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Registry-based trials have emerged as a potentially cost-saving study methodology. Early estimates of cost savings, however, conflated the benefits associated with registry utilisation and those associated with other aspects of pragmatic trial designs, which might not all be as broadly applicable. In this study, we sought to build a practical tool that investigators could use across disciplines to estimate the ranges of potential cost differences associated with implementing registry-based trials versus standard clinical trials.
We built simulation Markov models to compare unique costs associated with data acquisition, cleaning, and linkage under a registry-based trial design versus a standard clinical trial. We conducted one-way, two-way, and probabilistic sensitivity analyses, varying study characteristics over broad ranges, to determine thresholds at which investigators might optimally select each trial design.
Registry-based trials were more cost effective than standard clinical trials 98.6% of the time. Data-related cost savings ranged from $4300 to $600,000 with variation in study characteristics. Cost differences were most reactive to the number of patients in a study, the number of data elements per patient available in a registry, and the speed with which research coordinators could manually abstract data. Registry incorporation resulted in cost savings when as few as 3768 independent data elements were available and when manual data abstraction took as little as 3.4 seconds per data field.
Registries offer important resources for investigators. When available, their broad incorporation may help the scientific community reduce the costs of clinical investigation. We offer here a practical tool for investigators to assess potential costs savings.
It is unclear what session frequency is most effective in cognitive–behavioural therapy (CBT) and interpersonal psychotherapy (IPT) for depression.
Compare the effects of once weekly and twice weekly sessions of CBT and IPT for depression.
We conducted a multicentre randomised trial from November 2014 through December 2017. We recruited 200 adults with depression across nine specialised mental health centres in the Netherlands. This study used a 2 × 2 factorial design, randomising patients to once or twice weekly sessions of CBT or IPT over 16–24 weeks, up to a maximum of 20 sessions. Main outcome measures were depression severity, measured with the Beck Depression Inventory-II at baseline, before session 1, and 2 weeks, 1, 2, 3, 4, 5 and 6 months after start of the intervention. Intention-to-treat analyses were conducted.
Compared with patients who received weekly sessions, patients who received twice weekly sessions showed a statistically significant decrease in depressive symptoms (estimated mean difference between weekly and twice weekly sessions at month 6: 3.85 points, difference in effect size d = 0.55), lower attrition rates (n = 16 compared with n = 32) and an increased rate of response (hazard ratio 1.48, 95% CI 1.00–2.18).
In clinical practice settings, delivery of twice weekly sessions of CBT and IPT for depression is a way to improve depression treatment outcomes.
Smoking prevalence is higher amongst individuals with schizophrenia and depression compared with the general population. Mendelian randomisation (MR) can examine whether this association is causal using genetic variants identified in genome-wide association studies (GWAS).
We conducted two-sample MR to explore the bi-directional effects of smoking on schizophrenia and depression. For smoking behaviour, we used (1) smoking initiation GWAS from the GSCAN consortium and (2) we conducted our own GWAS of lifetime smoking behaviour (which captures smoking duration, heaviness and cessation) in a sample of 462690 individuals from the UK Biobank. We validated this instrument using positive control outcomes (e.g. lung cancer). For schizophrenia and depression we used GWAS from the PGC consortium.
There was strong evidence to suggest smoking is a risk factor for both schizophrenia (odds ratio (OR) 2.27, 95% confidence interval (CI) 1.67–3.08, p < 0.001) and depression (OR 1.99, 95% CI 1.71–2.32, p < 0.001). Results were consistent across both lifetime smoking and smoking initiation. We found some evidence that genetic liability to depression increases smoking (β = 0.091, 95% CI 0.027–0.155, p = 0.005) but evidence was mixed for schizophrenia (β = 0.022, 95% CI 0.005–0.038, p = 0.009) with very weak evidence for an effect on smoking initiation.
These findings suggest that the association between smoking, schizophrenia and depression is due, at least in part, to a causal effect of smoking, providing further evidence for the detrimental consequences of smoking on mental health.
There is increasing evidence that smoking is a risk factor for severe mental illness, including bipolar disorder. Conversely, patients with bipolar disorder might smoke more (often) as a result of the psychiatric disorder.
We conducted a bidirectional Mendelian randomisation (MR) study to investigate the direction and evidence for a causal nature of the relationship between smoking and bipolar disorder.
We used publicly available summary statistics from genome-wide association studies on bipolar disorder, smoking initiation, smoking heaviness, smoking cessation and lifetime smoking (i.e. a compound measure of heaviness, duration and cessation). We applied analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger, MR-Egger SIMEX, weighted-median, weighted-mode and Steiger-filtered analyses.
