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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 paper studies a class of singular fibrations, called self-crossing boundary fibrations, which play an important role in semitoric and generalized complex geometry. These singular fibrations can be conveniently described using the language of Lie algebroids. We will show how these fibrations arise from (nonfree) torus actions, and how to use them to construct and better understand self-crossing stable generalized complex four-manifolds. We moreover show that these fibrations are compatible with taking connected sums, and use this to prove a singularity trade result between two types of singularities occurring in these types of fibrations (a so-called nodal trade).
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.
Deposits of at least three glaciations are present in New Jersey and the New York City area. The oldest deposits are magnetically reversed. Pollen and stratigraphic relations suggest that they are from the earliest Laurentide advance at ~2.4 Ma. Deposits of a second advance are overlain by peat dated to 41 ka and so are pre-Marine Isotope Stage (pre-MIS) 2. Their relation to marine deposits indicates that they predate MIS 5 but postdate MIS 11 and may postdate MIS 7 or 9, suggesting an MIS 6 age. The most recent deposits are of MIS 2 (last glacial maximum [LGM]) age. Radiocarbon dates and varve counts tied to glacial-lake events indicate that LGM ice arrived at its terminus at 25 ka, stood at the terminus until ~24 ka, retreated at a rate of 80 m/yr until 23.5 ka, and then retreated at a rate of 12 m/yr to 18 ka. At 18 ka the retreat record connects to the base of the North American Varve Chronology at Newburgh, New York. The 25–24 ka age for the LGM is slightly younger than, but within the uncertainty of, cosmogenic ages; it is significantly older than the oldest dated macrofossils in postglacial deposits in the region.
Over half of individuals with eating disorders experience suicidal ideation at some point in their lives, yet few longitudinal studies have examined predictors of ideation in this at-risk group. Moreover, prospective research has focused on relatively distal or trait-level factors that are informative for distinguishing who is most at risk but not when. Little is known about more proximal or state-level risk factors that fluctuate within an individual, which is critical for determining when a person is most likely to engage in suicidal behaviors.
Methods
Women (N = 97) receiving treatment for their eating disorder completed questionnaires weekly to assess suicidal ideation and interpersonal constructs (i.e. perceived burdensomeness, thwarted belongingness) theorized to be proximal predictors of suicidal desire. Longitudinal multilevel models were conducted to examine both within- and between-person predictors of suicidal ideation across 12 weeks of treatment.
Results
Statistically significant within-person effects for burdensomeness (β = 0.06; p < 0.001) indicate that when individuals have greater feelings of burdensomeness compared to their own average, they also experience higher suicidal ideation. We did not find any significant influence of thwarted belongingness or the interaction between burdensomeness and belongingness on suicidal ideation.
Conclusions
This study was the first to examine dynamic associations between interpersonal constructs and suicidal ideation in individuals with eating disorders. Results are only partially consistent with the Interpersonal Theory of Suicide and suggest that short-term changes in burdensomeness may impact suicidal behavior in individuals with eating disorders.
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.
We sought to evaluate the risk and image quality from cardiovascular CT in patients across all stages of single-ventricle palliation, and to define accuracy by comparing findings with intervention and surgery.
Methods
Consecutive CT scans performed in patients with single-ventricle heart disease were retrospectively reviewed at a single institution. Diagnosis, sedation needs, estimated radiation dose, and adverse events were recorded. Anatomical findings, image quality (1–4, 1=optimal), and discrepancy compared with interventional findings were determined. Results are described as medians with their 25th and 75th percentiles.
Results
From January, 2010 to August, 2015, 132 CT scans were performed in single-ventricle patients of whom 20 were neonates, 52 were post-Norwood, 15 were post-Glenn, and 45 were post-Fontan. No sedation was used in 76 patients, 47 were under minimal or moderate sedation, and nine were under general anaesthesia. The median image quality score was 1.2. The procedural dose–length product was 24 mGy-cm, and unadjusted and adjusted radiation doses were 0.34 (0.2, 1.8) and 0.82 (0.55, 1.88) mSv, respectively. There was one adverse event. No major and two minor discrepancies were noted at the time of 79 surgical and 10 catheter-based interventions.
