Validation of a health-related quality of life instrument for primary ciliary dyskinesia (QOL-PCD)

Background: Quality of life (QOL)-primary ciliary dyskinesia (PCD) is the first disease-specific, health-related QOL instrument for PCD. Psychometric validation of QOL-PCD assesses the performance of this measure in adults, including its reliability, validity and responsiveness to change. Methods: Seventy-two adults (mean (range) age: 33 years (18–79 years); mean (range) FEV1% predicted: 68 (26–115)) with PCD completed the 49-item QOL-PCD and generic QOL measures: Short-Form 36 Health Survey, Sino-Nasal Outcome Test 20 (SNOT-20) and St George Respiratory Questionnaire (SGRQ)-C. Thirty-five participants repeated QOL-PCD 10–14 days later to measure stability or reproducibility of the measure. Results: Multitrait analysis was used to evaluate how the items loaded on 10 hypothesised scales: physical, emotional, role and social functioning, treatment burden, vitality, health perceptions, upper respiratory symptoms, lower respiratory symptoms and ears and hearing symptoms. This analysis of item-to-total correlations led to 9 items being dropped; the validated measure now comprises 40 items. Each scale had excellent internal consistency (Cronbach's α: 0.74 to 0.94). Two-week test–retest demonstrated stability for all scales (intraclass coefficients 0.73 to 0.96). Significant correlations were obtained between QOL-PCD scores and age and FEV1. Strong relationships were also found between QOL-PCD scales and similar constructs on generic questionnaires, for example, lower respiratory symptoms and SGRQ-C (r=0.72, p<0.001), while weak correlations were found between measures of different constructs. Conclusions: QOL-PCD has demonstrated good internal consistency, test–retest reliability, convergent and divergent validity. QOL-PCD offers a promising tool for evaluating new therapies and for measuring symptoms, functioning and QOL during routine care

Coordinated progression through two subtranscriptomes underlies the tachyzoite cycle of Toxoplasma gondii

BACKGROUND: Apicomplexan parasites replicate by varied and unusual processes where the typically eukaryotic expansion of cellular components and chromosome cycle are coordinated with the biosynthesis of parasite-specific structures essential for transmission. METHODOLOGY/PRINCIPAL FINDINGS: Here we describe the global cell cycle transcriptome of the tachyzoite stage of Toxoplasma gondii. In dividing tachyzoites, more than a third of the mRNAs exhibit significant cyclical profiles whose timing correlates with biosynthetic events that unfold during daughter parasite formation. These 2,833 mRNAs have a bimodal organization with peak expression occurring in one of two transcriptional waves that are bounded by the transition into S phase and cell cycle exit following cytokinesis. The G1-subtranscriptome is enriched for genes required for basal biosynthetic and metabolic functions, similar to most eukaryotes, while the S/M-subtranscriptome is characterized by the uniquely apicomplexan requirements of parasite maturation, development of specialized organelles, and egress of infectious daughter cells. Two dozen AP2 transcription factors form a series through the tachyzoite cycle with successive sharp peaks of protein expression in the same timeframes as their mRNA patterns, indicating that the mechanisms responsible for the timing of protein delivery might be mediated by AP2 domains with different promoter recognition specificities. CONCLUSION/SIGNIFICANCE: Underlying each of the major events in apicomplexan cell cycles, and many more subordinate actions, are dynamic changes in parasite gene expression. The mechanisms responsible for cyclical gene expression timing are likely crucial to the efficiency of parasite replication and may provide new avenues for interfering with parasite growth

