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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.
Limited analyses based on national samples have assessed whether early attention-deficit/hyperactivity disorder (ADHD) symptoms predict later internalizing and externalizing symptoms in youth and the influence of sex and pubertal timing on subsequent psychiatric symptoms. This study analyzed data (n = 2818) from the Environmental influences on Child Health Outcomes Program national cohort. Analyses used data from early childhood (mean age = 5.3 years) utilizing parent-reported ADHD symptoms to predict rates of internalizing and externalizing symptoms from late childhood/adolescence (mean age = 11.9 years). Within a subsample age at peak height velocity (APHV) acted as a proxy to assess pubertal timing from early childhood (mean age = 5.4 years) to adolescence (mean age = 12.3 years). Early-childhood ADHD symptoms predicted later psychiatric symptoms, including anxiety, depression, aggressive behavior, conduct problems, oppositional defiant disorder, and rule-breaking behavior. Earlier APHV was associated with increased Conduct Disorder symptoms from late childhood to adolescence for females only. A stronger relation between ADHD symptoms and later aggression was observed in females with earlier APHV, whereas this same pattern with aggression, conduct problems and depression was observed in males with later APHV. Clinicians should consider that both young girls and boys with elevated ADHD symptoms, particularly with off-set pubertal timing, may be at risk for later psychiatric symptoms.
Recent archaeological and paleoenvironmental research in the Ndali Crater Lakes Region (NCLR) of western Uganda provide important new insights into anthropogenic impacts on moist forests to the East of the Rwenzori Mountains. This research significantly changes previous interpretations of paleoenvironmental records in western Uganda and helps to distinguish climate change from human impacts. By drawing on multiple sources such as historical linguistics, archaeological evidence, and environmental proxies for change, a new picture emerges for a region that was a cultural crossroads for early Bantu-speakers and Central Sudanic-speakers between 400 BCE and 1000 CE. Detailed archaeological data and well-dated sites provide fine-grained evidence that closely fits episodes of significant environmental change, including a later and separate phase of forest clearance, soil degradation, and lake pollution caused by the saturation of the landscape by Bigo-related populations between 1300 and 1650 CE.
Fresque de changements environnementaux induits par l’homme et le climat dans l’ouest de l’Ouganda : la région des lacs du cratère de Ndali
The long-standing assumption that aboveground plant litter inputs have a substantial influence on soil organic carbon storage (SOC) and dynamics has been challenged by a new paradigm for SOC formation and persistence. We tested the importance of plant litter chemistry on SOC storage, distribution, composition, and age by comparing two highly contrasting ecosystems: an old-growth coast redwood (Sequoia sempervirens) forest, with highly aromatic litter, and an adjacent coastal prairie, with more easily decomposed litter. We hypothesized that if plant litter chemistry was the primary driver, redwood would store more and older SOC that was less microbially processed than prairie. Total soil carbon stocks to 110 cm depth were higher in prairie (35 kg C m−2) than redwood (28 kg C m−2). Radiocarbon values indicated shorter SOC residence times in redwood than prairie throughout the profile. Higher amounts of pyrogenic carbon and a higher degree of microbial processing of SOC appear to be instrumental for soil carbon storage and persistence in prairie, while differences in fine-root carbon inputs likely contribute to younger SOC in redwood. We conclude that at these sites fire residues, root inputs, and soil properties influence soil carbon dynamics to a greater degree than the properties of aboveground litter.
The overuse of antibiotics in medicine has led to concerns over management of wound infections where antibiotic-resistant bacteria are involved. Wound infections exhibit both acquired and biofilm-associated antibiotic resistance; innovative non-antibiotic therapeutic and preventive treatments are needed to limit emergence of conventional antimicrobial resistance and to address biofilm-associated resistance. Toward this goal, natural antibacterial clays have been identified that are effective at killing drug-resistant human pathogens in planktonic and biofilm states, in vitro. To move toward clinical testing of antibacterial clays, the present study was conducted to evaluate the topical application of a natural antibacterial clay to wounds in mice experimentally infected with methicillin-resistant Staphylococcus aureus (MRSA). Five preliminary animal trials were conducted to test various methods of applying hydrated antibacterial clay to infected wounds. None of the experiments yielded significantly reduced MRSA infection in vivo, compared to controls. Several hypotheses were tested to explore the diminished clay antibacterial activity in vivo including: (1) pH and Eh of mineral-bacterial suspensions may differ in wound fluids compared to growth media; (2) antibacterial reactants may complex with components of the wound; (3) hydrated clays may dry out in the wound; and (4) limited dissolved oxygen may reduce Fenton reactions. Ancillary in vitro tests were performed to explore these hypotheses. Results indicate that the clay application to wounds may require enhanced oxidation and possibly a longer treatment regimen. The experimental results foster understanding of the natural clay–bacterial interactions in wounds and may improve designs for medicinal applications.
