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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.
Response to lithium in patients with bipolar disorder is associated with clinical and transdiagnostic genetic factors. The predictive combination of these variables might help clinicians better predict which patients will respond to lithium treatment.
Aims
To use a combination of transdiagnostic genetic and clinical factors to predict lithium response in patients with bipolar disorder.
Method
This study utilised genetic and clinical data (n = 1034) collected as part of the International Consortium on Lithium Genetics (ConLi+Gen) project. Polygenic risk scores (PRS) were computed for schizophrenia and major depressive disorder, and then combined with clinical variables using a cross-validated machine-learning regression approach. Unimodal, multimodal and genetically stratified models were trained and validated using ridge, elastic net and random forest regression on 692 patients with bipolar disorder from ten study sites using leave-site-out cross-validation. All models were then tested on an independent test set of 342 patients. The best performing models were then tested in a classification framework.
Results
The best performing linear model explained 5.1% (P = 0.0001) of variance in lithium response and was composed of clinical variables, PRS variables and interaction terms between them. The best performing non-linear model used only clinical variables and explained 8.1% (P = 0.0001) of variance in lithium response. A priori genomic stratification improved non-linear model performance to 13.7% (P = 0.0001) and improved the binary classification of lithium response. This model stratified patients based on their meta-polygenic loadings for major depressive disorder and schizophrenia and was then trained using clinical data.
Conclusions
Using PRS to first stratify patients genetically and then train machine-learning models with clinical predictors led to large improvements in lithium response prediction. When used with other PRS and biological markers in the future this approach may help inform which patients are most likely to respond to lithium treatment.
The inaugural data from the first systematic program of sea-ice observations in Kotzebue Sound, Alaska, in 2018 coincided with the first winter in living memory when the Sound was not choked with ice. The following winter of 2018–19 was even warmer and characterized by even less ice. Here we discuss the mass balance of landfast ice near Kotzebue (Qikiqtaġruk) during these two anomalously warm winters. We use in situ observations and a 1-D thermodynamic model to address three research questions developed in partnership with an Indigenous Advisory Council. In doing so, we improve our understanding of connections between landfast ice mass balance, marine mammals and subsistence hunting. Specifically, we show: (i) ice growth stopped unusually early due to strong vertical ocean heat flux, which also likely contributed to early start to bearded seal hunting; (ii) unusually thin ice contributed to widespread surface flooding. The associated snow ice formation partly offset the reduced ice growth, but the flooding likely had a negative impact on ringed seal habitat; (iii) sea ice near Kotzebue during the winters of 2017–18 and 2018–19 was likely the thinnest since at least 1945, driven by a combination of warm air temperatures and a persistent ocean heat flux.
With over a century of records, we present a detailed analysis of the spatial and temporal occurrence of marine turtle sightings and strandings in the UK and Ireland between 1910 and 2018. Records of hard-shell turtles, including loggerhead turtles (Caretta caretta, N = 240) and Kemp's ridley turtles (Lepidochelys kempii, N = 61), have significantly increased over time. However, in the most recent years there has been a notable decrease in records. The majority of records of hard-shell turtles were juveniles and occurred in the boreal winter months when the waters are coolest in the North-east Atlantic. They generally occurred on the western aspects of the UK and Ireland highlighting a pattern of decreasing records with increasing latitude, supporting previous suggestions that juvenile turtles arrive in these waters via the North Atlantic current systems. Similarly, the majority of the strandings and sightings of leatherback turtles (Dermochelys coriacea, N = 1683) occurred on the western aspects of the UK and the entirety of Ireland's coastline. In contrast to hard-shell turtles, leatherback turtles were most commonly recorded in the boreal summer months with the majority of strandings being adult sized, of which there has been a recent decrease in annual records. The cause of the recent annual decreases in turtle strandings and sightings across all three species is unclear; however, changes to overall population abundance, prey availability, anthropogenic threats and variable reporting effort could all contribute. Our results provide a valuable reference point to assess species range modification due to climate change, identify possible evidence of anthropogenic threats and to assess the future trajectory of marine turtle populations in the North Atlantic.
The association between schizophrenia and decreased vitamin D levels is well documented. Low maternal and postnatal vitamin D levels suggest a possible etiological mechanism. Alternatively, vitamin D deficiency in patients with schizophrenia is presumably (also) the result of disease-related factors or demographic risk factors such as urbanicity.
Methods
In a study population of 347 patients with psychotic disorder and 282 controls, group differences in vitamin D concentration were examined. Within the patient group, associations between vitamin D, symptom levels and clinical variables were analyzed. Group × urbanicity interactions in the model of vitamin D concentration were examined. Both current urbanicity and urbanicity at birth were assessed.
