Use of pharmacological treatments by a sample of Italian patients affected by alcohol use disorders

Title: USE OF PHARMACOLOGICAL TREATMENTS BY A SAMPLE OF ITALIAN PATIENTS AFFECTED BY ALCOHOL USE DISORDERS Author name(s): R. Agabio; E.M. Diana; D. Grazzini; R. Pirastu; G.L. Gessa Institution: Department of Biochemical Sciences, Section of Neuroscience, Preclinical and Clinical Pharmacology, University of Cagliari, Italy Text Background: It has often been reported that the majority of patients affected by Alcohol Use Disorders (AUDs) do not receive any pharmacological treatment. This study was aimed at investigating the use of the medications available in Italy (disulfiram, naltrexone, acamprosate, and γ-hydroxybutyric acid) by a sample of outpatients affected by AUDs. Methods: Four trained psychologists interviewed outpatients affected by AUDs in an area of Sardinia, Italy, of approximately 550.000 adult inhabitants. Results: A total sample of 208 outpatients affected by AUDs was interviewed (~1/3 of total outpatients affected by AUDs of that area). Their main features were: 166 males (79.5%); mean age=48.6±0.6 year; duration of AUDs=15.8±0.7 years; number of drinks per drinking days=19.4±1.3; number of criteria of DSM-IV-Tr=5.8±0.1. Before the admission into specific services, 13 patients (6.2%) had already received medication for AUDs; 7 patients (3.4%) had received disulfiram and 6 patients (2.9%) γ-hydroxybutyric acid. Over the same period, 22 patients (10.6%) had already attended self-help groups and 4 patients (1.9%) had received thiamine (Vitamine B1). After the admission into specific medical settings for the treatment of AUDs, 113 patients (54.3%) received medication for AUDs: 58 patients (27.9%) received disulfiram, 65 patients (31.2%) γ-hydroxybutyric acid, 2 patients (1.0%) naltrexone, and 6 patients (2.9%) acamprosate. In the same period, 54 patients (26.0%) frequented self-help associations, and 21 patients (10.1%) received thiamine. Conclusions: The results of this study confirm that the number of patients who receive a treatment for AUDs continues to be surprisingly low. Despite the long duration and the high level of severity of the AUDs, the majority of patients affected by AUDs did not receive any treatment before their admission in specific medical settings for the treatment of AUDs (10% of patients frequented self-help groups, 6% received a medication for AUDs, and 2% thiamine). After the admission into specific medical settings, the number of patients who received a treatment increased: 26% frequented self-help associations, 54% received a specific medication, and 10% received thiamine. However, approximately half of the patients did not receive any pharmacological treatment even if they frequented medical settings for the treatment of AUDs. Additional work is needed to understand the reasons of such a scarce use of treatments. Acknowledgements: This study was supported by a grant from Regione Autonoma della Sardegna

The decline of autochthonous leprosy in the Valencia Region of Spain: patterns and trends 1940-2015

Objectives: The aim of this study was to describe the patterns and trends of autochthonous leprosy in the Valencia Region (Spain). Methods: We included all new leprosy cases originating from the Valencia Region between the years 1940 and 2015. Patients originating from other countries or other Spanish regions were excluded. New cases were analysed by age, sex, clinical type, occupation, and geographic distribution. Results: A total of 442 patients with presumably autochthonous leprosy were included. Incidence rates consistently declined over the study period. Mean age at onset gradually increased from 34.2 years during the period 1940-1949 to 59.5 years during 2000-2015. There were no cases with clinical onset after 2006 and no cases born after 1973. Patients were predominantly males (57.7%) and 85.4% had multibacillary leprosy. The proportion of multibacillary cases increased gradually after 1970. The majority of male patients (67.9%) worked in agriculture. Most of the cases, especially during the later periods, were concentrated in the coastal regions. Conclusions: Our findings are consistent with trends described in other regions with declining leprosy incidence rates and suggest that the transmission of M. leprae infection in this area may well have now stopped. Autochthonous leprosy in this region has had a male predominance and a high proportion of multibacillary cases. The geographic distribution and the high incidence in agricultural workers suggest that environmental factors should be further explored