In this study, an appropriate visual scoring system for foot-pad dermatitis was validated, considering the histologically measured depth of the inflammation zone and the histopathological grade (no lesion, mild lesion, ulcer). The aim being to evaluate whether the visual, macroscopic scoring of foot-pad dermatitis can represent the histological, microscopic findings. Two hundred Ross 308 broiler chicken feet (birds aged 39-42 fattening days) were collected at a slaughterhouse and scored macroscopically according to a modified version of the Welfare Quality® Assessment Protocol for Poultry. Afterwards, 200 histological slides (one per foot) were prepared, the extent of the inflammation measured and all slides scored by veterinarian pathologists using Michel et al's modified scheme. The statistical relationship between microscopic and macroscopic score and depth of inflammation were estimated via regression models. Increasing macroscopic score was found to be linked with an increase in microscopic score and the depth of inflammation. In particular, feet without lesions and feet with ulcers were identifiable using the macroscopic score. Macroscopic scoring of foot-pad dermatitis can mirror histological findings once certain limitations are taken into account (superficial lesions were not clearly identifiable). Foot-pad dermatitis is considered a useful indicator of animal welfare and our findings suggest that visual, macroscopic scoring could be a practicable assessment tool.
Previous studies have shown that the analysis of high frequency stress calls in pigs can serve as a reliable tool in welfare research. Our study focuses on the classification of three different classes of piglet vocalisation: grunting, squealing and screaming. In a castration experiment (Experiment 1), 3,285 vocalisations from 42 piglets were analysed for 21 different vocal characteristics. A first discriminant function for the three vocal types was derived from recordings made under laboratory-like conditions. A second discriminant function was derived from non-calibrated measurements of the relative sound energy content. These two classifications revealed 86.7% identical assignments of vocalisations to the three vocal types. The second classification allowed for vocalisation analyses of animals under on-farm recording conditions. This technique was validated during an open-field test (Experiment 2) with piglets housed in two different farrowing systems (11,089 vocalisations, 22 piglets). The proportion of screaming sounds was lower for piglets from a group-farrowing (GF) system than for those from a single-farrowing (SF) system. Sound properties showed differences between as well as within the two experiments for all three vocal types. Vocalisations from SF and GF piglets differed significantly in the duration, energy, and relative maximum levels. We conclude that vocal-type analysis can not only help to identify vocalisation indicative of pain during castration, but also vocal behaviour changes indicating separation stress during the open-field test. Therefore, classification of vocal types can add valuable information to studies that use pig vocalisation for the assessment of welfare.
High performance health financing requires funding levels that are adequate, sustainable and resilient to meet country health goals, pooling that is sufficient to spread the financial risks of ill-health across the population, and spending that is both efficient and equitable to assure the desired levels of health service coverage, quality, and financial protection for all people. This chapter describes the various components of health financing and how they interact to determine how rapidly countries can approach the goal of Universal Health Coverage.
Recent estimates suggest that 40% of dementia cases could be avoided by treating recognised cardiovascular risk factors such as hypertension, diabetes, smoking and physical inactivity. Whether diet is associated with dementia remains largely unknown. We tested if low adherence to established dietary guidelines is associated with elevated lipids and lipoproteins and with increased risk of Alzheimer's disease and non-Alzheimer's dementia – a dementia subtype with a high frequency of cardiovascular risk factors.
Methods
We used the prospective Copenhagen General Population Study including 94 184 individuals with dietary information and free of dementia at baseline. Mean age at study entry was 58 years, and 55% (N = 51 720) were women and 45% (N = 42 464) were men. Adherence to dietary guidelines was grouped into low, intermediate and high adherence based on food frequency questionnaires. Main outcomes were non-Alzheimer's dementia and Alzheimer's disease.
