC(O) and alkenylphosphatidylcholine, PC(P) subclasses). Furthermore, we examined the cluster structure of the twenty-five species within the top-ranked lipid class, and the relationship of those clusters with MDD. This analysis revealed that species containing arachidonic acid generally exhibited the greatest degree of genetic overlap with MDD.
Conclusions:
This study is the first to demonstrate a shared genetic etiology between MDD and ether-phosphatidylcholine species containing arachidonic acid, an omega-6 fatty acid that is a precursor to inflammatory mediators, such as prostaglandins. The study highlights the potential utility of the well-characterized linoleic/arachidonic acid inflammation pathway as a diagnostic marker and/or treatment target for MDD.
Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology.
Methods
Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits.
Results
Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2-q21.2, LOD = 3.322) and a broad anxiety phenotype (12q24.32-q24.33, LOD = 2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg = 0.550–0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1-q33.2, LOD = 3.054) and drug dependence-anxiety (18p11.23-p11.22, LOD = 3.425).
Conclusions
This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics.
At archaeological sites located on islands or near the coast, the potential exists for lipid extracts of potsherds to contain fatty acids (FA) from both aquatic and terrestrial organisms, meaning that consideration must be given to marine reservoir effects (MRE) in radiocarbon (14C) analyses. Here we studied the site of Bornais (Outer Hebrides, UK) where a local MRE, ΔR of –65 ± 45 yr was determined through the paired 14C determinations of terrestrial and marine faunal bones. Lipid analysis of 49 potsherds, revealed aquatic biomarkers in 45% of the vessels, and δ13C values of C16:0 and C18:0 FAs revealed ruminant and marine product mixing for 71% of the vessels. Compound-specific 14C analysis (CSRA) of FAs yielded intermediate 14C ages between those of terrestrial and marine bones from the same contexts, confirming an MRE existed. A database containing δ13C values for FAs from reference terrestrial and marine organisms provided endmembers for calculating the percentage marine-derived C (%marine) in FAs. We show that lipid 14C dates can be corrected using determined %marine and ΔR values, such that pottery vessels from coastal locations can be 14C dated by CSRA of FAs.
In this paper, we present the first data from an alternative extraction method for atmospheric 14CO2 analysis, based on the direct trapping of whole air samples onto a molecular sieve zeolite (13X) trap, incorporated into a commercially available automated graphitization system. Results are presented for both inter-laboratory comparison samples and an in-house reference standard. The in-house reference was used to calculate the standard deviation of measurements (2.0‰). This newly developed method will facilitate faster sample processing and therefore lower cost per analysis, critical for scaling up such studies.