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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Substantial progress has been made in the standardization of nomenclature for paediatric and congenital cardiac care. In 1936, Maude Abbott published her Atlas of Congenital Cardiac Disease, which was the first formal attempt to classify congenital heart disease. The International Paediatric and Congenital Cardiac Code (IPCCC) is now utilized worldwide and has most recently become the paediatric and congenital cardiac component of the Eleventh Revision of the International Classification of Diseases (ICD-11). The most recent publication of the IPCCC was in 2017. This manuscript provides an updated 2021 version of the IPCCC.
The International Society for Nomenclature of Paediatric and Congenital Heart Disease (ISNPCHD), in collaboration with the World Health Organization (WHO), developed the paediatric and congenital cardiac nomenclature that is now within the eleventh version of the International Classification of Diseases (ICD-11). This unification of IPCCC and ICD-11 is the IPCCC ICD-11 Nomenclature and is the first time that the clinical nomenclature for paediatric and congenital cardiac care and the administrative nomenclature for paediatric and congenital cardiac care are harmonized. The resultant congenital cardiac component of ICD-11 was increased from 29 congenital cardiac codes in ICD-9 and 73 congenital cardiac codes in ICD-10 to 318 codes submitted by ISNPCHD through 2018 for incorporation into ICD-11. After these 318 terms were incorporated into ICD-11 in 2018, the WHO ICD-11 team added an additional 49 terms, some of which are acceptable legacy terms from ICD-10, while others provide greater granularity than the ISNPCHD thought was originally acceptable. Thus, the total number of paediatric and congenital cardiac terms in ICD-11 is 367. In this manuscript, we describe and review the terminology, hierarchy, and definitions of the IPCCC ICD-11 Nomenclature. This article, therefore, presents a global system of nomenclature for paediatric and congenital cardiac care that unifies clinical and administrative nomenclature.
The members of ISNPCHD realize that the nomenclature published in this manuscript will continue to evolve. The version of the IPCCC that was published in 2017 has evolved and changed, and it is now replaced by this 2021 version. In the future, ISNPCHD will again publish updated versions of IPCCC, as IPCCC continues to evolve.
Ethnohistoric accounts indicate that the people of Australia's Channel Country engaged in activities rarely recorded elsewhere on the continent, including food storage, aquaculture and possible cultivation, yet there has been little archaeological fieldwork to verify these accounts. Here, the authors report on a collaborative research project initiated by the Mithaka people addressing this lack of archaeological investigation. The results show that Mithaka Country has a substantial and diverse archaeological record, including numerous large stone quarries, multiple ritual structures and substantial dwellings. Our archaeological research revealed unknown aspects, such as the scale of Mithaka quarrying, which could stimulate re-evaluation of Aboriginal socio-economic systems in parts of ancient Australia.
Glacier surges are periodic episodes of mass redistribution characterized by dramatic increases in ice flow velocity and, sometimes, terminus advance. We use optical satellite imagery to document five previously unexamined surge events of Sít’ Kusá (Turner Glacier) in the St. Elias Mountains of Alaska from 1983 to 2013. Surge events had an average recurrence interval of ~5 years, making it the shortest known regular recurrence interval in the world. Surge events appear to initiate in the winter, with speeds reaching up to ~25 m d−1. The surges propagate down-glacier over ~2 years, resulting in maximum thinning of ~100 m in the reservoir zone and comparable thickening at the terminus. Collectively, the rapid recurrence interval, winter initiation and down-glacier propagation suggest Sít’ Kusá's surges are driven by periodic changes in subglacial hydrology and glacier sliding. Elevation change observations from the northern tributary show a kinematic disconnect above and below an icefall located 23 km from the terminus. We suggest the kinematic disconnect inhibits drawdown from the accumulation zone above the icefall, which leads to a steady flux of ice into the reservoir zone, and contributes to the glacier's exceptionally short recurrence interval.
