achievement of red blood cell transfusion independence in red blood cell transfusion dependent patients with lower risk non del 5q myelodysplastic syndromes correlates with serum erythropoietin levels

AbstractIn the randomized, phase 3, MDS-005 study (NCT01029262), lenalidomide-induced red blood cell transfusion independence (RBC-TI) in 27% of transfusion-dependent patients with lower-risk non-d..

A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial.

The phase III AZA-001 study established that azacitidine significantly improves overall survival compared with conventional care regimens (hazard ratio 0.58 [95% confidence interval 0.43–0.77], P<0.001). This analysis was conducted to investigate the relationship between treatment response and overall survival. AZA-001 data were analyzed in a multivariate Cox regression analysis with response as a time-varying covariate. Response categories were “Overall Response” (defined as complete remission, partial remission, or any hematologic improvement) and “Stable Disease” (no complete or partial remission, hematologic improvement, or progression) or “Other” (e.g. disease progression). Achieving an Overall Response with azacitidine reduced risk of death by 95% compared with achieving an Overall Response with the conventional care regimens (hazard ratio 0.05 [95%CI: 0.01–0.43], P=0.006). Sensitivity analyses indicated that significantly improved overall survival remained manifest for patients with a hematologic improvement who had never achieved complete or partial remission (hazard ratio 0.19 [95%CI: 0.08–0.46], P<0.001). Stable Disease in both azacitidine-treated and conventional care-treated patients was also associated with a significantly reduced risk of death (hazard ratio 0.09, [95%CI: 0.06–0.15]; P<0.001). These results demonstrate azacitidine benefit on overall survival compared with conventional care regimens in patients with higher-risk myelodysplastic syndromes who achieve hematologic response but never attain complete or partial remission, in addition to the survival advantage conferred by achievement of complete or partial remission. This study was registered with clinicaltrials.gov (NCT00071799)

The effects of continued azacitidine treatment cycles on response in higher risk patients with myelodysplastic syndromes: an update

The international, phase III, multi-centre AZA-001 trial demonstrated azacitidine (AZA) is the first treatment to significantly extend overall survival (OS) in higher risk myelodysplastic syndromes (MDS) patients (Fenaux (2007) Blood 110 817). The current treatment paradigm, which is based on a relationship between complete remission (CR) and survival, is increasingly being questioned (Cheson (2006) Blood 108 419). Results of AZA-001 show CR is sufficient but not necessary to prolong OS (List (2008) Clin Oncol 26 7006). Indeed, the AZA CR rate in AZA-001 was modest (17%), while partial remission (PR, 12%) and haematological improvement (HI, 49%) were also predictive of prolonged survival. This analysis was conducted to assess the median number of AZA treatment cycles associated with achievement of first response, as measured by IWG 2000-defined CR, PR or HI (major + minor). The number of treatment cycles from first response to best response was also measured

Azacitidine prolongs overall survival and reduces infections and hospitalizations in patients with WHO-defined acute myeloid leukaemia compared with conventional care regimens: an update

Azacitidine (AZA), as demonstrated in the phase III trial (AZA-001), is the first MDS treatment to significantly prolong overall survival (OS) in higher risk MDS pts ((2007) Blood 110 817). Approximately, one-third of the patients (pts) enrolled in AZA-001 were FAB RAEB-T (≥20–30% blasts) and now meet the WHO criteria for acute myeloid leukaemia (AML) ((1999) Blood 17 3835). Considering the poor prognosis (median survival <1 year) and the poor response to chemotherapy in these pts, this sub-group analysis evaluated the effects of AZA versus conventional care regimens (CCR) on OS and on response rates in pts with WHO AML

What factors affect implementation of early rehabilitation into intensive care unit practice? A qualitative study with clinicians

: This study was funded by the Pat Cosh Trust Foundation,Australia. Dr Selina Parry is supported by a National Health and Medical ResearchCouncil early career fellowship. Dr Catherine Granger is supported in part by a NationalHealth and Medical Research Council and Cancer Australia Translating Research IntoPractice fellowshi

Cancer patients’ respect experiences in relation to perceived communication behaviours from hospital staff: analysis of the 2012-2013 National Cancer Patient Experience Survey

