Fagerstrom test for nicotine dependence vs heavy smoking index in a general population survey

<p>Abstract</p> <p>Background</p> <p>The Fagerström Test for Nicotine Dependence (FTND) is used for assessing nicotine dependence. A shorter test derived from the FTND used for the general population is the Heavy Smoking Index (HSI) (six questions vs. two). The objective of this study is to compare the validity of the HSI versus the FTND.</p> <p>Methods</p> <p>A survey of tobacco use in the general population was carried out in the northern Spanish region of Galicia using both the FTND and the HSI to study a representative sample of 1655 daily smokers. The HSI was compared with the FTND, considered the gold standard. Measures of sensitivity, specificity and predictive values were calculated. Concordance between the tests was also established (Cohen's kappa).</p> <p>Results</p> <p>Cohen's kappa showed good agreement between measures (Kappa = 0.7); specificity values were also high (Sp = 96.2%). Sensitivity analysis in females (Se = 62.3%) did not show good agreement.</p> <p>Conclusions</p> <p>The HSI can be used as a reasonably good screening test in order to identify daily smokers with high nicotine dependence. Nevertheless, for populations or subpopulations having low nicotine dependence, such as women, the FTND is more reliable.</p

A population-based controlled experiment assessing the epidemiological impact of digital contact tracing

While Digital contact tracing (DCT) has been argued to be a valuable complement to manual tracing in the containment of COVID-19, no empirical evidence of its effectiveness is available to date. Here, we report the results of a 4-week population-based controlled experiment that took place in La Gomera (Canary Islands, Spain) between June and July 2020, where we assessed the epidemiological impact of the Spanish DCT app Radar Covid. After a substantial communication campaign, we estimate that at least 33% of the population adopted the technology and further showed relatively high adherence and compliance as well as a quick turnaround time. The app detects about 6.3 close-contacts per primary simulated infection, a significant percentage being contacts with strangers, although the spontaneous follow-up rate of these notified cases is low. Overall, these results provide experimental evidence of the potential usefulness of DCT during an epidemic outbreak in a real population

Towards the clinical implementation of pharmacogenetics in bipolar disorder.

BackgroundBipolar disorder (BD) is a psychiatric illness defined by pathological alterations between the mood states of mania and depression, causing disability, imposing healthcare costs and elevating the risk of suicide. Although effective treatments for BD exist, variability in outcomes leads to a large number of treatment failures, typically followed by a trial and error process of medication switches that can take years. Pharmacogenetic testing (PGT), by tailoring drug choice to an individual, may personalize and expedite treatment so as to identify more rapidly medications well suited to individual BD patients.DiscussionA number of associations have been made in BD between medication response phenotypes and specific genetic markers. However, to date clinical adoption of PGT has been limited, often citing questions that must be answered before it can be widely utilized. These include: What are the requirements of supporting evidence? How large is a clinically relevant effect? What degree of specificity and sensitivity are required? Does a given marker influence decision making and have clinical utility? In many cases, the answers to these questions remain unknown, and ultimately, the question of whether PGT is valid and useful must be determined empirically. Towards this aim, we have reviewed the literature and selected drug-genotype associations with the strongest evidence for utility in BD.SummaryBased upon these findings, we propose a preliminary panel for use in PGT, and a method by which the results of a PGT panel can be integrated for clinical interpretation. Finally, we argue that based on the sufficiency of accumulated evidence, PGT implementation studies are now warranted. We propose and discuss the design for a randomized clinical trial to test the use of PGT in the treatment of BD

A high throughput screen for next-generation leads targeting malaria parasite transmission

Spread of parasite resistance to artemisinin threatens current frontline antimalarial therapies, highlighting the need for new drugs with alternative modes of action. Since only 0.2–1% of asexual parasites differentiate into sexual, transmission-competent forms, targeting this natural bottleneck provides a tangible route to interrupt disease transmission and mitigate resistance selection. Here we present a high-throughput screen of gametogenesis against a ~70,000 compound diversity library, identifying seventeen drug-like molecules that target transmission. Hit molecules possess varied activity profiles including male-specific, dual acting male–female and dual-asexual-sexual, with one promising N-((4-hydroxychroman-4-yl)methyl)-sulphonamide scaffold found to have sub-micromolar activity in vitro and in vivo efficacy. Development of leads with modes of action focussed on the sexual stages of malaria parasite development provide a previously unexplored base from which future therapeutics can be developed, capable of preventing parasite transmission through the population

