Sequential Allocation and Balancing Prognostic Factors in a Psychiatric Clinical Trial

In controlled clinical trials, each of several prognostic factors should be balanced across the trial arms. Traditional restricted randomization may be proved inadequate especially with small sample sizes. In psychiatric disorders such as obsessive compulsive disorder (OCD), small trials prevail. Therefore, procedures to minimize the chance of imbalance between treatment arms are advisable. This paper describes a minimization procedure specifically designed for a clinical trial that evaluates treatment efficacy for OCD patients. Aitchison's compositional distance was used to calculate vectors for each possibility of allocation in a covariate adaptive method. Two different procedures were designed to allocate patients in small blocks or sequentially one-by-one. Partial results of this allocation procedure as well as simulated ones are shown. In the clinical trial for which this procedure was developed, the balancing between treatment arms was achieved successfully. Simulations of results considering different arrival order of patients showed that most of the patients are allocated in a different treatment arm if arrival order is modified. Results show that a random factor is maintained with the random arrival order of patients. This specific procedure allows the use of a large number of prognostic factors for the allocation decision and was proved adequate for a psychiatric trial design

Sacrospinous ligament suspension with transobturator mesh versus sacral colpopexy for genital prolapse

OBJECTIVE: To compare the safety and efficacy of abdominal sacral colpopexy and sacrospinous ligament suspension with the use of vaginal mesh for apical prolapse. METHOD: This retrospective study was conducted from 2005 to 2012 and included 89 women with apical prolapse who underwent surgery. Assessments included pre- and postoperative Pelvic Organ Prolapse Quantification (POP-Q) stage. Rates of objective cure and immediate/late complications were compared. RESULTS: In total, 41 of the 89 women underwent sacrospinous ligament suspension, and 48 of the women underwent abdominal sacral colpopexy. A total of 40.4% of the women had vault prolapse (p=0.9361). Most of them had no complications (93.2%) (p=0.9418). Approximately 30% of the women had late complications; local pain was the main symptom and was found only in women who underwent the abdominal procedure (25.6%) (p=0.001). Only the women who were submitted to the vaginal procedure had mesh exposure (18.4%). The objective success rate and the rate of anterior vaginal prolapse (p=0.2970) were similar for both techniques. CONCLUSION: Sacrospinous ligament suspension was as effective and had a similar objective success rate as abdominal sacral colpopexy for the treatment of apical prolapse. Sacrospinous ligament suspension performed with the use of vaginal mesh in the anterior compartment was effective in preventing anterior vaginal prolapse after surgery

Clinical effectiveness and safety of analogue glargine in type 1 diabetes : systematic review and meta-analysis

INTRODUCTION: The use of insulin analogues for the treatment of type 1 diabetes mellitus (T1DM) is widespread; however, the therapeutic benefits still require further evaluation given their higher costs. Objective: To evaluate the effectiveness and safety of Analogue Glargine (AG) compared to Recombinant DNA insulin (rDNA) in patients with DM1 in observational studies, building on previous reviews of RCTs comparing NPH insulin and AG. METHODS: A systematic review (SR) with meta-analysis. The SR included cohort studies and registries available on PUBMED, LILACS, and CENTRAL as well as manual and gray literature searches. The meta-analysis was conducted in Review Manager ® 5.2 software. The primary outcomes were: glycohemoglobin (Hb1Ac), weight gain and hypoglycemia. Methodological quality was assessed using the Newcastle-Ottawa scale. RESULTS: Out of 796 publications, 11 studies were finally included. The meta-analysis favored AG in Hb1Ac outcomes (adult patients) and hypoglycemic episodes (p <0.05), but without reaching glycemic control (Hb1Ac to approximately 7%). The methodological quality of the studies was moderate, noting that 45% of studies were funded by pharmaceutical companies. CONCLUSION: Given the high heterogeneity of the studies, the discrete value presented by the estimated effect on effectiveness and safety, potential conflicts of interest of the studies and the appreciable higher cost of AG, there is still no support for recommending first line therapy with analogues. The role of analogues in the treatment DM1 could be better determined by further observational studies of good methodological quality to assess their long-term effectiveness, safety as well as cost-effectiveness