In recent years, a variety of efforts have been made in political science to enable, encourage, or require scholars to be more open and explicit about the bases of their empirical claims and, in turn, make those claims more readily evaluable by others. While qualitative scholars have long taken an interest in making their research open, reflexive, and systematic, the recent push for overarching transparency norms and requirements has provoked serious concern within qualitative research communities and raised fundamental questions about the meaning, value, costs, and intellectual relevance of transparency for qualitative inquiry. In this Perspectives Reflection, we crystallize the central findings of a three-year deliberative process—the Qualitative Transparency Deliberations (QTD)—involving hundreds of political scientists in a broad discussion of these issues. Following an overview of the process and the key insights that emerged, we present summaries of the QTD Working Groups’ final reports. Drawing on a series of public, online conversations that unfolded at www.qualtd.net, the reports unpack transparency’s promise, practicalities, risks, and limitations in relation to different qualitative methodologies, forms of evidence, and research contexts. Taken as a whole, these reports—the full versions of which can be found in the Supplementary Materials—offer practical guidance to scholars designing and implementing qualitative research, and to editors, reviewers, and funders seeking to develop criteria of evaluation that are appropriate—as understood by relevant research communities—to the forms of inquiry being assessed. We dedicate this Reflection to the memory of our coauthor and QTD working group leader Kendra Koivu.1
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.
Hyperprolific sows rear more piglets than they have teats, and to accommodate this, milk replacers are often offered as a supplement. Milk replacers are based on bovine milk, yet components of vegetable origin are often added. This may reduce growth, but could also accelerate maturational changes. Therefore, we investigated the effect of feeding piglets a milk replacer with gradually increasing levels of wheat flour on growth, gut enzyme activity and immune function compared with a diet based entirely on bovine milk. The hypothesis tested was that adding a starch component (wheat flour) induces maturation of the mucosa as measured by higher digestive activity and improved integrity and immunity of the small intestines (SI). To test this hypothesis, piglets were removed from the sow at day 3 and fed either a pure milk replacer diet (MILK) or from day 11 a milk replacer diet with increasing levels of wheat (WHEAT). The WHEAT piglets had an increased enzyme activity of maltase and sucrase in the proximal part of the SI compared with the MILK group. There were no differences in gut morphology, histopathology and gene expression between the groups. In conclusion, the pigs given a milk replacer with added wheat displayed immunological and gut mucosal enzyme maturational changes, indicatory of adaptation towards a vegetable-based diet. This was not associated with any clinical complications, and future studies are needed to show whether this could improve responses in the subsequent weaning process.
Cognitive deficits affect a significant proportion of patients with bipolar disorder (BD). Problems with sustained attention have been found independent of mood state and the causes are unclear. We aimed to investigate whether physical parameters such as activity levels, sleep, and body mass index (BMI) may be contributing factors.
Forty-six patients with BD and 42 controls completed a battery of neuropsychological tests and wore a triaxial accelerometer for 21 days which collected information on physical activity, sleep, and circadian rhythm. Ex-Gaussian analyses were used to characterise reaction time distributions. We used hierarchical regression analyses to examine whether physical activity, BMI, circadian rhythm, and sleep predicted variance in the performance of cognitive tasks.
Neither physical activity, BMI, nor circadian rhythm predicted significant variance on any of the cognitive tasks. However, the presence of a sleep abnormality significantly predicted a higher intra-individual variability of the reaction time distributions on the Attention Network Task.
This study suggests that there is an association between sleep abnormalities and cognition in BD, with little or no relationship with physical activity, BMI, and circadian rhythm.
We present a calibration component for the Murchison Widefield Array All-Sky Virtual Observatory (MWA ASVO) utilising a newly developed PostgreSQL database of calibration solutions. Since its inauguration in 2013, the MWA has recorded over 34 petabytes of data archived at the Pawsey Supercomputing Centre. According to the MWA Data Access policy, data become publicly available 18 months after collection. Therefore, most of the archival data are now available to the public. Access to public data was provided in 2017 via the MWA ASVO interface, which allowed researchers worldwide to download MWA uncalibrated data in standard radio astronomy data formats (CASA measurement sets or UV FITS files). The addition of the MWA ASVO calibration feature opens a new, powerful avenue for researchers without a detailed knowledge of the MWA telescope and data processing to download calibrated visibility data and create images using standard radio astronomy software packages. In order to populate the database with calibration solutions from the last 6 yr we developed fully automated pipelines. A near-real-time pipeline has been used to process new calibration observations as soon as they are collected and upload calibration solutions to the database, which enables monitoring of the interferometric performance of the telescope. Based on this database, we present an analysis of the stability of the MWA calibration solutions over long time intervals.
