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The Square Kilometre Array (SKA) is a planned large radio interferometer designed to operate over a wide range of frequencies, and with an order of magnitude greater sensitivity and survey speed than any current radio telescope. The SKA will address many important topics in astronomy, ranging from planet formation to distant galaxies. However, in this work, we consider the perspective of the SKA as a facility for studying physics. We review four areas in which the SKA is expected to make major contributions to our understanding of fundamental physics: cosmic dawn and reionisation; gravity and gravitational radiation; cosmology and dark energy; and dark matter and astroparticle physics. These discussions demonstrate that the SKA will be a spectacular physics machine, which will provide many new breakthroughs and novel insights on matter, energy, and spacetime.
We apply two methods to estimate the 21-cm bispectrum from data taken within the Epoch of Reionisation (EoR) project of the Murchison Widefield Array (MWA). Using data acquired with the Phase II compact array allows a direct bispectrum estimate to be undertaken on the multiple redundantly spaced triangles of antenna tiles, as well as an estimate based on data gridded to the uv-plane. The direct and gridded bispectrum estimators are applied to 21 h of high-band (167–197 MHz; z = 6.2–7.5) data from the 2016 and 2017 observing seasons. Analytic predictions for the bispectrum bias and variance for point-source foregrounds are derived. We compare the output of these approaches, the foreground contribution to the signal, and future prospects for measuring the bispectra with redundant and non-redundant arrays. We find that some triangle configurations yield bispectrum estimates that are consistent with the expected noise level after 10 h, while equilateral configurations are strongly foreground-dominated. Careful choice of triangle configurations may be made to reduce foreground bias that hinders power spectrum estimators, and the 21-cm bispectrum may be accessible in less time than the 21-cm power spectrum for some wave modes, with detections in hundreds of hours.
Item 9 of the Patient Health Questionnaire-9 (PHQ-9) queries about thoughts of death and self-harm, but not suicidality. Although it is sometimes used to assess suicide risk, most positive responses are not associated with suicidality. The PHQ-8, which omits Item 9, is thus increasingly used in research. We assessed equivalency of total score correlations and the diagnostic accuracy to detect major depression of the PHQ-8 and PHQ-9.
We conducted an individual patient data meta-analysis. We fit bivariate random-effects models to assess diagnostic accuracy.
16 742 participants (2097 major depression cases) from 54 studies were included. The correlation between PHQ-8 and PHQ-9 scores was 0.996 (95% confidence interval 0.996 to 0.996). The standard cutoff score of 10 for the PHQ-9 maximized sensitivity + specificity for the PHQ-8 among studies that used a semi-structured diagnostic interview reference standard (N = 27). At cutoff 10, the PHQ-8 was less sensitive by 0.02 (−0.06 to 0.00) and more specific by 0.01 (0.00 to 0.01) among those studies (N = 27), with similar results for studies that used other types of interviews (N = 27). For all 54 primary studies combined, across all cutoffs, the PHQ-8 was less sensitive than the PHQ-9 by 0.00 to 0.05 (0.03 at cutoff 10), and specificity was within 0.01 for all cutoffs (0.00 to 0.01).
PHQ-8 and PHQ-9 total scores were similar. Sensitivity may be minimally reduced with the PHQ-8, but specificity is similar.
Background: Spinal muscular atrophy (SMA) is a children’s neuromuscular disorder. Although motor neuron loss is a major feature of the disease, we have identified fatty acid abnormalities in SMA patients and in preclinical animal models, suggesting metabolic perturbation is also an important component of SMA. Methods: Biochemical, histological, proteomic, and high resolution respirometry were used. Results: SMA patients are more susceptible to dyslipidemia than the average population as determined by a standard lipid profile in a cohort of 72 pediatric patients. As well, we observed a non-alcoholic liver disease phenotype in apreclinical mouse model. Denervation alone was not sufficient to induce liver steatosis, as a mouse model of ALS, did not develop fatty liver. Hyperglucagonemia in Smn2B/-mice could explain the hepatic steatosis by increasing plasma substrate availability via glycogen depletion and peripheral lipolysis. Proteomic analysis identified mitochondrion and lipid metabolism as major clusters. Alterations in mitochondrial function were revealed by high-resolution respirometry. Finally, low-fat diets led to increased survival in Smn2B/-mice. Conclusions: These results provide strong evidence for lipid metabolism defects in SMA. Further investigation will be required to establish the primary mechanism of these alterations and understand how they lead to additional co-morbidities in SMA patients.
Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.
To evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics.
Data collected for an individual participant data meta-analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit.
A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15–3.87). Compared with semi-structured interviews, fully structured interviews (MINI excluded) were non-significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores ≤6) as having major depression (OR = 3.13; 95% CI = 0.98–10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7–15) (OR = 0.96; 95% CI = 0.56–1.66) and significantly less likely for high-level symptoms (PHQ-9 scores ≥16) (OR = 0.50; 95% CI = 0.26–0.97).
The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.
Declaration of interest
Drs Jetté and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication.
We examined longitudinally the course and predictors of treatment resistance in a large cohort of first-episode psychosis (FEP) patients from initiation of antipsychotic treatment. We hypothesized that antipsychotic treatment resistance is: (a) present at illness onset; and (b) differentially associated with clinical and demographic factors.
The study sample comprised 323 FEP patients who were studied at first contact and at 10-year follow-up. We collated clinical information on severity of symptoms, antipsychotic medication and treatment adherence during the follow-up period to determine the presence, course and predictors of treatment resistance.
From the 23% of the patients, who were treatment resistant, 84% were treatment resistant from illness onset. Multivariable regression analysis revealed that diagnosis of schizophrenia, negative symptoms, younger age at onset, and longer duration of untreated psychosis predicted treatment resistance from illness onset.
The striking majority of treatment-resistant patients do not respond to first-line antipsychotic treatment even at time of FEP. Clinicians must be alert to this subgroup of patients and consider clozapine treatment as early as possible during the first presentation of psychosis.
Background: Planning for neurology training necessitated a reflection on the experience of graduates. We explored practice characteristics, and training experience of recent graduates. Methods: Graduates from 2010-2014 completed a survey. Results: Response rate was 37% of 211. 56% were female. 91% were adult neurologists. 65% practiced in an outpatient setting. 63% worked in academics. 85% completed subspecialty training (median 1 year). 36% work 3 days a week or less. 82% took general call (median 1 night weekly). Role preparation was considered very good or excellent for most; however poor or fair ratings were 17% in advocacy and 8% in leadership. Training feedback was at least “good” for 87%. Burnout a few times a week or more was noted by 5% (6% during residency, particularly PGY1 and 5). 64% felt overly burdened by paperwork. Although most felt training was adequate, it was poor or fair at preparing for practice management (85%) and personal balance (55%). Most conditions were under-observed in training environment. Many noted a need for more independent practice development and community neurology. Conclusions: Although our training was found to be very good, some identified needs included advocacy training, and more training in general neurology in the longitudinal outpatient/community settings.
Introduction: Acute upper gastrointestinal (UGI) bleeding is a relatively common emergency resulting in death in 6 to 8% of cases. UGI endoscopy is the intervention of choice which requires procedural sedation and analgesia (PSA). The Halifax Infirmary emergency department (ED) performs 1000 PSAs annually, performed by advanced care paramedics (ACPs). This has been shown safe for other indications for PSA, such as orthopedic procedures. Considering that UGI endoscopy involves upper airway manipulation, and patients are at an increased risk of massive bleeding, this procedure would be expected to be more complex and have an increased risk of adverse events (AEs). This study aims to compare PSA for UGI endoscopy performed by ACPs to that for orthopedic procedures for AEs, airway intervention and medication use. Methods: This study is a retrospective review of an ACP-performed ED PSA quality control database. A dataset was built matching 64 UGI endoscopy PSAs to 192 orthopedic PSAs by propensity scores calculated using age, gender and ASA classification. Outcomes assessed were hypotension (SBP < 100, or 15% decrease from baseline), hypoxia (SaO2 < 90), apnea (> 30sec), vomiting, arrhythmias and death in the ED. The need for airway intervention and medication use was assessed. Results: The UGI endoscopy group was 4.60 times more likely to suffer hypotension than the orthopedic group (OR=4.6, CI:2.2-9.6), and a fifth as likely to require airway repositioning (OR=0.2, CI:0.1-0.5). One endoscopy patient required endotracheal intubation. No patient died in either group. Compared to the orthopedic group, the UGI endoscopy group was one-third as likely to receive fentanyl (OR=0.3, CI:0.2-0.6). When fentanyl was administered, endoscopy patients received an average 26.7 mcg less than orthopedic patients. The endoscopy group was 15.4 times more likely to receive ketamine (OR=15.4, CI:4.7-66.5), and received 34.4 mg less on average. Four endoscopy patients received phenylephrine compared to none in the orthopedic group. There were no other differences. Conclusion: ED PSA for UGI endoscopy appears to differ significantly from that performed for orthopedic procedures. It was associated with more frequent hypotension and increased use of ketamine as a sedative. Patients undergoing UGI endoscopy were less likely to receive fentanyl and require airway repositioning. Only patients in the endoscopy group required intubation or a vasopressor agent.
