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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.
Research indicates that sexual harassment and assault commonly occur during archaeological field research, and students, trainees, and early career professionals are more frequently subjected to harassing behaviors compared to mid-career and senior scientists. Specific to archaeological education, the undergraduate educational requirement of a field school puts students and trainees in situations where harassment historically has been unchecked. We present the results of a systematic content analysis of 24 sets of field school documents. We analyzed these documents with attention to how field school policies, procedures, and language may impact students’ perceptions of their expected behaviors, logistics and means of reporting, and stated policies surrounding sexual harassment and assault. Coding was conducted using an a priori coding scheme to identify practices that should lead to a safe and supportive field learning environment. Our coding scheme resulted in 11 primary codes that we summarized as three primary themes: (1) field school organization and expected student behavior, (2) logistics of the course, and (3) stated policies surrounding sexual harassment and assault. Based on these themes, we provide recommendations to modify field school documents and practices to create a field school that provides safe opportunities for students to learn.
Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
Aims
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Method
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Results
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
Conclusions
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
The rapid development of high-intensity laser-generated particle and photon secondary sources has attracted widespread interest during the last 20 years not only due to fundamental science research but also because of the important applications of this developing technology. For instance, the generation of relativistic particle beams, betatron-type coherent X-ray radiation and high harmonic generation have attracted interest from various fields of science and technology owing to their diverse applications in biomedical, material science, energy, space, and security applications. In the field of biomedical applications in particular, laser-driven particle beams as well as laser-driven X-ray sources are a promising field of study. This article looks at the research being performed at the Institute of Plasma Physics and Lasers (IPPL) of the Hellenic Mediterranean University Research Centre. The recent installation of the ZEUS 45 TW laser system developed at IPPL offers unique opportunities for research in laser-driven particle and X-ray sources. This article provides information about the facility and describes initial experiments performed for establishing the baseline platforms for secondary plasma sources.
Gravitational waves from coalescing neutron stars encode information about nuclear matter at extreme densities, inaccessible by laboratory experiments. The late inspiral is influenced by the presence of tides, which depend on the neutron star equation of state. Neutron star mergers are expected to often produce rapidly rotating remnant neutron stars that emit gravitational waves. These will provide clues to the extremely hot post-merger environment. This signature of nuclear matter in gravitational waves contains most information in the 2–4 kHz frequency band, which is outside of the most sensitive band of current detectors. We present the design concept and science case for a Neutron Star Extreme Matter Observatory (NEMO): a gravitational-wave interferometer optimised to study nuclear physics with merging neutron stars. The concept uses high-circulating laser power, quantum squeezing, and a detector topology specifically designed to achieve the high-frequency sensitivity necessary to probe nuclear matter using gravitational waves. Above 1 kHz, the proposed strain sensitivity is comparable to full third-generation detectors at a fraction of the cost. Such sensitivity changes expected event rates for detection of post-merger remnants from approximately one per few decades with two A+ detectors to a few per year and potentially allow for the first gravitational-wave observations of supernovae, isolated neutron stars, and other exotica.
Introduction: CAEP recently developed the acute atrial fibrillation (AF) and flutter (AFL) [AAFF] Best Practices Checklist to promote optimal care and guidance on cardioversion and rapid discharge of patients with AAFF. We sought to assess the impact of implementing the Checklist into large Canadian EDs. Methods: We conducted a pragmatic stepped-wedge cluster randomized trial in 11 large Canadian ED sites in five provinces, over 14 months. All hospitals started in the control period (usual care), and then crossed over to the intervention period in random sequence, one hospital per month. We enrolled consecutive, stable patients presenting with AAFF, where symptoms required ED management. Our intervention was informed by qualitative stakeholder interviews to identify perceived barriers and enablers for rapid discharge of AAFF patients. The many interventions included local champions, presentation of the Checklist to physicians in group sessions, an online training module, a smartphone app, and targeted audit and feedback. The primary outcome was length of stay in ED in minutes from time of arrival to time of disposition, and this was analyzed at the individual patient-level using linear mixed effects regression accounting for the stepped-wedge design. We estimated a sample size of 800 patients. Results: We enrolled 844 patients with none lost to follow-up. Those in the control (N = 316) and intervention periods (N = 528) were similar for all characteristics including mean age (61.2 vs 64.2 yrs), duration of AAFF (8.1 vs 7.7 hrs), AF (88.6% vs 82.9%), AFL (11.4% vs 17.1%), and mean initial heart rate (119.6 vs 119.9 bpm). Median lengths of stay for the control and intervention periods respectively were 413.0 vs. 354.0 minutes (P < 0.001). Comparing control to intervention, there was an increase in: use of antiarrhythmic drugs (37.4% vs 47.4%; P < 0.01), electrical cardioversion (45.1% vs 56.8%; P < 0.01), and discharge in sinus rhythm (75.3% vs. 86.7%; P < 0.001). There was a decrease in ED consultations to cardiology and medicine (49.7% vs 41.1%; P < 0.01), but a small but insignificant increase in anticoagulant prescriptions (39.6% vs 46.5%; P = 0.21). Conclusion: This multicenter implementation of the CAEP Best Practices Checklist led to a significant decrease in ED length of stay along with more ED cardioversions, fewer ED consultations, and more discharges in sinus rhythm. Widespread and rigorous adoption of the CAEP Checklist should lead to improved care of AAFF patients in all Canadian EDs.