We describe 14 yr of public data from the Parkes Pulsar Timing Array (PPTA), an ongoing project that is producing precise measurements of pulse times of arrival from 26 millisecond pulsars using the 64-m Parkes radio telescope with a cadence of approximately 3 weeks in three observing bands. A comprehensive description of the pulsar observing systems employed at the telescope since 2004 is provided, including the calibration methodology and an analysis of the stability of system components. We attempt to provide full accounting of the reduction from the raw measured Stokes parameters to pulse times of arrival to aid third parties in reproducing our results. This conversion is encapsulated in a processing pipeline designed to track provenance. Our data products include pulse times of arrival for each of the pulsars along with an initial set of pulsar parameters and noise models. The calibrated pulse profiles and timing template profiles are also available. These data represent almost 21 000 h of recorded data spanning over 14 yr. After accounting for processes that induce time-correlated noise, 22 of the pulsars have weighted root-mean-square timing residuals of
in at least one radio band. The data should allow end users to quickly undertake their own gravitational wave analyses, for example, without having to understand the intricacies of pulsar polarisation calibration or attain a mastery of radio frequency interference mitigation as is required when analysing raw data files.
Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged antipsychotic use. RE KINECT, a real-world screening study of antipsychotic-treated outpatients, included patients with movements that were clinician-confirmed as possible TD (Cohort 2) and patients with no involuntary movements (Cohort 1). Baseline data from the patient rated EuroQoL 5-Dimension 5-Level questionnaire (EQ-5D-5L) and Sheehan Disability Scale (SDS) were analyzed to evaluate health related quality of life (Cohort 2 vs. Cohort 1) and the effects of possible TD on quality of life (Cohort 2).
Assessments included EQ-5D-5L utility score (0=equivalent to death to 1=perfect health); SDS total score (0=no impact to 30=highest impact); patient- and clinician-rated severity of possible TD in 4 body regions (0=none, 1=some, and 2=a lot; summary score, 0 to 8); and patient-rated impact of possible TD in 7 daily activities (0=none, 1=some, and 2=a lot; summary score, 0 to 14). Populations included Cohort 1 (N=450); full Cohort 2 (N=204); and limited Cohort 2 (N=111, patients who self-reported “some” or “a lot” of TD severity in ≥1 body region). Mean differences between Cohort 2 and Cohort 1 in EQ-5D-5L utility and SDS total scores were analyzed using a generalized linear regression model that was adjusted for potentially confounding factors (e.g., age, sex, psychiatric diagnosis). Associations between TD summary scores (severity, impact) and quality of life (EQ-5D-5L utility, SDS total) were analyzed using a regression model.
The mean score difference between full Cohort 2 (N=204) and Cohort 1 (N=450) was significant for EQ-5D-5L utility (-0.037; P<0.05 [adjusted analysis]) but not SDS total (0.267; P>0.05). However, when limited to Cohort 2 patients who self-reported “a lot” of TD severity (n=53) or impact (n=33), both EQ 5D 5L utility and SDS total scores were significantly worse than in Cohort 1 (P<0.05). Regression coefficients indicated significant associations between patient-rated impact and EQ 5D-5L utility in the full Cohort 2 (-0.021, P<0.001) and limited Cohort 2 (-0.024, P<0.001). A significant association was also found with patient rated severity in limited Cohort 2 (P<0.05), but not with clinician-rated severity. Similar results were found for SDS total score.
RE-KINECT patients were consistent in evaluating the severity and impact of TD, whether based on subjective assessments or standardized patient-reported instruments (EQ-5D-5L, SDS). Clinician-rated severity of TD may not always correlate with patient perceptions of the significance of TD. Patient self-assessments (focused on symptom impact) can be clinically relevant; incorporating such measures into everyday practice may provide a more comprehensive approach to TD assessment and management.
UK Biobank is a well-characterised cohort of over 500 000 participants including genetics, environmental data and imaging. An online mental health questionnaire was designed for UK Biobank participants to expand its potential.
Describe the development, implementation and results of this questionnaire.
