The role of azacitidine in the management of myelodysplastic syndromes (MDS)

Myelodysplastic syndromes (MDS) are a group of common bone marrow disorders characterized by ineffective hematopoiesis, peripheral cytopenias, and a propensity for transformation to acute myeloid leukemia (AML). For many years, the main treatment option for MDS was best supportive care which alleviates symptoms but has no effect on the natural course of the disease. The recent approval of the demethylating agent azacitidine represents a significant advance in the treatment of MDS. The results of two randomized trials with azacitidine have shown an overall response rate between 40% and 60%, an improved quality of life, a reduced risk of transformation to AML and a definite survival advantage compared to best supportive care or low-dose chemotherapy. Current data on azacitidine and its place in the treatment of MDS are reviewed

Home based exercise programme for knee pain and knee osteoarthritis: randomised controlled trial

Objectives To determine whether a home based exercise programme can improve outcomes in patients with knee pain. Design Pragmatic, factorial randomised controlled trial of two years' duration. Setting Two general practices in Nottingham. Participants 786 men and women aged >45 years with self reported knee pain. Interventions Participants were randomised to four groups to receive exercise therapy, monthly telephone contact, exercise therapy plus telephone contact, or no intervention. Patients in the no intervention and combined exercise and telephone groups were randomised to receive or not receive a placebo health food tablet. Main outcome measures Primary outcome was self reported score for knee pain on the Western Ontario and McMaster universities (WOMAC) osteoarthritis index at two years. Secondary outcomes included knee specific physical function and stiffness (scored on WOMAC index), general physical function (scored on SF­36 questionnaire), psychological outlook (scored on hospital anxiety and depression scale), and isometric muscle strength. Results 600 (76.3%) participants completed the study. At 24 months, highly significant reductions in knee pain were apparent for the pooled exercise groups compared with the non­exercise groups (mean difference –0.82, 95% confidence interval –1.3 to –0.3). Similar improvements were observed at 6, 12, and 18 months. Regular telephone contact alone did not reduce pain. The reduction in pain was greater the closer patients adhered to the exercise plan. Conclusions A simple home based exercise programme can significantly reduce knee pain. The lack of improvement in patients who received only telephone contact suggests that improvements are not just due to psychosocial effects because of contact with the therapist

A Study of Initialization in Linux and OpenBSD

The code that initializes a system can be notoriously difficult to understand. In secure systems, initialization is critical for establishing a starting state that is secure. This paper explores two architectures used for bringing an operating system to its initial state, once the operating system gains control from the boot loader. Specifically, the ways in which the OpenBSD and Linux operating systems handle initialization are dissected

Studying a disease with no home - lessons in trial recruitment from the PATCH II study

<p>Abstract</p> <p>Background</p> <p>Cellulitis is a very common condition that often recurs. The PATCH II study was designed to explore the possibility of preventing future episodes of cellulitis, with resultant cost savings for the NHS. This was the first trial to be undertaken by the UK Dermatology Clinical Trials Network. As such, it was the first to test a recruitment model that involved many busy clinicians each contributing just a few patients.</p> <p>Methods</p> <p>A double-blind randomised controlled trial comparing prophylactic antibiotics (penicillin V) with placebo tablets, for the prevention of repeat episodes of cellulitis of the leg. Primary outcome was time to subsequent recurrence of cellulitis.</p> <p>Results</p> <p>The PATCH II study was closed to recruitment having enrolled 123 participants from a target of 400. Whilst the recruitment period was extended by 12 months, it was not possible to continue beyond this point without additional funds. Many factors contributed to poor recruitment: (i) changes in hospital policy and the introduction of community-based intravenous teams resulted in fewer cellulitis patients being admitted to hospital; ii) those who were admitted were seen by many different specialties, making it difficult for a network of dermatology clinicians to identify suitable participants; and iii) funding for research staff was limited to a trial manager and a trial administrator at the co-ordinating centre. With no dedicated research nurses at the recruiting centres, it was extremely difficult to maintain momentum and interest in the study. Attempts to boost recruitment by providing some financial support for principal investigators to employ local research staff was of limited success.</p> <p>Discussion</p> <p>The model of a network of busy NHS clinicians all recruiting a few patients into large clinical studies requires further testing. It did not work very well for PATCH II, but this was probably because patients were not routinely seen by dermatologists, and recruitment took place prior to research support being available through the Comprehensive Clinical Research Network (CCRN). There is a balance to be struck between asking a lot of centres to recruit just a few patients, and asking a few centres to recruit a lot of patients. Giving modest funds to principal investigators to buy local research nurse time did not work well, probably because too little research time was bought, and it was difficult to separate research tasks from the nurses existing clinical duties. National research infrastructure networks such as the Comprehensive Clinical Research Network will overcome many of the problems encountered in the PATCH II trial.</p> <p>Trial Registration</p> <p>The trial registration number is ISRCTN03813200.</p