Whitebark Pine Stand Condition, Tree Abundance, and Cone Production as Predictors of Visitation by Clark's Nutcracker

Accurately quantifying key interactions between species is important for developing effective recovery strategies for threatened and endangered species. Whitebark pine (Pinus albicaulis), a candidate species for listing under the Endangered Species Act, depends on Clark's nutcracker (Nucifraga columbiana) for seed dispersal. As whitebark pine succumbs to exotic disease and mountain pine beetles (Dendroctonus ponderosae), cone production declines, and nutcrackers visit stands less frequently, reducing the probability of seed dispersal.We quantified whitebark pine forest structure, health metrics, and the frequency of nutcracker occurrence in national parks within the Northern and Central Rocky Mountains in 2008 and 2009. Forest health characteristics varied between the two regions, with the northern region in overall poorer health. Using these data, we show that a previously published model consistently under-predicts the proportion of survey hours resulting in nutcracker observations at all cone density levels. We present a new statistical model of the relationship between whitebark pine cone production and the probability of Clark's nutcracker occurrence based on combining data from this study and the previous study.Our model clarified earlier findings and suggested a lower cone production threshold value for predicting likely visitation by nutcrackers: Although nutcrackers do visit whitebark pine stands with few cones, the probability of visitation increases with increased cone production. We use information theoretics to show that beta regression is a more appropriate statistical framework for modeling the relationship between cone density and proportion of survey time resulting in nutcracker observations. We illustrate how resource managers may apply this model in the process of prioritizing areas for whitebark pine restoration

Association of the CpG Methylation Pattern of the Proximal Insulin Gene Promoter with Type 1 Diabetes

The insulin (INS) region is the second most important locus associated with Type 1 Diabetes (T1D). The study of the DNA methylation pattern of the 7 CpGs proximal to the TSS in the INS gene promoter revealed that T1D patients have a lower level of methylation of CpG -19, -135 and -234 (p = 2.10−16) and a higher methylation of CpG -180 than controls, while methylation was comparable for CpG -69, -102, -206. The magnitude of the hypomethylation relative to a control population was 8–15% of the corresponding levels in controls and was correlated in CpGs -19 and -135 (r = 0.77) and CpG -135 and -234 (r = 0.65). 70/485 (14%) of T1D patients had a simultaneous decrease in methylation of CpG -19, -135, -234 versus none in 317 controls. CpG methylation did not correlate with glycated hemoglobin or with T1D duration. The methylation of CpG -69, -102, -180, -206, but not CpG -19, -135, -234 was strongly influenced by the cis-genotype at rs689, a SNP known to show a strong association with T1D. We hypothesize that part of this genetic association could in fact be mediated at the statistical and functional level by the underlying changes in neighboring CpG methylation. Our observation of a CpG-specific, locus-specific methylation pattern, although it can provide an epigenetic biomarker of a multifactorial disease, does not indicate whether the reported epigenetic pattern preexists or follows the establishment of T1D. To explore the effect of chronic hyperglycemia on CpG methylation, we studied non obese patients with type 2 diabetes (T2D) who were found to have decreased CpG-19 methylation versus age-matched controls, similar to T1D (p = 2.10−6) but increased CpG-234 methylation (p = 5.10−8), the opposite of T1D. The causality and natural history of the different epigenetic changes associated with T1D or T2D remain to be determined

Evaluation of a community pharmacy-based intervention for improving patient adherence to antihypertensives: a randomised controlled trial