Higher Dimensional Cylindrical or Kasner Type Electrovacuum Solutions

We consider a D dimensional Kasner type diagonal spacetime where metric functions depend only on a single coordinate and electromagnetic field shares the symmetries of spacetime. These solutions can describe static cylindrical or cosmological Einstein-Maxwell vacuum spacetimes. We mainly focus on electrovacuum solutions and four different types of solutions are obtained in which one of them has no four dimensional counterpart. We also consider the properties of the general solution corresponding to the exterior field of a charged line mass and discuss its several properties. Although it resembles the same form with four dimensional one, there is a difference on the range of the solutions for fixed signs of the parameters. General magnetic field vacuum solution are also briefly discussed, which reduces to Bonnor-Melvin magnetic universe for a special choice of the parameters. The Kasner forms of the general solution are also presented for the cylindrical or cosmological cases.Comment: 16 pages, Revtex. Text and references are extended, Published versio

The nature of NV absorbers at high redshift

We present a study of NV absorption systems at 1.5 < z < 2.5 in the optical spectra of 19 QSOs. Our analysis includes both absorbers arising from the intergalactic medium as well as systems in the vicinity of the background quasar. We construct detailed photoionization models to study the physical conditions and abundances in the absorbers and to constrain the spectral hardness of the ionizing radiation. The rate of incidence for intervening NV components is dN/dz = 3.38 +/- 0.43, corresponding to dN/dX = 1.10 +/- 0.14. The column density distribution function is fitted by the slope beta = 1.89 +/- 0.22, consistent with measurements for CIV and OVI. The narrow line widths (b_NV ~ 6 km/s) imply photoionization rather than collisions as dominating ionization process. The column densities of CIV and NV are correlated but show different slopes for intervening and associated absorbers, which indicates different ionizing spectra. Associated systems are found to be more metal-rich, denser, and more compact than intervening absorbers. This conclusion is independent of the adopted ionizing radiation. For the intervening NV systems we find typical values of [C/H] ~ -0.6 and n_H ~ 10^-3.6 cm^-3, and sizes of a few kpc, while for associated NV absorbers we obtain [C/H] ~ +0.7, n_H ~ 10^-2.8 cm^-3, and sizes of several 10 pc. The abundance of nitrogen relative to carbon [N/C] and alpha-elements like oxygen and silicon [N/alpha] is correlated with [N/H], indicating the enrichment by secondary nitrogen. The larger scatter in [N/alpha] in intervening systems suggests an inhomogeneous enrichment of the IGM. There is an anti-correlation between [N/alpha] and [alpha/C], which could be used to constrain the initial mass function of the carbon- and nitrogen-producing stellar population.Comment: accepted by A&A, revised versio

Functional analysis reveals driver cooperativity and novel mechanisms in endometrial carcinogenesis

Data availability Microarray data from this study have been deposited in GEO under accession number GSE232356: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE232356.For more information: Author website: https://www.well.ox.ac.uk/research/research-groups/church-group . Endometrial cancer driver mutations: https://www.intogen.org/search?cancer=UCEC . Endometrial cancer information and patient support: https://peachestrust.org .Supporting Information is available online at: https://www.embopress.org/doi/full/10.15252/emmm.202217094#support-information-section .Copyright © 2023 The Authors. High-risk endometrial cancer has poor prognosis and is increasing in incidence. However, understanding of the molecular mechanisms which drive this disease is limited. We used genetically engineered mouse models (GEMM) to determine the functional consequences of missense and loss of function mutations in Fbxw7, Pten and Tp53, which collectively occur in nearly 90% of high-risk endometrial cancers. We show that Trp53 deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show that Fbxw7 missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused by Pten loss or Trp53 missense mutation. By transcriptomic analysis, we identify LEF1 signalling as upregulated in Fbxw7/FBXW7-mutant mouse and human endometrial cancers, and in human isogenic cell lines carrying FBXW7 mutation, and validate LEF1 and the additional Wnt pathway effector TCF7L2 as novel FBXW7 substrates. Our study provides new insights into the biology of high-risk endometrial cancer and suggests that targeting LEF1 may be worthy of investigation in this treatment-resistant cancer subgroup.Cancer Research UK (CRUK). Grant Number: C26642/A27963; KWF Kankerbestrijding; HHS¦NIH¦Office of Extramural Research, National Institutes of Health (OER). Grant Numbers: RO1 HD042311, Z1AES103311; Medical Research Council; Oxford NIHR Biomedical Research Centre (BRC); Verein zur F#x00F6;rderung von Wissenschaft und Forschung an der Medizinischen Fakult#x00E4;t der LMU M#x00FC;nchen e.. Grant Number: 203141/Z/16/Z; Wellcome Trust (WT)