Introduction: The Brain Injury Guidelines (BIG) stratifies complicated mild traumatic brain injury (mTBI) patients into 3 groups to guide hospitalization, neurosurgical consultation and repeat head-CT. BIG-1 patients could be managed safely without neurosurgical consultation or transfer. Systematic transfer to neurotrauma centers provide few benefits to this subgroup leading to overtriage. Similarly, unnecessary clinical and radiological follow-ups utilize significant health-care resources. Objective: to validate the safety and efficacy of the BIG for complicated mTBIs. Methods: We performed a multicenter historical cohort study in 3 level-1 trauma centers in Quebec. Patients ≥16 years old assessed in the Emergency Department (ED) with complicated mTBI between 2014 and 2017 were included. Patients with penetrating trauma, cerebral aneurysm or tumor were excluded. Clinical, demographic and radiological data, BIG variables, TBI-related death and neurosurgical intervention were collected using a standardized form. A second reviewer assessed all ambiguous files. Descriptive statistics, over- and under-triage were calculated. Results: A total of 342 patients’ records were assessed. Mean age was 63 ± 20,7 and 236 (69 %) were male. Thirty-five patients were classified under BIG-1 (10.2%), 110 under BIG-2 (32.2%) and 197 under BIG-3 (57.6%). Twenty-six patients (7%) required neurosurgical intervention, all were BIG-3. 90% of TBI-related deaths occurred in BIG-3 and none were classified BIG-1. Among the 192 transfers (51%), 14 were classified under BIG-1 (7.3%) and should not have been transferred according to the guidelines and 50 under BIG-2 (26%). In addition, 40% of BIG-1 received a repeat head computed tomography, although not indicated. Similarly, 7 % of all patients had a neurosurgical consult even if not required. Projected implementation of BIG would lead to 47% of overtriage and 0.3% of undertriage. Conclusion: Our results suggest that the Brain Injury Guidelines could safely identify patients with negative outcomes and could lead to a safe and effective management of complicated mTBI. Applying these guidelines to our cohort could have resulted in significantly fewer repeat head CTs, neurosurgical consults and transfers to level 1 neurotrauma centers.
Bipolar disorder (BD) is associated with impaired psychosocial behaviours. Little is known about deficits in neurocognitive functions like decision-making possibly related both to these behaviours and to the nature of the disorder.
Objectives
To determine whether decision-making impairments exist in manic (M), depressed (D) and euthymic (E) bipolar patients (BP) and to determine whether illness and course-of-illness characteristics can predict participants’ performance
Methods
A power analysis was conducted. A total of 315 subjects, including 45 M and 32 D inpatients and 90 E outpatients with BD I, medicated, and 150 Healthy Controls (HC), age, IQ and gender-matched, were included. Decision-making ability and sensitivity to punishment frequency were assessed with the Iowa Gambling Task (IGT).
Results
On the IGT, MBP (p< 0.001), DBP (p< 0.01) and EBP (p< 0.05) selected significantly more cards from the risky decks than HC with no significant differences between BP groups. Unlike HC, MBP (p< 0.001), DBP (p< 0.05) and EBP (p< 0.05) showed little capacity to learn from incurred losses with no significant differences between BP groups, but, like HC, BP preferred decks that yielded infrequent penalties over those decks that yielded frequent penalties. In a multivariate analysis, decision-making impairment in the BP was significantly (p=0.001) predicted by low level of education, high total number of admissions and family history of BD.
Conclusions
BP clearly show defects in decision-making predicted by course-of-illness illness characteristics. Impaired decision-making might be a trait-related neurocognitive deficit in BD and partly explain impaired psychosocial behaviours of BP.
The purpose of this paper was to examine national differences in the desire to participate in decision-making of people with severe mental illness in six European countries.
Methods
The data was taken from a European longitudinal observational study (CEDAR; ISRCTN75841675). A sample of 514 patients with severe mental illness from the study centers in Ulm, Germany, London, England, Naples, Italy, Debrecen, Hungary, Aalborg, Denmark and Zurich, Switzerland were assessed as to desire to participate in medical decision-making. Associations between desire for participation in decision-making and center location were analyzed with generalized estimating equations.