An expert working group designed the questionnaire, using established measures where possible, and consulting a patient group. Operational criteria were agreed for defining likely disorder and risk states, including lifetime depression, mania/hypomania, generalised anxiety disorder, unusual experiences and self-harm, and current post-traumatic stress and hazardous/harmful alcohol use.
A total of 157 366 completed online questionnaires were available by August 2017. Participants were aged 45–82 (53% were ≥65 years) and 57% women. Comparison of self-reported diagnosed mental disorder with a contemporary study shows a similar prevalence, despite respondents being of higher average socioeconomic status. Lifetime depression was a common finding, with 24% (37 434) of participants meeting criteria and current hazardous/harmful alcohol use criteria were met by 21% (32 602), whereas other criteria were met by less than 8% of the participants. There was extensive comorbidity among the syndromes. Mental disorders were associated with a high neuroticism score, adverse life events and long-term illness; addiction and bipolar affective disorder in particular were associated with measures of deprivation.
The UK Biobank questionnaire represents a very large mental health survey in itself, and the results presented here show high face validity, although caution is needed because of selection bias. Built into UK Biobank, these data intersect with other health data to offer unparalleled potential for crosscutting biomedical research involving mental health.
The climate crisis requires nations to achieve human well-being with low national levels of carbon emissions. Countries vary from one another dramatically in how effectively they convert resources into well-being, and some nations with low levels of emissions have relatively high objective and subjective well-being. We identify urgent research and policy agendas for four groups of countries with either low or high emissions and well-being indicators. Least studied are those with low well-being and high emissions. Understanding social and political barriers to switching from high-carbon to lower-carbon modes of production and consumption, and ways to overcome them, will be fundamental.
Tardive dyskinesia (TD) is a hyperkinetic movement disorder associated with antipsychotic treatment. RE KINECT (NCT03062033), a real-world study of outpatients prescribed antipsychotics, was designed to identify the presence of possible TD and characterize the impact of involuntary movements on functioning and quality of life. Data from RE-KINECT were used to compare the impact of possible TD in patients with schizophrenia/schizoaffective disorder [SZD] versus mood/other psychiatric disorders [Mood].
Adults with ≥3months of lifetime exposure to antipsychotics and ≥1 psychiatric disorder were recruited. The presence of possible TD was based on clinicians’ observation of involuntary movements in 4 body regions (head, trunk, upper extremities, and lower extremities). Baseline outcomes included demographics, medication history, location/severity of abnormal movements, impact of abnormal movements on daily activities, the Sheehan Disability Scale (SDS), and the EuroQoL 5-Dimensional questionnaire (EQ-5D-5L).
Of 204 patients with clinician-confirmed possible TD, 111 (54.4%) had a SZD diagnosis and 93 (45.6%) had a mood/other psychiatric diagnosis. Significant differences found between groups (Mood vs SZD) included: mean age (56.9 vs 52.7 years; P=0.0263); male sex (33.3% vs 62.2%; P<0.0001); African-American race (7.5% vs 26.1%; P=0.0005); mean lifetime exposure to antipsychotics (9.5 vs 19.5 years; P<0.0001); and percentage of patients currently taking ≥2 psychiatric medications (93.5% vs 79.3%; P=0.0093). Based on clinician observation, there were no significant differences between diagnosis groups in the number of body regions impacted by abnormal movements, maximum severity score across all 4 regions, or patient awareness of possible TD. Over 30% of patients in both groups reported that involuntary movements had “some” or “a lot” of impact on their ability to continue usual activities, be productive, and socialize. No significant differences between the diagnosis groups (Mood vs SZD) were found for mean SDS total score (12.8 vs 10.8), SDS domain scores (work/school [4.1 vs 4.2], social life [4.3 vs 3.7], family life [4.1 vs 3.5]), EQ-5D-5L utility score (0.68 vs 0.74), or EQ-5D-5L health state VAS (64.8 vs 68.5).
In this cohort of outpatients with possible TD, those with Mood disorders were more likely to be older, female, and white than patients with SZD. The ability to function and quality of life were equally impaired in both groups. Further studies on the impact of TD are needed.
Funding Acknowledgements: Neurocrine Biosciences, Inc.