Results
Vitamin D concentrations were significantly lower in patients (B = −8.05; 95% confidence interval (CI) −13.68 to −2.42; p = 0.005). In patients, higher vitamin D concentration was associated with lower positive (B = −0.02; 95% CI −0.04 to 0.00; p = 0.049) and negative symptom levels (B = −0.03; 95% CI −0.05 to −0.01; p = 0.008). Group differences were moderated by urbanicity at birth (χ2 = 6.76 and p = 0.001), but not by current urbanicity (χ2 = 1.50 and p = 0.224). Urbanicity at birth was negatively associated with vitamin D concentration in patients (B = −5.11; 95% CI −9.41 to −0.81; p = 0.020), but not in controls (B = 0.72; 95% CI −4.02 to 5.46; p = 0.765).
Conclusions
Lower vitamin D levels in patients with psychotic disorder may in part reflect the effect of psychosis risk mediated by early environmental adversity. The data also suggest that lower vitamin D and psychopathology may be related through direct or indirect mechanisms.
This paper presents latest thinking from the Institute and Faculty of Actuaries’ Model Risk Working Party and follows on from their Phase I work, Model Risk: Daring to Open the Black Box. This is a more practical paper and presents the contributors’ experiences of model risk gained from a wide range of financial and non-financial organisations with suggestions for good practice and proven methods to reduce model risk. After a recap of the Phase I work, examples of model risk communication are given covering communication: to the Board; to the regulator; and to external stakeholders. We present a practical framework for model risk management and quantification with examples of the key actors, processes and cultural challenge. Lessons learned are then presented from other industries that make extensive use of models and include the weather forecasting, software and aerospace industries. Finally, a series of case studies in practical model risk management and mitigation are presented from the contributors’ own experiences covering primarily financial services.
Children and adolescents are a vulnerable group to develop post-traumatic stress symptoms after natural or man-made disasters. In the light of increasing numbers of refugees under the age of 18 years worldwide, there is a significant need for effective treatments. This meta-analytic review investigates specific psychosocial treatments for children and adolescents after man-made and natural disasters. In a systematic literature search using MEDLINE, EMBASE and PsycINFO, as well as hand-searching existing reviews and contacting professional associations, 36 studies were identified. Random- and mixed-effects models were applied to test for average effect sizes and moderating variables. Overall, treatments showed high effect sizes in pre–post comparisons (Hedges' g = 1.34) and medium effect sizes as compared with control conditions (Hedges' g = 0.43). Treatments investigated by at least two studies were cognitive–behavioural therapy (CBT), eye movement desensitization and reprocessing (EMDR), narrative exposure therapy for children (KIDNET) and classroom-based interventions, which showed similar effect sizes. However, studies were very heterogenic with regard to their outcomes. Effects were moderated by type of profession (higher level of training leading to higher effect sizes). A number of effective psychosocial treatments for child and adolescent survivors of disasters exist. CBT, EMDR, KIDNET and classroom-based interventions can be equally recommended. Although disasters require immediate reactions and improvisation, future studies with larger sample sizes and rigorous methodology are needed.
The aim of this study was to assess the efficacy of meaning-centered group psychotherapy for cancer survivors (MCGP-CS) to improve personal meaning, compared with supportive group psychotherapy (SGP) and care as usual (CAU).
Method
A total of 170 cancer survivors were randomly assigned to one of the three study arms: MCGP-CS (n = 57); SGP (n = 56); CAU (n = 57). The primary outcome measure was the Personal Meaning Profile (PMP; total score). Secondary outcome measures were subscales of the PMP, psychological well-being (Scales of Psychological Well-being; SPWB), post-traumatic growth (Posttraumatic Growth Inventory), Mental Adjustment to Cancer (MAC), optimism (Life Orientation Test-Revised), hopelessness (Beck's Hopelessness Scale), psychological distress (anxiety and depression, Hospital Anxiety and Depression Scale; HADS) and quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ-C30). Outcome measures were assessed before randomization, post-intervention, and after 3 and 6 months of follow-up (FU).
Results
Linear mixed model analyses (intention-to-treat) showed significant differences between MCGP-CS, SGP and CAU on the total PMP score, and on (sub)scales of the PMP, SPWB, MAC and HADS. Post-hoc analyses showed significantly stronger treatment effects of MCGP-CS compared with CAU on personal meaning (d = 0.81), goal-orientedness (d = 1.07), positive relations (d = 0.59), purpose in life (d = 0.69); fighting spirit (d = 0.61) (post-intervention) and helpless/hopeless (d = −0.87) (3 months FU); and distress (d = −0.6) and depression (d = −0.38) (6 months FU). Significantly stronger effects of MCGP-CS compared with SGP were found on personal growth (d = 0.57) (3 months FU) and environmental mastery (d = 0.66) (6 months FU).
Conclusions
MCGP-CS is an effective intervention for cancer survivors to improve personal meaning, psychological well-being and mental adjustment to cancer in the short term, and to reduce psychological distress in the long run.