Introduction: Point of care ultrasound (PoCUS) provides invaluable information during resuscitation efforts in cardiac arrest by determining presence/absence of cardiac activity and identifying reversible causes such as pericardial tamponade. There is no agreed guideline on how to safely and effectively incorporate PoCUS into the advanced cardiac life support (ACLS) algorithm. We consider that a consensus-based priority checklist using a “4 F’s” approach (Fluid; Form; Function; Filling), would provide a better algorithm during ACLS. Methods: The ultrasound subcommittee of the Australasian College for Emergency Medicine (ACEM) drafted a checklist incorporating PoCUS into the ACLS algorithm. This was further developed using the input of 24 international experts associated with five professional organizations led by the International Federation of Emergency Medicine. A modified Delphi tool was developed to reach an international consensus on how to integrate ultrasound into cardiac arrest algorithms for emergency department patients. Results: Consensus was reached following 3 rounds. The agreed protocol focuses on the timing of PoCUS as well as the specific clinical questions. Core cardiac windows performed during the rhythm check pause in chest compressions are the sub-xiphoid and parasternal cardiac views. Either view should be used to detect pericardial fluid, as well as examining ventricular form (e.g. right heart strain) and function, (e.g. asystole versus organized cardiac activity). Supplementary views include lung views (for absent lung sliding in pneumothorax and for pleural fluid), and IVC views for filling. Additional ultrasound applications are for endotracheal tube confirmation, proximal leg veins for DVT, or for sources of blood loss (AAA, peritoneal/pelvic fluid). Conclusion: The authors hope that this process will lead to a consensus-based SHoC-cardiac arrest guideline on incorporating PoCUS into the ACLS algorithm.
Very sensitive low-noise amplifiers designed to receive transmissions from spacecraft are not necessarily suitable receivers for radio astronomy. In the former case a good signalto- noise ratio is required so that high data rates can be achieved. In the latter the ratio of signal to noise power may be as low as 10-4 and the stability of receiver gain and that of ail sources of noise during long integration times become of equal importance.
This paper describes a novel solution to the problem, which allowed important astronomy to be performed while the ruby maser receivers belonging to the European Space Agency were installed on the Parkes radio telescope for an extended period of time.
Major depressive disorder (MDD) is moderately heritable, however genome-wide association studies (GWAS) for MDD, as well as for related continuous outcomes, have not shown consistent results. Attempts to elucidate the genetic basis of MDD may be hindered by heterogeneity in diagnosis. The Center for Epidemiological Studies Depression (CES-D) scale provides a widely used tool for measuring depressive symptoms clustered in four different domains which can be combined together into a total score but also can be analysed as separate symptom domains.
We performed a meta-analysis of GWAS of the CES-D symptom clusters. We recruited 12 cohorts with the 20- or 10-item CES-D scale (32 528 persons).
One single nucleotide polymorphism (SNP), rs713224, located near the brain-expressed melatonin receptor (MTNR1A) gene, was associated with the somatic complaints domain of depression symptoms, with borderline genome-wide significance (pdiscovery = 3.82 × 10−8). The SNP was analysed in an additional five cohorts comprising the replication sample (6813 persons). However, the association was not consistent among the replication sample (pdiscovery+replication = 1.10 × 10−6) with evidence of heterogeneity.