Albuminuria is a marker of increasing intracranial and extracranial vascular involvement in Type 2 diabetic Chinese patients

AIMS/HYPOTHESIS: Albuminuria has been reported to be a marker of cardiovascular risk factors and disease morbidity and mortality, but its relationship with intracerebral atherosclerotic disease is less clear. The aim of this study was to investigate the association between albuminuria and intracranial and extracranial vascular involvement in Chinese Type 2 diabetic patients. METHODS: The anthropometric and fasting biochemical measurements of 966 Type 2 diabetic patients with normoalbuminuria (55.6%), microalbuminuria (27.7%) or macroalbuminuria (16.7%) were compared. The prevalence of microvascular and macrovascular disease and middle cerebral artery (MCA) stenosis, measured by transcranial Doppler ultrasound, were also compared between the groups. RESULTS: Albuminuria was closely associated with a range of adverse parameters, including high BP, dyslipidaemia, smoking and adiposity (all p<0.01). The prevalence of microvascular disease (retinopathy p<0.001) and macrovascular disease (peripheral vascular disease p=0.012, myocardial infarction, p=0.004, MCA stenosis p<0.001) increased significantly with increasing levels of albuminuria. Albuminuria was also found to be an independent predictor of microvascular and macrovascular disease. CONCLUSIONS/INTERPRETATION: Albuminuria was an independent predictor of increasing levels of vascular risk factors and microvascular and macrovascular disease in this group of Type 2 diabetic patients, and a possible role for albuminuria as a marker of intracranial cerebrovascular disease should be further investigated.postprin

Influenza vaccination and hospitalisation in Elderly Health Centres.

1. A cohort of Elderly Health Centres was examined to determine whether influenza vaccination decreased hospitalisation and mortality. 2. In the influenza season, influenza vaccination reduced all-cause mortality by half and cardiorespiratory hospitalisation by a quarter. The extent to which influenza vaccination protects older people from serious morbidity and mortality needs to be confirmed in appropriately designed studies, so that scarce health care resources can be used effectivelypublished_or_final_versio

Systemic therapy for vulval Erosive Lichen Planus (the 'hELP' trial): study protocol for a randomised controlled trial

BACKGROUND: Erosive lichen planus affecting the vulva (ELPV) is a relatively rare, chronic condition causing painful raw areas in the vulvovaginal region. Symptoms are pain and burning, which impact upon daily living. There is paucity of evidence regarding therapy. A 2012 Cochrane systematic review found no randomised controlled trials (RCTs) in this field. Topically administered corticosteroids are the accepted first-line therapy: however, there is uncertainty as to which second-line treatments to use. Several systemic agents have been clinically noted to show promise for ELPV refractory to topically administered corticosteroids but there is no RCT evidence to support these. The 'hELP' study is a RCT with an internal pilot phase designed to provide high-quality evidence. METHODS/DESIGN: The objective is to test whether systemic therapy in addition to standard topical therapy is a beneficial second-line treatment for ELPV. Adjunctive systemic therapies used are hydroxychloroquine, methotrexate, mycophenolate mofetil and prednisolone. Topical therapy plus a short course of prednisolone given orally is considered the comparator intervention. The trial is a four-armed, open-label, pragmatic RCT which uses a blinded independent clinical assessor. To provide 80 % power for each comparison, 96 participants are required in total. The pilot phase aims to recruit 40 participants. The primary clinical outcome is the proportion of patients achieving treatment success at 6 months. 'Success' is defined by a composite measure of Patient Global Assessment score of 0 or 1 on a 4-point scale plus improvement from baseline on clinical photographs scored by a clinician blinded to treatment allocation. Secondary clinical outcomes include 6-month assessment of: (1) Reduction in pain/soreness; (2) Global assessment of disease; (3) Response at other affected mucosal sites; (4) Hospital Anxiety and Depression Scale scores; (5) Sexual function; (6) Health-related quality of life using 'Short Form 36' and 'Skindex-29' questionnaires; (7) Days of topical steroid use; (8) Treatment satisfaction; (9) Discontinuation of medications due to treatment failure; (10) Per participant cost of intervention in each treatment group. Adverse events will also be reported. DISCUSSION: 'hELP' is the first RCT to address second-line treatment of ELPV. The trial has encountered unique methodological challenges and has required collaborative efforts of the UK Dermatology Clinical Trials Network alongside expert clinicians. TRIAL REGISTRATION: CURRENT CONTROLLED TRIALS: ISRCTN 81883379 . Date of registration 12 June 2014