Herbicide soil/solution distribution coefficients (Kd) are used in mathematical models to predict the movement of herbicides in soil and groundwater. Herbicides bind to various soil constituents to differing degrees. The universal soil colloid that binds most herbicides is organic matter (OM), however clay minerals (CM) and metallic hydrous oxides are more retentive for cationic, phosphoric, and arsenic acid compounds. Weakly basic herbicides bind to both organic and inorganic soil colloids. The soil organic carbon (OC) affinity coefficient (Koc) has become a common parameter for comparing herbicide binding in soil; however, because OM and OC determinations vary greatly between methods and laboratories, Koc values may vary greatly. This proposal discusses this issue and offers suggestions for obtaining the most accurate Kd, Freundlich constant (Kf), and Koc values for herbicides listed in the WSSA Herbicide Handbook and Supplement.
Data on gender-specific profiles of cognitive functions in patients with Parkinson's disease (PD) are rare and inconsistent, and possible disease-confounding factors have been insufficiently considered.
Method
The LANDSCAPE study on cognition in PD enrolled 656 PD patients (267 without cognitive impairment, 66% male; 292 with mild cognitive impairment, 69% male; 97 with PD dementia, 69% male). Raw values and age-, education-, and gender-corrected Z scores of a neuropsychological test battery (CERAD-Plus) were compared between genders. Motor symptoms, disease duration, l-dopa equivalent daily dose, depression - and additionally age and education for the raw value analysis - were taken as covariates.
Results
Raw-score analysis replicated results of previous studies in that female PD patients were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.03), while men outperformed women in visuoconstruction (p = 0.002) and figural memory (p = 0.005). In contrast, gender-corrected Z scores showed that men were superior in verbal memory (word list learning, p = 0.02; recall, p = 0.02; recognition, p = 0.04), while no difference was found for visuospatial tests. This picture could be observed both in the overall analysis of PD patients as well as in a differentiated group analysis.
Conclusions
Normative data corrected for gender and other sociodemographic variables are relevant, since they may elucidate a markedly different cognitive profile compared to raw scores. Our study also suggests that verbal memory decline is stronger in women than in men with PD. Future studies are needed to replicate these findings, examine the progression of gender-specific cognitive decline in PD and define different underlying mechanisms of this dysfunction.
Anti-pneumococcal polysaccharide antibody (anti-PPS) levels were measured in 153 serum samples collected from children aged between 2 and 47 months living in the highlands of Papua New Guinea (PNG). Fifty-seven of the samples were collected during acute episodes of lower respiratory tract infection (ALRI). Total IgA and IgG increased steadily with age; however, no association was found between the levels of these antibodies and the health status of the child. Total IgM levels showed little relationship to the age of the child but under 12 months of age levels were somewhat higher on average in children with pneumonia. For most of eight pneumococcal serotypes tested, specific IgG levels were found to decline rapidly in the first 6–8 months, reaching a minimum at approximately 12 months of age. Serotype 3 was exceptional in having very low titres in the youngest children. A separate analysis of 24 cord sera suggested that antibodies to this serotype do not usually cross the placenta in PNG. Children with pneumonia tended to have lower levels of specific IgG than healthy controls of the same age. Specific anti-PPS IgA levels were found to increase steadily with age, but were not associated with health status.
Several years ago the Walter Reed Army Institute of Research (WRAIR) initiated an independent analysis of the candidate malaria blood stage vaccine SPf66. WRAIR contracted for the synthesis and formulation of SPf66 in United States Food and Drug Administration (FDA) inspected laboratories within the U.S., and in 1992, filed an Investigational New Drug (IND) application with the FDA. Preclinical studies indicated that the vaccine could be synthesized to meet its release specifications, and when adjuvanted with alum, was essentially equivalent to Colombian produced SPf66 in regards to immunogenicity in preclinical studies of rodents and primates, and in human volunteers in Phase I studies. The goal of these efforts was ultimately to conduct a Phase IIb field trial to determine the safety and efficacy of SPf66 produced under current Good Manufacturing Practices (cGMP). Such a trial is currently underway in a malaria endemic refugee camp along the Thai–Burmese border. Here we briefly describe the study and present the formal analytic plan that was submitted to regulatory authorities in the United States for analysis of the study results. We believe such independent confirmatory studies are an essential part of the vaccine development process and are required to provide important data regarding the safety and efficacy of candidate vaccines in diverse geographical regions, and as a means to assess their role in the context of broader malaria control programmes.
The DNA of all organisms has a complex and essential topology. The three topological properties of naturally occurring DNA are supercoiling, catenation, and knotting. Although these properties are denned rigorously only for closed circular DNA, even linear DNA in vivo can have topological properties because it is divided into topologically separate subdomains (Drlica 1987; Roberge & Gasser, 1992). The essentiality of topological properties is demonstrated by the lethal consequence of interfering with topoisomerases, the enzymes that regulate the level of DNA supercoiling and that unlink DNA during its replication (reviewed in Wang, 1991; Bjornsti, 1991; Drlica, 1992; Ullsperger et al. 1995).