Results
Low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol and plasma triglyceride levels were higher in individuals with intermediate and low adherence to dietary guidelines compared with individuals with high adherence (all p for trends <0.001). Age and sex-adjusted hazard ratios (HRs) for non-Alzheimer's dementia v. individuals with high adherence were 1.19 (95% confidence interval 0.97–1.46) for intermediate adherence, and 1.54 (1.18–2.00) for low adherence. Corresponding HRs in multivariable-adjusted models including APOE genotype were 1.14 (0.92–1.40) and 1.35 (1.03–1.79). These relationships were not observed in individuals on lipid-lowering therapy.
Conclusions
Low adherence to national dietary guidelines is associated with an atherogenic lipid profile and with increased risk of non-Alzheimer's dementia – the subtype of dementia with a high frequency of vascular risk factors. This study suggests that implementation of dietary guidelines associated with an anti-atherogenic lipid profile could be important for prevention of non-Alzheimer's dementia.
Volume reductions in brain structures of patients with schizophrenia spectrum disorder (SSD) have repeatedly been found in voxel-based morphometry MRI studies. Hence, an underlying neurodegenerative etiological component of SSD is currently being discussed. In recent years, the imaging method of optical coherence tomography (OCT) has shown its potential in evaluating structural changes in the retina in patients with confirmed neurodegenerative disorders, providing a window into the brain.
Objectives
To evaluate potential differences in measurements of retinal layers between patients with schizophrenia spectrum disorder and healthy controls with OCT.
Methods
Twenty-six patients with schizophrenia or schizoaffective disorder and 23 age- and sex-matched healthy controls were examined with the Heidelberg Spectralis OCT system to derive a single-layer analysis of both retinas. The segmentation of retinal layers was manually corrected to minimize artifacts and software imprecisions.
Results
Compared to the control group, SSD patients showed reduced thickness and volume measurements for nearly all retinal layers, and these differences reached significance for macular volume, macular thickness, retinal nerve fiber layer (RNFL) and inner nucleiform layer (INL). Furthermore, a significant correlation between the duration of illness and the total volume of the RNFL was found.
Conclusions
Our OCT measurements demonstrate reduced single retinal layer thickness in patients with SSD. In the context of the MRI volume changes, our results provide further evidence that structural changes seen in the brain of patients are also observable in the retina, potentially allowing further insights into the different components of the nervous system that are altered in this highly etiologically complex disorder.
The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors.
Method
Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change.
Results
Prospective symptom analyses showed small decreases in depression (PHQ-9: −0.43 points) and anxiety [generalised anxiety disorder scale – 7 items (GAD)-7: −0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status.
Conclusions
We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.
Although associations among borderline personality disorder (BPD), social rejection, and frontal EEG alpha asymmetry scores (FAA, a neural correlate of emotion regulation and approach-withdrawal motivations) have been explored in different studies, relatively little work has examined these relations during adolescence in the same study. We examined whether FAA moderated the relation between BPD features and rejection sensitivity following a validated social exclusion paradigm, Cyberball. A mixed, clinical-community sample of 64 adolescents (females = 62.5%; Mage = 14.45 years; SD = 1.6; range = 11-17 years) completed psychodiagnostic interviews and a self-report measure of BPD (Time 1). Approximately two weeks later (Time 2), participants completed a resting EEG recording followed by Cyberball. FAA moderated the relation between BPD features and overall feelings of rejection following Cyberball: individuals with greater relative left FAA had the highest and lowest feelings of social rejection depending on whether they had high and low BPD feature scores, respectively. Results remained after controlling for age, sex, gender, depression, and BPD diagnosis. These results suggest that FAA may moderate the relation between BPD features and social rejection, and that left frontal brain activity at rest may be differentially associated with those feelings in BPD. Findings are discussed in terms of the link between left frontal brain activity in the regulation and dysregulation of social approach behaviors, characteristic of BPD.