Long-term behavioural rewriting of maladaptive drinking memories via reconsolidation-update mechanisms

BACKGROUND: Alcohol use disorders can be conceptualised as a learned pattern of maladaptive alcohol-consumption behaviours. The memories encoding these behaviours centrally contribute to long-term excessive alcohol consumption and are therefore an important therapeutic target. The transient period of memory instability sparked during memory reconsolidation offers a therapeutic window to directly rewrite these memories using targeted behavioural interventions. However, clinically-relevant demonstrations of the efficacy of this approach are few. We examined key retrieval parameters for destabilising naturalistic drinking memories and the ability of subsequent counterconditioning to effect long-term reductions in drinking. METHODS: Hazardous/harmful beer-drinking volunteers (N = 120) were factorially randomised to retrieve (RET) or not retrieve (No RET) alcohol reward memories with (PE) or without (No PE) alcohol reward prediction error. All participants subsequently underwent disgust-based counterconditioning of drinking cues. Acute responses to alcohol were assessed pre- and post-manipulation and drinking levels were assessed up to 9 months. RESULTS: Greater long-term reductions in drinking were found when counterconditioning was conducted following retrieval (with and without PE), despite a lack of short-term group differences in motivational responding to acute alcohol. Large variability in acute levels of learning during counterconditioning was noted. 'Responsiveness' to counterconditioning predicted subsequent responses to acute alcohol in RET + PE only, consistent with reconsolidation-update mechanisms. CONCLUSIONS: The longevity of behavioural interventions designed to reduce problematic drinking levels may be enhanced by leveraging reconsolidation-update mechanisms to rewrite maladaptive memory. However, inter-individual variability in levels of corrective learning is likely to determine the efficacy of reconsolidation-updating interventions and should be considered when designing and assessing interventions

Fungal Communities in Sediments Along a Depth Gradient in the Eastern Tropical Pacific

Deep waters represent the largest biome on Earth and the largest ecosystem of Costa Rica. Fungi play a fundamental role in global biogeochemical cycling in marine sediments, yet, they remain little explored. We studied fungal diversity and community composition in several marine sediments from 16 locations sampled along a bathymetric gradient (from a depth of 380 to 3,474 m) in two transects of about 1,500 km length in the Eastern Tropical Pacific (ETP) of Costa Rica. Sequence analysis of the V7-V8 region of the 18S rRNA gene obtained from sediment cores revealed the presence of 787 fungal amplicon sequence variants (ASVs). On average, we detected a richness of 75 fungal ASVs per sample. Ascomycota represented the most abundant phylum with Saccharomycetes constituting the dominant class. Three ASVs accounted for ca. 63% of all fungal sequences: the yeast Metschnikowia (49.4%), Rhizophydium (6.9%), and Cladosporium (6.7%). We distinguished a cluster composed mainly by yeasts, and a second cluster by filamentous fungi, but we were unable to detect a strong effect of depth and the overlying water temperature, salinity, dissolved oxygen (DO), and pH on the composition of fungal communities. We highlight the need to understand further the ecological role of fungi in deep-sea ecosystems.UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Ciencias del Mar y Limnología (CIMAR)UCR::Vicerrectoría de Docencia::Ciencias Básicas::Facultad de Ciencias::Escuela de Biologí