Conclusions
Cardiovascular CT can be performed with a low radiation exposure in patients with single-ventricle heart disease. Its accuracy compared with that of interventional findings is excellent. CT is an effective advanced imaging modality when a non-invasive pathway is desired, particularly if cardiac MRI poses a high risk or is contraindicated.
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.
Phorate {O,O-diethyl S-[(ethylthio)methyl] phosphorodithioate}, disulfoton {O,O-diethyl S-[2-(ethylthio)ethyl] phosphorodithioate}, linuron [3-(3,4-dichlorophenyl)-1-methoxy-1-methylurea], or metribuzin [4-amino-6-tert-butyl-3-(methylthio)-as-triazin-5(4H)-one] when used alone did not reduce soybean [Glycine max (L.) Merr. ‘Calland’] grain yield or plant population. However, combinations of metribuzin with either phorate or disulfoton interacted synergistically to reduce both soybean grain yield and plant population significantly even at recommended rates of both chemicals. Combinations of linuron with either phorate or disulfoton at recommended rates did not reduce soybean grain yield or plant population. Greenhouse studies further substantiated the synergistic interaction of phorate or disulfoton with metribuzin.
The dissipation of four commonly used soil-applied herbicides was examined in a standardized field experiment in three southern states (Kentucky, Mississippi, and Tennessee). Averaged over the three soils and 2 yr, the relative order of increasing half-life defined as time for 50% disappearance in days (DT50) was acetochlor (6.3 d) = alachlor (6.3 d) = SAN 582 (7.3 d) < metolachlor (13.7 d). Metolachlor was the most persistent in the soil surface, and this could potentially translate into greater duration of weed control into the growing season. All examined herbicides had a DT50 that averaged less than 14 d in all states in both years, so full-season weed control of susceptible species would not be expected. Rapid herbicide degradation was encouraged in these field sites by adequate to excessive soil moisture and warm temperatures throughout the sampling interval. The soils also were light textured, and the lower adsorption of the herbicide allowed for degradation ease and perhaps leaching below the sampling depth.
Field experiments were conducted in Princeton, KY, in 1982, 1983, and 1984 to evaluate johnsongrass [Sorghum halepense (L.) Pers. # SORHA] control programs in no-tillage, doublecropped soybeans [Glycine max (L.) Merr. ‘Essex′]. Sequential applications of sethoxydim {2-[1-(ethoxyimino)butyl]-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one} or fluazifop {(±)-2-[4-[[5-(trifluoromethyl)-2-pyridinyl] oxy] phenoxy] propanoic acid} at 0.2 kg ai/ha provided 36 to 94% johnsongrass control. The lower control values from these treatments were obtained in the droughty 1983 growing season while the higher and acceptable control ratings were obtained in 1982 and 1984 when rainfall was more plentiful. Preplant applications that contained glyphosate [N-(phosphonomethyl)glycine] provided johnsongrass control greater than those containing paraquat (1,1′-dimethyl-4,4′-bypyridinium ion). Soybean yields and soil moisture were greater with preplant applications of glyphosate than with preplant applications of paraquat or foliar applications of sethoxydim, fluazifop, or glyphosate. Greatest yields were obtained with a combination of a preplant application of glyphosate and a postemergence application of sethoxydim.
Mechanical scarification of burcucumber (Sicyos angulatus L.) seeds resulted in increased water absorption and germination. Burcucumber germination occurred at temperatures ranging from 15 to 35 C with optimum germination occurring from 20 to 30 C. Scarified burcucumber seeds were more sensitive to simulated moisture stress than were either soybean [Glycine max (L.) Merr. ‘Williams’] or corn [Zea mays L. ‘Pioneer Brand 3369A’]. Regardless of osmotic potential, intact burcucumber seeds did not germinate; scarified seeds germinated at osmotic potentials to −6 bars. Cold stratification at 4 C for 18 weeks modified seedcoat permeability so that 11% of non-scarified burcucumber seeds germinated. Increasing depth of planting decreased emergence with limited emergence occurring at depths of 15 and 16 cm in field and growth chamber studies, respectively.
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.