The final publication is available at Springer via http://dx.DOI 10.1007/s00520-015-2973-5Purpose: Respect experiences are poorly understood despite respect being central to professionalism in healthcare and patient well-being, and needed for optimal patient care. This study explores which patient-perceived communication behaviours from hospital staff contribute most to cancer patients’ respect experiences and account for variation in their experience by socio-demographic and clinical characteristics. Methods: Secondary analysis of data from the 2012-2013 National Cancer Patient Experience Survey of 45191 patients with a primary cancer diagnosis treated in English National Health Service trusts providing adult acute cancer services who provided data on experienced respect and dignity. Results: Both autonomy-supportive and caring/emotionally sensitive behaviours were associated with reported respect, although the latter showed stronger associations and accounted for most differences in reports of respect between patient groups. Differences in respect were found by gender, race/ethnicity, age, the presence of long-standing conditions, treatment response, time since first treated for cancer (p<.001), employment and type of cancer (p<.05). Conclusions: The study questions the tendency to conceptualise respect primarily in terms of autonomy-supportive behaviours and shows the relative contribution of autonomy-supportive and caring/emotionally sensitive behaviours in explaining disparities in respect experiences. More attention should be paid to affective communication behaviours from hospital staff to reduce disparities in respect experiences

Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease

Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD

A randomised controlled trial to compare a range of commercial or primary care led weight reduction programmes with a minimal intervention control for weight loss in obesity: the Lighten Up trial

<p>Abstract</p> <p>Background</p> <p>Developed countries are facing a huge rise in the prevalence of obesity and its associated chronic medical problems. In the UK Primary Care Trusts are charged with addressing this in the populations they serve, but evidence about the most effective ways of delivering services is not available. The aim of this study is to determine the effectiveness of a range of weight loss programmes for obese patients in primary care and to determine the characteristics of patients who respond to an invitation to a free weight management programme.</p> <p>Methods/Design</p> <p>Lighten Up is a randomised controlled trial comparing a range of 12-week commercial and NHS weight reduction programmes with a comparator group who are provided with 12 vouchers enabling free entrance to a local leisure centre. The weight reduction programmes are: (i) Weight Watchers, (ii) Slimming World, (iii) Rosemary Conley, (iv) a group-based dietetics-led programme (Size Down), (v) general practice one-to-one counselling, (vi) pharmacy-led one-to-one counselling, (vii) choice of any of the 6 programmes. People with obesity or overweight with a co-morbid disorder are invited to take part by a letter from their general practitioner. The sample size is 740 participants.</p> <p>The primary outcome is weight loss at programme-end (3 months). Secondary outcomes are weight-loss at one year, self-reported physical activity at 3 and 12 months follow-up and percentage weight-loss at 3 months and one year.</p> <p>Discussion</p> <p>This trial will provide evidence about the effectiveness of a range of different weight management programmes in a primary care population.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN25072883</p

Genome-Wide Analysis of Structural Variants in Parkinson Disease

OBJECTIVE: Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD. METHODS: We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data. RESULTS: We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4. INTERPRETATION: We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 202

Computational modelling of meiotic entry and commitment

In response to developmental and environmental conditions, cells exit the mitotic cell cycle and enter the meiosis program to generate haploid gametes from diploid germ cells. Once cells decide to enter the meiosis program they become irreversibly committed to the completion of meiosis irrespective of the presence of cue signals. How meiotic entry and commitment occur due to the dynamics of the regulatory network is not well understood. Therefore, we constructed a mathematical model of the regulatory network that controls the transition from mitosis to meiosis in Schizosaccharomyces pombe. Upon nitrogen starvation, yeast cells exit mitosis and undergo conjugation and meiotic entry. The model includes the regulation of Mei2, an RNA binding protein required for conjugation and meiotic entry, by multiple feedback loops involving Pat1, a kinase that keeps cells in mitosis, and Ste11, a transcription activator required for the sexual differentiation. The model accounts for various experimental observations and demonstrates that the activation of Mei2 is bistable, which ensures the irreversible commitment to meiosis. Further, we show by integrating the meiosis-specific regulation with a cell cycle model, the dynamics of cell cycle exit, G1 arrest and entry into meiosis under nitrogen starvation. © 2017 The Author(s)