Despite the effort to harmonize the phenotypes across cohorts and participants, our study is still underpowered to detect consistent association for depression, even by means of symptom classification. On the contrary, the SNP-based heritability and co-heritability estimation results suggest that a very minor part of the variation could be captured by GWAS, explaining the reason of sparse findings.
A number of authors have hypothesized that psychotic patients who consume cannabis constitute a differentiated subgroup of patients that have better cognitive and social skills, necessary to engage in illegal drug consumption, than non-using patients.
Given that the prevalence, and patterns, of cannabis use are culturally driven, we wanted to study first-episode psychosis (FEP) cannabis-using and non-using patients coming from different European countries as part of the EUGEI-STUDY.
We tested the hypothesis of better premorbid social adjustment in cannabis-using FEP patients, by comparing them to FEP non cannabis users and to their respective healthy controls.
A total of 1745 people (746 cases; 999 controls) completed the assessment for premorbid adjustment [Premorbid Adjustment Scale (PAS)] and cannabis use (CEQ-Revised). We first extracted the Premorbid Social Adjustment Factor (PSA) from PAS and then performedlinear mixed models with PSA as dependent variable and cannabis lifetime (Yes/No) and subject status (Cases/Controls) as independent variables. We then considered “Country” as random intercept.
Across all countries, PSA scores were better in patients who had smoked cannabis in their lifetime than patients who had not (P = 0.009). The difference in PSA score between cannabis users and non-users was significantly greater in cases than controls (P = 0.038). The relationship between PSA, cannabis lifetime (Yes/No) and subject status among nations (random intercept) is shown on Fig. 1.
Cannabis-using psychotic patients show better premorbid social adjustment than non-using patients, across 5 European countries.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Depression is characterized by poor executive function, but – counterintuitively – in some studies, it has been associated with highly accurate performance on certain cognitively demanding tasks. The psychological mechanisms responsible for this paradoxical finding are unclear. To address this issue, we applied a drift diffusion model (DDM) to flanker task data from depressed and healthy adults participating in the multi-site Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care for Depression (EMBARC) study.
One hundred unmedicated, depressed adults and 40 healthy controls completed a flanker task. We investigated the effect of flanker interference on accuracy and response time, and used the DDM to examine group differences in three cognitive processes: prepotent response bias (tendency to respond to the distracting flankers), response inhibition (necessary to resist prepotency), and executive control (required for execution of correct response on incongruent trials).
Consistent with prior reports, depressed participants responded more slowly and accurately than controls on incongruent trials. The DDM indicated that although executive control was sluggish in depressed participants, this was more than offset by decreased prepotent response bias. Among the depressed participants, anhedonia was negatively correlated with a parameter indexing the speed of executive control (r = −0.28, p = 0.007).
Executive control was delayed in depression but this was counterbalanced by reduced prepotent response bias, demonstrating how participants with executive function deficits can nevertheless perform accurately in a cognitive control task. Drawing on data from neural network simulations, we speculate that these results may reflect tonically reduced striatal dopamine in depression.
The extent to which different symptom dimensions vary according to epidemiological factors associated with categorical definitions of first-episode psychosis (FEP) is unknown. We hypothesized that positive psychotic symptoms, including paranoid delusions and depressive symptoms, would be more prominent in more urban environments.
We collected clinical and epidemiological data on 469 people with FEP (ICD-10 F10–F33) in two centres of the Aetiology and Ethnicity in Schizophrenia and Other Psychoses (AESOP) study: Southeast London and Nottinghamshire. We used multilevel regression models to examine neighbourhood-level and between-centre differences in five symptom dimensions (reality distortion, negative symptoms, manic symptoms, depressive symptoms and disorganization) underpinning Schedules for Clinical Assessment in Neuropsychiatry (SCAN) Item Group Checklist (IGC) symptoms. Delusions of persecution and reference, along with other individual IGC symptoms, were inspected for area-level variation.