Early intervention for obsessive compulsive disorder : An expert consensus statement

© 2019 Elsevier B.V.and ECNP. All rights reserved.Obsessive-compulsive disorder (OCD) is common, emerges early in life and tends to run a chronic, impairing course. Despite the availability of effective treatments, the duration of untreated illness (DUI) is high (up to around 10 years in adults) and is associated with considerable suffering for the individual and their families. This consensus statement represents the views of an international group of expert clinicians, including child and adult psychiatrists, psychologists and neuroscientists, working both in high and low and middle income countries, as well as those with the experience of living with OCD. The statement draws together evidence from epidemiological, clinical, health economic and brain imaging studies documenting the negative impact associated with treatment delay on clinical outcomes, and supporting the importance of early clinical intervention. It draws parallels between OCD and other disorders for which early intervention is recognized as beneficial, such as psychotic disorders and impulsive-compulsive disorders associated with problematic usage of the Internet, for which early intervention may prevent the development of later addictive disorders. It also generates new heuristics for exploring the brain-based mechanisms moderating the ‘toxic’ effect of an extended DUI in OCD. The statement concludes that there is a global unmet need for early intervention services for OC related disorders to reduce the unnecessary suffering and costly disability associated with under-treatment. New clinical staging models for OCD that may be used to facilitate primary, secondary and tertiary prevention within this context are proposed.Peer reviewe

A panchromatic spatially resolved study of the inner 500pc of NGC1052 -- II: Gas excitation and kinematics

We map the optical and near-infrared (NIR) emission-line flux distributions and kinematics of the inner 320$\times$535pc$^2$ of the elliptical galaxy NGC1052. The integral field spectra were obtained with the Gemini Telescope using the GMOS-IFU and NIFS instruments, with angular resolutions of 0''88 and 0''1 in the optical and NIR, respectively. We detect five kinematic components: (1 and 2) Two spatially unresolved components, being a broad line region visible in H$\alpha$, with a FWHM of $\sim$3200km s$^{-1}$ and an intermediate-broad component seen in the [OIII]$\lambda \lambda$4959,5007 doublet; (3) an extended intermediate-width component with 280<FWHM<450km s$^{-1}$ and centroid velocities up to 400km s$^{-1}$, which dominates the flux in our data, attributed either to a bipolar outflow related to the jets, rotation in an eccentric disc or a combination of a disc and large-scale gas bubbles; (4 and 5) two narrow (FWHM<150km s$^{-1}$) components, one visible in [OIII], and one visible in the other emission lines, extending beyond the field-of-view of our data, which is attributed to large-scale shocks. Our results suggest that the ionization within the observed field of view cannot be explained by a single mechanism, with photoionization being the dominant mechanism in the nucleus with a combination of shocks and photoionization responsible for the extended ionization.Comment: Accepted at MNRAS. 17 pages, 17 figure

Brain structural correlates of sensory phenomena in patients with obsessive-compulsive disorder

Background: sensory phenomena (SP) are uncomfortable feelings, including bodily sensations, sense of inner tension, 'just-right' perceptions, feelings of incompleteness, or 'urge-only' phenomena, which have been described to precede, trigger or accompany repetitive behaviours in individuals with obsessive-compulsive disorder (OCD). Sensory phenomena are also observed in individuals with tic disorders, and previous research suggests that sensorimotor cortex abnormalities underpin the presence of SP in such patients. However, to our knowledge, no studies have assessed the neural correlates of SP in patients with OCD. Methods: we assessed the presence of SP using the University of São Paulo Sensory Phenomena Scale in patients with OCD and healthy controls from specialized units in São Paulo, Brazil, and Barcelona. All participants underwent a structural magnetic resonance examination, and brain images were examined using DARTEL voxel-based morphometry. We evaluated grey matter volume differences between patients with and without SP and healthy controls within the sensorimotor and premotor cortices. Results: we included 106 patients with OCD and 87 controls in our study. Patients with SP (67% of the sample) showed grey matter volume increases in the left sensorimotor cortex in comparison to patients without SP and bilateral sensorimotor cortex grey matter volume increases in comparison to controls. No differences were observed between patients without SP and controls. Limitations: most patients were medicated. Participant recruitment and image acquisition were performed in 2 different centres. Conclusion: we have identified a structural correlate of SP in patients with OCD involving grey matter volume increases within the sensorimotor cortex; this finding is in agreement with those of tic disorder studies showing that abnormal activity and volume increases within this region are associated with the urges preceding tic onset