A quality-of-life measure for adults with primary ciliary dyskinesia: QOL-PCD

Primary ciliary dyskinesia (PCD) is characterised by chronic suppurative lung disease, rhino-sinusitis, hearing impairment and sub-fertility. We have developed the first multidimensional measure to assess health-related quality of life (HRQoL) in adults with PCD (QOL-PCD). Following a literature review and expert panel meeting, open-ended interviews with patients investigated the impact of PCD on HRQoL in the UK and North America (n=21). Transcripts were content analysed to derive saturation matrices. Items were rated for relevance by patients (n=49). Saturation matrices, relevance scores, literature review, evaluation of existing measures, and expert opinion contributed to development of a preliminary questionnaire. The questionnaire was refined following cognitive interviews (n=18). Open-ended interviews identified a spectrum of issues unique to adults with PCD. Saturation matrices confirmed comprehensive coverage of content. QOL-PCD includes 48 items covering the following seven domains: Physical Functioning, Emotional Functioning, Treatment Burden, Respiratory and Sinus Symptoms, Ears and Hearing, Social Functioning, and Vitality and Health Perceptions. Cognitive testing confirmed that content was comprehensive and the items were well-understood by respondents. Content validity and cognitive testing supported the items and structure. QOL-PCD has been translated into other languages and is awaiting psychometric testing

Immune profiles and DNA methylation alterations related with non-muscle-invasive bladder cancer outcomes

Background: Non-muscle-invasive bladder cancer (NMIBC) patients receive frequent monitoring because ≥ 70% will have recurrent disease. However, screening is invasive, expensive, and associated with significant morbidity making bladder cancer the most expensive cancer to treat per capita. There is an urgent need to expand the understanding of markers related to recurrence and survival outcomes of NMIBC. Methods and results: We used the Illumina HumanMethylationEPIC array to measure peripheral blood DNA methylation profiles of NMIBC patients (N = 603) enrolled in a population-based cohort study in New Hampshire and applied cell type deconvolution to estimate immune cell-type proportions. Using Cox proportional hazard models, we identified that increasing CD4T and CD8T cell proportions were associated with a statistically significant decreased hazard of tumor recurrence or death (CD4T: HR = 0.98, 95% CI = 0.97–1.00; CD8T: HR = 0.97, 95% CI = 0.95–1.00), whereas increasing monocyte proportion and methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) were associated with the increased hazard of tumor recurrence or death (monocyte: HR = 1.04, 95% CI = 1.00–1.07; mdNLR: HR = 1.12, 95% CI = 1.04–1.20). Then, using an epigenome-wide association study (EWAS) approach adjusting for age, sex, smoking status, BCG treatment status, and immune cell profiles, we identified 2528 CpGs associated with the hazard of tumor recurrence or death (P \u3c 0.005). Among these CpGs, the 1572 were associated with an increased hazard and were significantly enriched in open sea regions; the 956 remaining CpGs were associated with a decreased hazard and were significantly enriched in enhancer regions and DNase hypersensitive sites. Conclusions: Our results expand on the knowledge of immune profiles and methylation alteration associated with NMIBC outcomes and represent a first step toward the development of DNA methylation-based biomarkers of tumor recurrence

Primary Ciliary Dyskinesia: First Health-related Quality of Life Measures for Pediatric Patients

Rationale: Primary ciliary dyskinesia (PCD) is a rare disease. There are no available data on disease-specific pediatric patient–reported outcomes

Worldwide experience with a totally subcutaneous implantable defibrillator: Early results from the EFFORTLESS S-ICD registry

Aims The totally subcutaneous implantable-defibrillator (S-ICD) is a new alternative to the conventional transveno

TESS asteroseismology of the known red-giant host stars HD 212771 and HD 203949

International audienc

The harvest plot: A method for synthesising evidence about the differential effects of interventions