Clearance of interstitial fluid (ISF) and CSF (CLIC) group-part of Vascular Professional Interest Area (PIA), updates in 2022-2023. Cerebrovascular disease and the failure of elimination of Amyloid-β from the brain and retina with age and Alzheimer's disease:Opportunities for therapy

This editorial summarizes advances from the Clearance of Interstitial Fluid and Cerebrospinal Fluid (CLIC) group, within the Vascular Professional Interest Area (PIA) of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment (ISTAART). The overarching objectives of the CLIC group are to: (1) understand the age-related physiology changes that underlie impaired clearance of interstitial fluid (ISF) and cerebrospinal fluid (CSF) (CLIC); (2) understand the cellular and molecular mechanisms underlying intramural periarterial drainage (IPAD) in the brain; (3) establish novel diagnostic tests for Alzheimer's disease (AD), cerebral amyloid angiopathy (CAA), retinal amyloid vasculopathy, amyloid-related imaging abnormalities (ARIA) of spontaneous and iatrogenic CAA-related inflammation (CAA-ri), and vasomotion; and (4) establish novel therapies that facilitate IPAD to eliminate amyloid β (Aβ) from the aging brain and retina, to prevent or reduce AD and CAA pathology and ARIA side events associated with AD immunotherapy

Stroke Correlates in Chagasic and Non-Chagasic Cardiomyopathies

BACKGROUND: Aging and migration have brought changes to the epidemiology and stroke has been shown to be independently associated with Chagas disease. We studied stroke correlates in cardiomyopathy patients with focus on the chagasic etiology. METHODOLOGY/PRINCIPAL FINDINGS: We performed a cross-sectional review of medical records of 790 patients with a cardiomyopathy. Patients with chagasic (329) and non-chagasic (461) cardiomyopathies were compared. There were 108 stroke cases, significantly more frequent in the Chagas group (17.3% versus 11.1%; p<0.01). Chagasic etiology (odds ratio [OR], 1.79), pacemaker (OR, 2.49), atrial fibrillation (OR, 3.03) and coronary artery disease (OR, 1.92) were stroke predictors in a multivariable analysis of the entire cohort. In a second step, the population was split into those with or without a Chagas-related cardiomyopathy. Univariable post-stratification stroke predictors in the Chagas cohort were pacemaker (OR, 2.73), and coronary artery disease (CAD) (OR, 2.58); while atrial fibrillation (OR, 2.98), age over 55 (OR, 2.92), hypertension (OR, 2.62) and coronary artery disease (OR, 1.94) did so in the non-Chagas cohort. Chagasic stroke patients presented a very high frequency of individuals without any vascular risk factors (40.4%; OR, 4.8). In a post-stratification logistic regression model, stroke remained associated with pacemaker (OR, 2.72) and coronary artery disease (OR, 2.60) in 322 chagasic patients, and with age over 55 (OR, 2.38), atrial fibrillation (OR 3.25) and hypertension (OR 2.12; p = 0.052) in 444 non-chagasic patients. CONCLUSIONS/SIGNIFICANCE: Chagas cardiomyopathy presented both a higher frequency of stroke and an independent association with it. There was a high frequency of strokes without any vascular risk factors in the Chagas as opposed to the non-Chagas cohort. Pacemaker rhythm and CAD were independently associated with stroke in the Chagas group while age over 55 years, hypertension and atrial fibrillation did so in the non-Chagas cardiomyopathies

Early and Late Direct Costs in a Southern African Antiretroviral Treatment Programme: A Retrospective Cohort Analysis

Gary Maartens and colleagues describe the direct heath care costs and identify the drivers of cost over time in an HIV managed care program in Southern Africa