BackgroundThe majority of patients using antihypertensive medications fail to achieve their recommended target blood pressure. Poor daily adherence with medication regimens and a lack of persistence with medication use are two of the major reasons for failure to reach target blood pressure. There is no single intervention to improve adherence with antihypertensives that is consistently effective. Community pharmacists are in an ideal position to promote adherence to chronic medications. This study aims to test a specific intervention package that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications - Hypertension Adherence Program in Pharmacy (HAPPY).Methods/DesignThe HAPPY trial is a multi-centre prospective randomised controlled trial. Fifty-six pharmacies have been recruited from three Australian states. To identify potential patients, a software application (MedeMine CVD) extracted data from a community pharmacy dispensing software system (FRED Dispense&reg;). The pharmacies have been randomised to either \u27Pharmacist Care Group\u27 (PCG) or \u27Usual Care Group\u27 (UCG). To check for \u27Hawthorne effect\u27 in the UCG, a third group of patients \u27Hidden Control Group\u27 (HCG) will be identified in the UCG pharmacies, which will be made known to the pharmacists at the end of six months. Each study group requires 182 patients. Data will be collected at baseline, three and six months in the PCG and at baseline and six months in the UCG. Changes in patient adherence and persistence at the end of six months will be measured using the self-reported Morisky score, the Tool for Adherence Behaviour Screening and medication refill data.DiscussionTo our knowledge, this is the first research testing a comprehensive package of evidence-based interventions that could be integrated into the community pharmacy workflow to enable pharmacists to improve patient adherence and/or persistence with antihypertensive medications. The unique features of the HAPPY trial include the use of MedeMine CVD to identify patients who could potentially benefit from the service, control for the \u27Hawthorne effect\u27 in the UCG and the offer of the intervention package at the end of six months to patients in the UCG, a strategy that is expected to improve retention.Trial RegistrationAustralian New Zealand Clinical Trial Registry ACTRN12609000705280<br /

Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood

Funding Information: We would like to thank all the patients and their relatives as well as the treatment teams for their participation in this study. We also thank Dr. Mischa Keizer for his help in developing the MRP8/14 ELISA. We would like to thank the EUCLIDS Consortium, PERFORM Consortium, and the Genetic Determinants of Kawasaki Disease Study group (UK). Funding. This work was partially supported by the European Seventh Framework Program for Research and Technological Development (FP7) under EUCLIDS grant agreement no. 279185; from the European Union's Horizon 2020 research and innovation program under grant agreement no. 668303; by STINAFO and anonymous donor; and by Sanquin Blood Supply Product and Process Development Cellular Products Fund (PPOC 1957). Publisher Copyright: © Copyright © 2020 Zandstra, van de Geer, Tanck, van Stijn-Bringas Dimitriades, Aarts, Dietz, van Bruggen, Schweintzger, Zenz, Emonts, Zavadska, Pokorn, Usuf, Moll, Schlapbach, Carrol, Paulus, Tsolia, Fink, Yeung, Shimizu, Tremoulet, Galassini, Wright, Martinón-Torres, Herberg, Burns, Levin, Kuijpers, EUCLIDS Consortium, PERFORM Consortium and UK Kawasaki Disease Genetics Study Network. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication—the development of coronary artery aneurysms (CAA)—can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. Methods and Results: The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients (n = 48) from patients with infection (n = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients (n = 26) from those with infections (n = 150), with an AUC of 0.78. The second validation cohort of acute KD patients (n = 25) and febrile controls (n = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. Conclusion: When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.publishersversionPeer reviewe

Can Research Assessments Themselves Cause Bias in Behaviour Change Trials? A Systematic Review of Evidence from Solomon 4-Group Studies