<p>Abstract</p> <p>Background</p> <p>One attraction of meta-analysis is the forest plot, a compact overview of the essential data included in a systematic review and the overall 'result'. However, meta-analysis is not always suitable for synthesising evidence about the effects of interventions which may influence the wider determinants of health. As part of a systematic review of the effects of population-level tobacco control interventions on social inequalities in smoking, we designed a novel approach to synthesis intended to bring aspects of the graphical directness of a forest plot to bear on the problem of synthesising evidence from a complex and diverse group of studies.</p> <p>Methods</p> <p>We coded the included studies (n = 85) on two methodological dimensions (suitability of study design and quality of execution) and extracted data on effects stratified by up to six different dimensions of inequality (income, occupation, education, gender, race or ethnicity, and age), distinguishing between 'hard' (behavioural) and 'intermediate' (process or attitudinal) outcomes. Adopting a hypothesis-testing approach, we then assessed which of three competing hypotheses (positive social gradient, negative social gradient, or no gradient) was best supported by each study for each dimension of inequality.</p> <p>Results</p> <p>We plotted the results on a matrix ('harvest plot') for each category of intervention, weighting studies by the methodological criteria and distributing them between the competing hypotheses. These matrices formed part of the analytical process and helped to encapsulate the output, for example by drawing attention to the finding that increasing the price of tobacco products may be more effective in discouraging smoking among people with lower incomes and in lower occupational groups.</p> <p>Conclusion</p> <p>The harvest plot is a novel and useful method for synthesising evidence about the differential effects of population-level interventions. It contributes to the challenge of making best use of all available evidence by incorporating all relevant data. The visual display assists both the process of synthesis and the assimilation of the findings. The method is suitable for adaptation to a variety of questions in evidence synthesis and may be particularly useful for systematic reviews addressing the broader type of research question which may be most relevant to policymakers.</p

Endothelial Dysfunction: Associations with Exposure to Ambient Fine Particles in Diabetic Individuals

BACKGROUND: Exposure to fine airborne particulate matter [&lt;= 2.5 mu m in aerodynamic diameter (PM2.5)] has been associated with cardiovascular and hematologic effects, especially in older people with cardiovascular disease. Some epidemiologic studies suggest that adults with diabetes also may be a particularly susceptible population. OBJECTIVES: The purpose of this study was to analyze the short-term effects of ambient PM2.5 on markers of endothelial function in diabetic volunteers.METHODS: We conducted a prospective panel study in 22 people with type 2 diabetes mellitus in Chapel Hill, North Carolina (USA), from November 2004 to December 2005. We acquired daily measurements of PM2.5 and meteorologic data at central monitoring sites. On 4 consecutive days, we measured endothelial function by brachial artery ultrasound in all participants and by pulsewave measurements in a subgroup. Data were analyzed using additive mixed models with a random participant effect and adjusted for season, day of the week, and meteorology. RESULTS: Flow-mediated dilatation decreased in association with PM2.5 during the first 24 hr, whereas small-artery elasticity index decreased with a delay of 1 and 3 days. These PM2.5-associated decrements in endothelial function were greater among participants with a high body mass index, high glycosylated hemoglobin Ale, low adiponectin, or the null polymorphism of glutathione S-transferase M1. However, high levels of myeloperoxidase on the examination day led to strongest effects on endothelial dysfunction. CONCLUSIONS: These data demonstrate that PM2.5 exposure may cause immediate endothelial dysfunction. Clinical characteristics associated with insulin resistance were associated with enhanced effects of PM on endothelial function. In addition, participants with greater oxidative potential seem to be more susceptible

Analysis of FOXP3+ Regulatory T Cells That Display Apparent Viral Antigen Specificity during Chronic Hepatitis C Virus Infection

We reported previously that a proportion of natural CD25+ cells isolated from the PBMC of HCV patients can further upregulate CD25 expression in response to HCV peptide stimulation in vitro, and proposed that virus-specific regulatory T cells (Treg) were primed and expanded during the disease. Here we describe epigenetic analysis of the FOXP3 locus in HCV-responsive natural CD25+ cells and show that these cells are not activated conventional T cells expressing FOXP3, but hard-wired Treg with a stable FOXP3 phenotype and function. Of ∼46,000 genes analyzed in genome wide transcription profiling, about 1% were differentially expressed between HCV-responsive Treg, HCV-non-responsive natural CD25+ cells and conventional T cells. Expression profiles, including cell death, activation, proliferation and transcriptional regulation, suggest a survival advantage of HCV-responsive Treg over the other cell populations. Since no Treg-specific activation marker is known, we tested 97 NS3-derived peptides for their ability to elicit CD25 response (assuming it is a surrogate marker), accompanied by high resolution HLA typing of the patients. Some reactive peptides overlapped with previously described effector T cell epitopes. Our data offers new insights into HCV immune evasion and tolerance, and highlights the non-self specific nature of Treg during infection