Protein methyltransferase 7 deficiency in Leishmania major increases neutrophil associated pathology in murine model

Leishmania major is the main causative agent of cutaneous leishmaniasis in the Old World. In Leishmania parasites, the lack of transcriptional control is mostly compensated by post-transcriptional mechanisms. Methylation of arginine is a conserved post-translational modification executed by Protein Arginine Methyltransferase (PRMTs). The genome from L. major encodes five PRMT homologs, including the cytosolic protein associated with several RNA-binding proteins, LmjPRMT7. It has been previously reported that LmjPRMT7 could impact parasite infectivity. In addition, a more recent work has clearly shown the importance of LmjPRMT7 in RNA-binding capacity and protein stability of methylation targets, demonstrating the role of this enzyme as an important epigenetic regulator of mRNA metabolism. In this study, we unveil the impact of PRMT7-mediated methylation on parasite development and virulence. Our data reveals that higher levels of LmjPRMT7 can impair parasite pathogenicity, and that deletion of this enzyme rescues the pathogenic phenotype of an attenuated strain of L. major. Interestingly, lesion formation caused by LmjPRMT7 knockout parasites is associated with an exacerbated inflammatory reaction in the tissue correlated with an excessive neutrophil recruitment. Moreover, the absence of LmjPRMT7 also impairs parasite development within the sand fly vector Phlebotomus duboscqi. Finally, a transcriptome analysis shed light onto possible genes affected by depletion of this enzyme. Taken together, this study highlights how post-transcriptional regulation can affect different aspects of the parasite biology

Macroecological links between the Linnean, Wallacean, and Darwinian shortfalls

Species are the currency of most biodiversity studies. However, many shortfalls and biases remain in our biodiversity estimates, preventing a comprehensive understanding of the eco-evolutionary processes that have shaped the biodiversity currently available on Earth. Biased biodiversity estimates also jeopardize the effective implementation of data-driven conservation strategies, ultimately leading to biodiversity loss. Here, we delve into the concept of the Latitudinal Taxonomy Gradient (LTG) and show how this new idea provides an interesting conceptual link between the Linnean (i.e., our ignorance of how many species there are on Earth), Darwinian (i.e., our ignorance of species evolutionary relationships), and Wallacean (i.e., our ignorance on species distribution) shortfalls. More specifically, we contribute to an improved understanding of LTGs and establish the basis for the development of new methods that allow us to: (i) better account for the integration between different shortfalls and, (ii) estimate how these interactions may affect our understanding about the evolutionary components of richness gradients at macroecological scales.This manuscript is partially derived from a working group on “Biodiversity Shortfalls” held in November 2019 and sponsored by the National Institutes for Science and Technology (INCT) in Ecology, Evolution, and Biodiversity Conservation (CNPq proc. 465610/2014-5 and FAPEG proc. 201810267000023). JJMG and LEF are supported by Ph.D. and M.Sc. scholarships from CAPES, while LM and RBP are supported by postdoctoral fellowships from CAPES (PNPD). JS was funded by the funded by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie Action (grant agreement #843234; project: TAXON-TIME) and by the Spanish Council for Scientific Research (IF_ERC). GT and LJ are supported by a DTI fellowships from CNPq, while JAFD-F, LGL, and CJBC are supported by Productivity Grants from CNPq.Peer reviewe