Results
We found large cross-national differences in patients’ desire to participate in decision-making, with the center explaining 47.2% of total variance in the desire for participation (P < 0.001). Averaged over time and independent of patient characteristics, London (mean = 2.27), Ulm (mean = 2.13) and Zurich (mean = 2.14) showed significantly higher scores in desire for participation, followed by Aalborg (mean = 1.97), where scores were in turn significantly higher than in Debrecen (mean = 1.56). The lowest scores were reported in Naples (mean = 1.14). Over time, the desire for participation in decision-making increased significantly in Zurich (b = 0.23) and decreased in Naples (b = −0.14). In all other centers, values remained stable.
Conclusions
This study demonstrates that patients’ desire for participation in decision-making varies by location. We suggest that more research attention be focused on identifying specific cultural and social factors in each country to further explain observed differences across Europe.
Chronic suppurative otitis media is a massive public health problem in numerous low- and middle-income countries. Unfortunately, few low- and middle-income countries can offer surgical therapy.
Methods
A six-month long programme in Cambodia focused on training local surgeons in type I tympanoplasty was instigated. Qualitative educational and quantitative surgical outcomes were evaluated in the 12 months following programme completion. A four-month long training programme in mastoidectomy and homograft ossiculoplasty was subsequently implemented, and the preliminary surgical and educational outcomes were reported.
Results
A total of 124 patients underwent tympanoplasty by the locally trained surgeons. Tympanic membrane closure at six weeks post-operation was 88.5 per cent. Pure tone audiometry at three months showed that 80.9 per cent of patients had improved hearing, with a mean gain of 17.1 dB. The trained surgeons reported high confidence in performing tympanoplasty. Early outcomes suggest the local surgeons can perform mastoidectomy and ossiculoplasty as safely as overseas-trained surgeons, with reported surgeon confidence reflecting these positive outcomes.
Conclusion
The training programme has demonstrated success, as measured by surgeon confidence and operative outcomes. This approach can be emulated in other settings to help combat the global burden of chronic suppurative otitis media.
The ability of the aorta to buffer blood flow and provide diastolic perfusion (Windkessel function) is a determinant of cardiovascular health. We have reported cardiac dysfunction indicating downstream vascular abnormalities in young adult baboons who were intrauterine growth restricted (IUGR) at birth as a result of moderate maternal nutrient reduction. Using 3 T MRI, we examined IUGR offspring (eight male, eight female; 5.7 years; human equivalent 25 years) and age-matched controls (eight male, eight female; 5.6 years) to quantify distal descending aortic cross-section (AC) and distensibility (AD). ANOVA showed decreased IUGR AC/body surface area (0.9±0.05 cm2/m2v. 1.2±0.06 cm2/m2, M±s.e.m., P<0.005) and AD (1.7±0.2 v. 4.0±0.5×10−3/mmHg, P<0.005) without sex difference or group-sex interaction, suggesting intrinsic vascular pathology and impaired development persisting in adulthood. Future studies should evaluate potential consequences of these changes on coronary perfusion, afterload and blood pressure.
Healthy adults (n 30) participated in a placebo-controlled, randomised, double-blinded, cross-over study consisting of two 28 d treatments (β2-1 fructan or maltodextrin; 3×5 g/d) separated by a 14-d washout. Subjects provided 1 d faecal collections at days 0 and 28 of each treatment. The ability of faecal bacteria to metabolise β2-1 fructan was common; eighty-seven species (thirty genera, and four phyla) were isolated using anaerobic medium containing β2-1 fructan as the sole carbohydrate source. β2-1 fructan altered the faecal community as determined through analysis of terminal restriction fragment length polymorphisms and 16S rRNA genes. Supplementation with β2-1 fructan reduced faecal community richness, and two patterns of community change were observed. In most subjects, β2-1 fructan reduced the content of phylotypes aligning within the Bacteroides, whereas increasing those aligning within bifidobacteria, Faecalibacterium and the family Lachnospiraceae. In the remaining subjects, supplementation increased the abundance of Bacteroidetes and to a lesser extent bifidobacteria, accompanied by decreases within the Faecalibacterium and family Lachnospiraceae. β2-1 Fructan had no impact on the metagenome or glycoside hydrolase profiles in faeces from four subjects. Few relationships were found between the faecal bacterial community and various host parameters; Bacteroidetes content correlated with faecal propionate, subjects whose faecal community contained higher Bacteroidetes produced more caproic acid independent of treatment, and subjects having lower faecal Bacteroidetes exhibited increased concentrations of serum lipopolysaccharide and lipopolysaccharide binding protein independent of treatment. We found no evidence to support a defined health benefit for the use of β2-1 fructans in healthy subjects.