Guided by principles from life-history theory, theories of adaptive calibration provide an overarching theoretical framework for understanding the developmental roots of impulsivity and externalizing psychopathology. The current research provides evidence for robust associations between perceptions of childhood unpredictability, delay discounting (Studies 1a and 1b), and adult externalizing traits and behaviors (Study 2). Both associations were observed while controlling for perceptions of the harshness of childhood environments, as well as a range of demographic characteristics. The association with externalizing traits and behavior was observed over and above current mood and depressive symptoms. Study 2 also replicated a previously documented association between changes in maternal employment, residence, and cohabitation during childhood and externalizing behavior and, furthermore, suggested that this association was mediated by perceptions of unpredictability. These studies provided no evidence for links between perceived childhood unpredictability and basic forms of risk-taking (Studies 1a and 1c). This research adds to a growing body of work leveraging principles from life-history theory to demonstrate links between childhood experiences, impulsivity, and potentially debilitating forms of mental illness. This work also highlights the value of assessing people’s perceptions of their childhood environments.
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.
Intake of vegetables is recommended for the prevention of myocardial infarction (MI). However, vegetables make up a heterogeneous group, and subgroups of vegetables may be differentially associated with MI. The aim of this study was to examine replacement of potatoes with other vegetables or subgroups of other vegetables and the risk of MI. Substitutions between subgroups of other vegetables and risk of MI were also investigated. We followed 29 142 women and 26 029 men aged 50–64 years in the Danish Diet, Cancer and Health cohort. Diet was assessed at baseline by using a detailed validated FFQ. Hazard ratios (HR) with 95 % CI for the incidence of MI were calculated using Cox proportional hazards regression. During 13·6 years of follow-up, 656 female and 1694 male cases were identified. Among women, the adjusted HR for MI was 1·02 (95 % CI 0·93, 1·13) per 500 g/week replacement of potatoes with other vegetables. For vegetable subgroups, the HR was 0·93 (95 % CI 0·77, 1·13) for replacement of potatoes with fruiting vegetables and 0·91 (95 % CI 0·77, 1·07) for replacement of potatoes with other root vegetables. A higher intake of cabbage replacing other vegetable subgroups was associated with a statistically non-significant higher risk of MI. A similar pattern of associations was found when intake was expressed in kcal/week. Among men, the pattern of associations was overall found to be similar to that for women. This study supports food-based dietary guidelines recommending to consume a variety of vegetables from all subgroups.
Most measures of anxious avoidance are limited to disorder-specific mechanisms and ignore the measurement of courage/approach responding in confronting fearful situations.
Aims:
The purpose of the present study was to construct and validate a self-report assessment of the tendency towards avoidant or approach responding in fearful situations, the Response to Fearful Situations Scale (RFSS).
Method and Results:
In Study 1 (n = 241), exploratory factor analysis resulted in two factors, avoidance and approach. Study 2 (n = 423) replicated the two-factor structure and established test–re-test reliability. In Study 3 (n = 44), the RFSS demonstrated predictive validity on a behavioural avoidance task. In Studies 4 (n = 253) and 5 (n = 256), the RFSS was associated with clinical symptoms above existing measures of avoidance.
Discussion:
These results validate the use of the RFSS as a transdiagnostic measure of avoidance and approach.
The Road Not Taken: A Documented Biography of Randall Thompson chronicles the extraordinary career of a composer, conductor, arts administrator, teacher, and reformer of music curricula. Based on extensive archival research, interviews, and a thorough knowledge of his compositions, it is the first full-length study of "The Dean of American Choral Composers" as he was affectionately known. Thompson's life intersected with numerous composers and conductors including George Antheil, Leonard Bernstein, Ernest Bloch, Aaron Copland, Walter Damrosch, Archibald "Doc" Davison, Serge Koussevitzky, Gian Francesco Malipiero, Walter Piston, Fritz Reiner, Harold Schmidt, Roger Sessions, Bruno Walter, and G. Wallace Woodworth, among many others. Illustrated with more than fifty photographs, the book emphasizes his study at Harvard (1916-20), his year with Bloch (1921-22), his Damrosch Fellowship years at the American Academy in Rome (1922-25), his work heading the College Music Study (1932-35), and his academic life at Wellesley College, University of California at Berkeley, Curtis Institute, University of Virginia, Princeton, and Harvard (1928-65). Virtually all of his more than 120 compositions are considered with emphasis given to his most important works such as Symphony no. 2, Alleluia, The Testament of Freedom, The Last Words of David, Requiem, Frostiana, and The Passion according to Saint Luke. It argues that he followed a more conservative compositional path compared to other composers of his generation whose music often stressed atonality, rhythmic complexity, and serialism, which was for Thompson the road not taken.