Reality distortion [estimated effect size (EES) 0.15, 95% confidence interval (CI) 0.06–0.24] and depressive symptoms (EES 0.21, 95% CI 0.07–0.34) were elevated in people with FEP living in more urban Southeast London but disorganized symptomatology was lower (EES –0.06, 95% CI –0.10 to –0.02), after controlling for confounders. Delusions of persecution were not associated with increased neighbourhood population density [adjusted odds ratio (aOR) 1.01, 95% CI 0.83–1.23], although an effect was observed for delusions of reference (aOR 1.41, 95% CI 1.12–1.77). Hallucinatory symptoms showed consistent elevation in more densely populated neighbourhoods (aOR 1.32, 95% CI 1.09–1.61).
In people experiencing FEP, elevated levels of reality distortion and depressive symptoms were observed in more urban, densely populated neighbourhoods. No clear association was observed for paranoid delusions; hallucinations were consistently associated with increased population density. These results suggest that urban environments may affect the syndromal presentation of psychotic disorders.
White matter (WM) abnormalities are proposed as potential endophenotypic markers of bipolar disorder (BD). In a diffusion tensor imaging (DTI) voxel-based analysis (VBA) study of families multiply affected with BD, we previously reported that widespread abnormalities of fractional anisotropy (FA) are associated with both BD and genetic liability for illness. In the present study, we further investigated the endophenotypic potential of WM abnormalities by applying DTI tractography to specifically investigate tracts implicated in the pathophysiology of BD.
Diffusion magnetic resonance imaging (MRI) data were acquired from 19 patients with BD type I from multiply affected families, 21 of their unaffected first-degree relatives and 18 healthy volunteers. DTI tractography was used to identify the cingulum, uncinate fasciculus (UF), arcuate portion of the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), corpus callosum, and the anterior limb of the internal capsule (ALIC). Regression analyses were conducted to investigate the effect of participant group and genetic liability on FA and radial diffusivity (RD) in each tract.
We detected a significant effect of group on both FA and RD in the cingulum, SLF, callosal splenium and ILF driven by reduced FA and increased RD in patients compared to controls and relatives. Increasing genetic liability was associated with decreased FA and increased RD in the UF, and decreased FA in the SLF, among patients.
WM microstructural abnormalities in limbic, temporal and callosal pathways represent microstructural abnormalities associated with BD whereas alterations in the SLF and UF may represent potential markers of endophenotypic risk.
Approximately 25% of people with bulimia nervosa (BN) who undertake therapy are treated in groups. National guidelines do not discriminate between group and individual therapy, yet each has potential advantages and disadvantages and it is unclear how their effects compare. We therefore evaluated how group therapy for BN compares with individual therapy, no treatment, or other therapies, in terms of remission from binges and binge frequency.
We performed a systematic review and meta-analysis of randomized controlled trials of group therapies for BN, following standard guidelines.
A total of 10 studies were included. Studies were generally small with unclear risk of bias. There was low-quality evidence of a clinically relevant advantage for group cognitive behavioural therapy (CBT) over no treatment at therapy end. Remission was more likely with group CBT versus no treatment [relative risk (RR) 0.77, 95% confidence interval (CI) 0.62–0.96]. Mean weekly binges were lower with group CBT versus no treatment (2.9 v. 6.9, standardized mean difference = −0.56, 95% CI −0.96 to −0.15). One study provided low-quality evidence that group CBT was inferior compared with individual CBT to a clinically relevant degree for remission at therapy end (RR 1.24, 95% CI 1.03–1.50); there was insufficient evidence regarding frequency of binges.
Conclusions could only be reached for CBT. Low-quality evidence suggests that group CBT is effective compared with no treatment, but there was insufficient or very limited evidence about how group and individual CBT compared. The risk of bias and imprecise estimates of effect invite further research to refine and increase confidence in these findings.
The UK has seen a significant transition from Defined Benefit (“DB”) to Defined Contribution (“DC”) for occupational pension saving. The planned automatic enrolment program starting in 2012 is expected to increase the use of DC. The main features of DC are that investment risk falls onto the individual during the pre-retirement phase and that there are no guarantees as to investment returns or the level of pension. In July 2012, Steve Webb, the Pensions Minister, challenged industry to think hard about meeting the need for more certainty about pension savings in DC plans and to consider providing an affordable ‘Money Safe’ guarantee where the member would get back at least the nominal value of their contributions (individual, employer and tax relief). This paper explores whether this is viable for the mass market.