Across different methods of MR, consistent evidence was found for a positive effect of smoking on the odds of bipolar disorder (smoking initiation ORIVW = 1.46, 95% CI 1.28–1.66, P = 1.44 × 10−8, lifetime smoking ORIVW = 1.72, 95% CI 1.29–2.28, P = 1.8 × 10−4). The MR analyses of the effect of liability to bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking heaviness betaIVW = 0.028, 95% CI 0.003–0.053, P = 2.9 × 10−2).
These findings suggest that smoking initiation and lifetime smoking are likely to be a causal risk factor for developing bipolar disorder. We found some evidence that liability to bipolar disorder increased smoking heaviness. Given that smoking is a modifiable risk factor, these findings further support investment into smoking prevention and treatment in order to reduce mental health problems in future generations.
Declaration of interest
W.v.d.B received fees in the past 3 years from Indivior, C&A Pharma, Opiant and Angelini. G.M.G. is a National Institute for Health Research (NIHR) Emeritus Senior Investigator, holds shares in P1vital and has served as consultant, advisor or CME speaker in the past 3 years for Allergan, Angelini, Compass Pathways, MSD, Lundbeck (/Otsuka and /Takeda), Medscape, Minervra, P1Vital, Pfizer, Sage, Servier, Shire and Sun Pharma.
Machine learning techniques have proven to be increasingly useful in astronomical applications over the last few years, for example in object classification, estimating redshifts and data mining. One example of object classification is classifying galaxy morphology. This is a tedious task to do manually, especially as the datasets become larger with surveys that have a broader and deeper search-space. The Kaggle Galaxy Zoo competition presented the challenge of writing an algorithm to find the probability that a galaxy belongs in a particular class, based on SDSS optical spectroscopy data. The use of convolutional neural networks (convnets), proved to be a popular solution to the problem, as they have also produced unprecedented classification accuracies in other image databases such as the database of handwritten digits (MNIST †) and large database of images (CIFAR ‡). We experiment with the convnets that comprised the winning solution, but using broad classifications. The effect of changing the number of layers is explored, as well as using a different activation function, to help in developing an intuition of how the networks function and to see how they can be applied to radio galaxy images.
Previous studies have suggested that prenatal maternal folate deficiency is associated with reduced prenatal brain growth and psychological problems in offspring. However, little is known about the longer-term impact. The aims of this study were to investigate whether prenatal maternal folate insufficiency, high total homocysteine levels and low vitamin B12 levels are associated with altered brain morphology, cognitive and/or psychological problems in school-aged children. This study was embedded in Generation R, a prospective population-based cohort study. The study sample consisted of 256 Dutch children aged between 6 and 8 years from whom structural brain scans were collected using MRI. The mothers of sixty-two children had insufficient (<8 nmol/l) plasma folate concentrations in early pregnancy. Cognitive development was assessed by the Snijders-Oomen Niet-verbale intelligentietest – Revisie and the NEPSY-II-NL. Psychological problems were assessed at age 6 years using the parent report of the Child Behavior Checklist. Low prenatal folate levels were associated with a smaller total brain volume (B –33·34; 95 % CI –66·7, 0·02; P=050) and predicted poorer performance on the language (B –0·28; 95 % CI –0·52, –0·04; P=0·020) and visuo-spatial domains (B –0·27; 95 % CI –0·50, –0·04; P=0·021). High homocysteine levels (>9·1 µmol/l) predicted poorer performance on the language (B –0·31; 95 % CI –0·56, –0·06; P=0·014) and visuo-spatial domains (B –0·36; 95 % CI –0·60, –0·11; P=0·004). No associations with psychological problems were found. Our findings suggest that folate insufficiency in early pregnancy has a long-lasting, global effect on brain development and is, together with homocysteine levels, associated with poorer cognitive performance.
Most research on interventions to counter stigma and discrimination has
focused on short-term outcomes and has been conducted in high-income
To synthesise what is known globally about effective interventions to
reduce mental illness-based stigma and discrimination, in relation first
to effectiveness in the medium and long term (minimum 4 weeks), and
second to interventions in low- and middle-income countries (LMICs).
We searched six databases from 1980 to 2013 and conducted a
multi-language Google search for quantitative studies addressing the
research questions. Effect sizes were calculated from eligible studies
where possible, and narrative syntheses conducted. Subgroup analysis
compared interventions with and without social contact.
Eighty studies (n = 422 653) were included in the
review. For studies with medium or long-term follow-up (72, of which 21
had calculable effect sizes) median standardised mean differences were
0.54 for knowledge and −0.26 for stigmatising attitudes. Those containing
social contact (direct or indirect) were not more effective than those
without. The 11 LMIC studies were all from middle-income countries.