To identify potential participants for clinical trials, electronic health records (EHRs) are searched at potential sites. As an alternative, we investigated using medical devices used for real-time diagnostic decisions for trial enrollment.
To project cohorts for a trial in acute coronary syndromes (ACS), we used electrocardiograph-based algorithms that identify ACS or ST elevation myocardial infarction (STEMI) that prompt clinicians to offer patients trial enrollment. We searched six hospitals’ electrocardiograph systems for electrocardiograms (ECGs) meeting the planned trial’s enrollment criterion: ECGs with STEMI or > 75% probability of ACS by the acute cardiac ischemia time-insensitive predictive instrument (ACI-TIPI). We revised the ACI-TIPI regression to require only data directly from the electrocardiograph, the e-ACI-TIPI using the same data used for the original ACI-TIPI (development set n = 3,453; test set n = 2,315). We also tested both on data from emergency department electrocardiographs from across the US (n = 8,556). We then used ACI-TIPI and e-ACI-TIPI to identify potential cohorts for the ACS trial and compared performance to cohorts from EHR data at the hospitals.
Receiver-operating characteristic (ROC) curve areas on the test set were excellent, 0.89 for ACI-TIPI and 0.84 for the e-ACI-TIPI, as was calibration. On the national electrocardiographic database, ROC areas were 0.78 and 0.69, respectively, and with very good calibration. When tested for detection of patients with > 75% ACS probability, both electrocardiograph-based methods identified eligible patients well, and better than did EHRs.
Using data from medical devices such as electrocardiographs may provide accurate projections of available cohorts for clinical trials.
A 3-yr watermelon experiment was established in fall 2013 to evaluate cover crop, polyethylene mulch, tillage, and herbicide application components for weed control, yield, and profitability. Conservation tillage, either with a cereal rye cover crop alone or integrated with polyethylene mulch, was compared to the standard industry practice of conventional tillage with bedded polyethylene mulch. The study also used a non-bedded conventional tillage system without polyethylene to determine polyethylene and cover crop residue effects. Within each of the four systems, herbicide treatments comprised halosulfuron applied (1) at 26.3 g ai ha–1 PRE, (2) at 26.3 g ai ha–1 POST, or (3) sequentially at 26.3 g ai ha–1 PRE and POST. Each system also had a nontreated control. In addition, clethodim was applied in all plots twice POST at 140 g ai ha–1, except for nontreated in each system. In 2014, polyethylene or cereal rye cover crop effectively controlled tall morningglory, coffee senna, and carpetweed early season in nontreated plots, whereas the integration of the two was effective at controlling common purslane. Tall morningglory and purslane control was insufficient late season regardless of production system and herbicide application. In 2015, polyethylene effectively controlled cutleaf eveningprimrose, sicklepod, and arrowleaf sida early season in nontreated plots. Yellow nutsedge control was insufficient late season regardless of production system and herbicide application. Utilizing sequential halosulfuron applications did not increase weed control over PRE or POST alone in all years. Polyethylene use resulted in yields higher than systems without in all years. Across all 3 yr, net returns were highest for polyethylene mulch systems. The results of this experiment underscore the need for more progress in developing integrated conservation systems for watermelon production. Effective herbicides, low-disturbance cultivation, and/or hand weeding are most likely the key to success in conservation specialty crop systems.
Seven half-day regional listening sessions were held between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide-resistance management. The objective of the listening sessions was to connect with stakeholders and hear their challenges and recommendations for addressing herbicide resistance. The coordinating team hired Strategic Conservation Solutions, LLC, to facilitate all the sessions. They and the coordinating team used in-person meetings, teleconferences, and email to communicate and coordinate the activities leading up to each regional listening session. The agenda was the same across all sessions and included small-group discussions followed by reporting to the full group for discussion. The planning process was the same across all the sessions, although the selection of venue, time of day, and stakeholder participants differed to accommodate the differences among regions. The listening-session format required a great deal of work and flexibility on the part of the coordinating team and regional coordinators. Overall, the participant evaluations from the sessions were positive, with participants expressing appreciation that they were asked for their thoughts on the subject of herbicide resistance. This paper details the methods and processes used to conduct these regional listening sessions and provides an assessment of the strengths and limitations of those processes.