BACKGROUND: The possible effects of research assessments on participant behaviour have attracted research interest, especially in studies with behavioural interventions and/or outcomes. Assessments may introduce bias in randomised controlled trials by altering receptivity to intervention in experimental groups and differentially impacting on the behaviour of control groups. In a Solomon 4-group design, participants are randomly allocated to one of four arms: (1) assessed experimental group; (2) unassessed experimental group (3) assessed control group; or (4) unassessed control group. This design provides a test of the internal validity of effect sizes obtained in conventional two-group trials by controlling for the effects of baseline assessment, and assessing interactions between the intervention and baseline assessment. The aim of this systematic review is to evaluate evidence from Solomon 4-group studies with behavioural outcomes that baseline research assessments themselves can introduce bias into trials. METHODOLOGY/PRINCIPAL FINDINGS: Electronic databases were searched, supplemented by citation searching. Studies were eligible if they reported appropriately analysed results in peer-reviewed journals and used Solomon 4-group designs in non-laboratory settings with behavioural outcome measures and sample sizes of 20 per group or greater. Ten studies from a range of applied areas were included. There was inconsistent evidence of main effects of assessment, sparse evidence of interactions with behavioural interventions, and a lack of convincing data in relation to the research question for this review. CONCLUSIONS/SIGNIFICANCE: There were too few high quality completed studies to infer conclusively that biases stemming from baseline research assessments do or do not exist. There is, therefore a need for new rigorous Solomon 4-group studies that are purposively designed to evaluate the potential for research assessments to cause bias in behaviour change trials

Impact of Daily Thermocycles on Hatching Rhythms, Larval Performance and Sex Differentiation of Zebrafish

In the wild, water temperature cycles daily: it warms up after sunrise, and cools rapidly after sunset. Surprisingly, the impact of such daily thermocycles during the early development of fish remains neglected. We investigated the influence of constant vs daily thermocycles in zebrafish, from embryo development to sexual differentiation, by applying four temperature regimens: two constant (24&deg;C and 28&deg;C) and two daily thermocycles: 28:24&deg;C, TC (thermophase coinciding with daytime, and cryophase coinciding with night-time) and 24:28&deg;C, CT (opposite to TC) in a 12:12 h light:dark cycle (LD). Embryo development was temperature-dependent but enhanced at 28&deg;C and TC. Hatching rhythms were diurnal (around 4 h after lights on), but temperature- and cycle-sensitive, since hatching occurred sooner at 28&deg;C (48 hours post fertilization; hpf) while it was delayed at 24&deg;C (96 hpf). Under TC, hatching occurred at 72 hpf, while under CT hatching displayed two peaks (at 70 hpf and 94 hpf). In constant light (LL) or darkness (DD), hatching rhythms persisted with tau close to 24 h, suggesting a clock-controlled "gating" mechanism. Under 28&deg;C or TC, larvae showed the best performance (high growth and survival, and low malformations). The sex ratio was strongly influenced by temperature, as the proportion of females was higher in CT and TC (79 and 83% respectively), contrasting with 28&deg;C and 24&deg;C, which led to more males (83 and 76%). Ovarian aromatase (cyp19a) expression in females was highest in TC and CT (6.5 and 4.6 fold higher than at 28&deg;C, respectively); while anti-m&uuml;llerian hormone (amh) expression in males increased in testis at 24&deg;C (3.6 fold higher compared to TC) and particularly at 28&deg;C (14.3 fold increase). Taken together, these findings highlight the key role of environmental cycles during early development, which shaped the daily rhythms in fish embryo and larvae, and ultimately influenced sex differentiation

Identification and Characterization of an Unusual Class I Myosin Involved in Vesicle Traffic in Trypanosoma brucei

Myosins are a multimember family of motor proteins with diverse functions in eukaryotic cells. African trypanosomes possess only two candidate myosins and thus represent a useful system for functional analysis of these motors. One of these candidates is an unusual class I myosin (TbMyo1) that is expressed at similar levels but organized differently during the life cycle of Trypanosoma brucei. This myosin localizes to the polarized endocytic pathway in bloodstream forms of the parasite. This organization is actin dependent. Knock down of TbMyo1 results in a significant reduction in endocytic activity, a cessation in cell division and eventually cell death. A striking morphological feature in these cells is an enlargement of the flagellar pocket, which is consistent with an imbalance in traffic to and from the surface. In contrast TbMyo1 is distributed throughout procyclic forms of the tsetse vector and a loss of ∼90% of the protein has no obvious effects on growth or morphology. These results reveal a life cycle stage specific requirement for this myosin in essential endocytic traffic and represent the first description of the involvement of a motor protein in vesicle traffic in these parasites