Effect sizes were rarely calculable for behavioural outcomes or in LMIC
There is modest evidence for the effectiveness of anti-stigma
interventions beyond 4 weeks follow-up in terms of increasing knowledge
and reducing stigmatising attitudes. Evidence does not support the view
that social contact is the more effective type of intervention for
improving attitudes in the medium to long term. Methodologically strong
research is needed on which to base decisions on investment in
We have mapped cold atomic gas in 21cm line H i self-absorption (HISA) at arcminute resolution over more than 90% of the Milky Way's disk. To probe the formation of H2 clouds, we have compared our HISA distribution with CO J = 1-0 line emission. Few HISA features in the outer Galaxy have CO at the same position and velocity, while most inner-Galaxy HISA has overlapping CO. But many apparent inner-Galaxy HISA-CO associations can be explained as chance superpositions, so most inner-Galaxy HISA may also be CO-free. Since standard equilibrium cloud models cannot explain the very cold H i in many HISA features without molecules being present, these clouds may instead have significant CO-dark H2.
Clovis sites occur throughout the southwestern United States and northwestern Mexico, but are poorly documented in the central Rio Grande rift region. Here, we present data from two relatively unknown Clovis projectile point assemblages from this region: the first is from the Mockingbird Gap Clovis site and the second is from a survey of the surrounding region. Our goals are to reconstruct general features of the paleoecological adaptation of Clovis populations in the region using raw material sourcing and then to compare the point technology in the region to other Clovis assemblages in the Southwest and across the continent. Our results show that both assemblages were manufactured from similar suites of raw materials that come almost exclusively from the central Rio Grande rift region and the adjacent mountains of New Mexico. Additionally, we show that Clovis projectile points in the study region are significantly smaller than the continental average. Our results suggest that Clovis populations in this region operated within a large, well-known, and relatively high-elevation territory encompassing much of northern and western New Mexico.
This brief report investigated coping strategies and their perceived effectiveness in response to a social stressor for 7–12 year olds with high-functioning autism spectrum disorders (HFASDs). Ninety-eight participants completed a self-report coping scale in response to a self-identified socially stressful situation. Responses yielded three categories of use and perceived effectiveness: (1) strategies used frequently and viewed as effective, (2) strategies not used frequently and not perceived as effective, and (3) strategies used frequently but not perceived as effective. Respondents reported high frequency use and high perceived effectiveness of six strategies that are generally considered as positive/engagement oriented coping. They also indicated low frequency use and low perceived effectiveness of five strategies broadly regarded as negative and avoidant/disengagement coping. The last cluster of four strategies, identified as frequently used but not effective, consisted of strategies less clearly categorised as positive/engaged vs. negative/disengaged. Implications for future research and clinical considerations are proposed.
The Single Solid Source precursor Cadmium Acetylacetonate, Cd[C5H7O2]2 was prepared and Cadmium Oxide thin films were deposited on Sodalime glass substrate using Metal Organic Chemical Vapour Deposition (MOCVD) technique at deposition temperature of 420 oC The films were characterized using Scanning Electron Microscopy (SEM) with Energy Dispersive XRay (EDX) facility attached to it, X-Ray Diffractometry (XRD) and UV-visible spectrometry. SEM micrographs showed the formation of textured surface with identifiable cubic and hexagonal structures, having average grain size greater than 1 μm. XRD studies indicated the formation of polycrystalline cubic CdO phase with preferred orientation in (111) plane. A direct optical band gap of 2.10 eV was obtained from the analysis of the UV-visible spectrum with an enhanced light absorption in 750 – 1000 nm spectrum range. This enhancement is as a result of light trapping by the textured crystalline structure.
Commensal epizoozoans and episkeletozoans are rarely preserved attached to the external exoskeleton of the Late Ordovician trilobite Flexicalymene. Of nearly 15,000 Flexicalymene specimens examined, 0.1% show epizoozoans or episkeletozoans. Factors limiting Flexicalymene fouling include a shallow burrowing life style, frequent molting of the host, larval preference for other substrates, observational bias caused by overlooking small fouling organisms, and the loss of the non-calcified, outermost cuticle prior to fossilization or as the trilobite weathers from the encasing sediment. Trepostome bryozoans, articulate and inarticulate brachiopods, cornulitids, and a tube-dwelling/boring nonbiomineralized organism represent the preserved members of the Late Ordovician marine hard substrate community fouling Flexicalymene. This assemblage of organisms is less diverse than the hard substrate community fouling Late Ordovician sessile epibenthic organisms. Fouling is not restricted to only large Flexicalymene specimens as observed in previous studies but occurs in medium to large individuals interpreted as early to late holaspid specimens.
Epizoozoans fouling the carcasses or molt ensembles of 16 Flexicalymene specimens provide insight into the life habits of the host and these fouling organisms. Trepostome bryozoans, articulate and inarticulate brachiopods, and cornulitids preferentially attached to elevated portions of the dorsal exoskeleton, and preferentially aligned in either the direct line or lee side of currents generated by Flexicalymene walking on the sea floor or swimming through the water column.