In very low birth weight infants, persistence of a patent ductus arteriosus results in morbidity and mortality. Therapies to close the ductus are effective, but clinical outcomes may depend on the accuracy of diagnosis and the timing of administration. The objective of the present study was to characterise the association between early echocardiography, therapy for patent ductus arteriosus, and outcomes in very low birth weight infants.
Methods
This retrospective cohort study used electronic health record data on inborn infants of gestational age ⩽28 weeks and birth weight <1500 g who were discharged after day of life 7 from 362 neonatal ICU from 1997 to 2013. The primary outcome was death between day of life 7 and discharge. Secondary outcomes included bronchopulmonary dysplasia, necrotising enterocolitis, and grade 3 or 4 intraventricular haemorrhage.
Results
This study included a total of 48,551 infants with a median gestational age of 27 weeks (interquartile range 25, 28) and birth weight 870 g (706, 1050). Early echocardiography – that is, performed during days of life 2 to 6 – was performed in 15,971/48,551 (33%) infants, and patent ductus arteriosus was diagnosed in 31,712/48,551 (65%). The diagnosis was more common in infants who had undergone early echocardiography (14,549/15,971 [91%] versus 17,163/32,580 [53%], p<0.001). In multivariable analysis, early echocardiography was not associated with reduced mortality (odds ratio 0.97, 95% CI 0.89–1.05). Results were similar in the subset of infants who received therapy for patent ductus arteriosus (odds ratio 1.01, 95% CI 0.90–1.15).
Conclusions
Early echocardiography was associated with an increased diagnosis of patent ductus arteriosus, but not with decreased mortality.
Precision agriculture (PA) may improve the sustainability of Chinese agriculture. Ten experts were interviewed and 34 farm workers surveyed regarding their understanding, attitudes and perceptions towards PA. PA technologies were considered inaccessible, unsuitable and unnecessary for smaller farms. High cost, lack of perceived benefits, and skills and capability required to adopt PA represented barriers to adoption. Financial incentives/subsidies, the need for tangible benefits and tailored solutions to be demonstrated to farmers, and agronomic and peer support were desired. Future research should further explore PA with Chinese stakeholders and end-users in China, to inform future socio-technological developments.
Background: Patients who require hospitalization for a mild or moderate traumatic brain injury (TBI) are often discharged home with uncertainty around their full recovery. This study examines the frequency and severity of common post-TBI symptoms, as assessed by the Rivermead Post-Concussion Symptoms Questionnaire (RPCQ). Methods: All adult TBI inpatients discharged home from the Neurosurgery service were interviewed by phone at two weeks by a rehab-based nurse practitioner. RPCQ components (cognitive, emotional, and somatic) were analyzed; findings and management recommendations were communicated to family practitioners and the treating neurosurgeon. Results: In 46 patients, cognitive symptoms were present in 52%, 91% had somatic, and 100% had emotional symptoms. Fatigue was the most common symptom (67%). Double vision was the least common symptom (4%). Recommendations for managing symptoms, return to work, and need for formal clinical assessment were provided for 37% of cases. Conclusions: All patients admitted to neurosurgery with mild or moderate TBI had symptoms at two weeks. The RPCQ is a low-cost structured evaluative tool which highlights needs and provides guidance for patients and care-givers; it also seems effective in identifying those who may require formal clinical assessment.
Systemic hypertension is increasingly recognised in premature infants. There is limited evidence regarding treatment, and most published treatment recommendations are based solely on expert opinions.
Methods
We identified all infants born ⩽32 weeks of gestation and ⩽1500 g birth weight discharged from one of 348 neonatal ICUs managed by the Pediatrix Medical Group between 1997 and 2013. We defined antihypertensive drugs as vasodilators, angiotensin-converting enzyme inhibitors, β receptor blockers, calcium channel blockers, and central α2 receptor agonists. We compared characteristics between infants who were treated with at least one antihypertensive drug during their initial hospitalisation and infants who were not prescribed antihypertensive drugs using Wilcoxon’s ranked sum test or Pearson’s χ2-test.
Results
We identified 2504/119,360 (2.1%) infants who required at least one antihypertensive drug. The median postnatal age of first exposure was 48 days (25th, 75th percentile 15, 86), and the median length of therapy was 6 days (1, 16). Hydralazine was the most commonly prescribed antihypertensive with 1280/2504 (51.1%) treated infants exposed to the drug. More than two antihypertensive drugs were administered in 582/2504 (23.2%) infants, and 199/2097 (9.5%) of the treated infants were discharged home on antihypertensive therapy. Infants who received antihypertensive drugs were of lower gestational age (p<0.001) and birth weight (p<0.001) compared with infants not prescribed antihypertensive drugs.
Conclusions
Our study is the largest to describe current antihypertensive drug exposure in a cohort of exclusively premature infants born ⩽32 weeks of gestation. We found wide variations in practice for treating hypertension in premature infants.