Replication of an empirical approach to delineate the heterogeneity of chronic unexplained fatigue

<p>Abstract</p> <p>Background</p> <p>Chronic fatigue syndrome (CFS) is defined by self-reported symptoms. There are no diagnostic signs or laboratory markers, and the pathophysiology remains inchoate. In part, difficulties identifying and replicating biomarkers and elucidating the pathophysiology reflect the heterogeneous nature of the syndromic illness CFS. We conducted this analysis of people from defined metropolitan, urban, and rural populations to replicate our earlier empirical delineation of medically unexplained chronic fatigue and CFS into discrete endophenotypes. Both the earlier and current analyses utilized quantitative measures of functional impairment and symptoms as well as laboratory data. This study and the earlier one enrolled participants from defined populations and measured the internal milieu, which differentiates them from studies of clinic referrals that examine only clinical phenotypes.</p> <p>Methods</p> <p>This analysis evaluated 386 women identified in a population-based survey of chronic fatigue and unwellness in metropolitan, urban, and rural populations of the state of Georgia, USA. We used variables previously demonstrated to effectively delineate endophenotypes in an attempt to replicate identification of these endophenotypes. Latent class analyses were used to derive the classes, and these were compared and contrasted to those described in the previous study based in Wichita, Kansas.</p> <p>Results</p> <p>We identified five classes in the best fit analysis. Participants in Class 1 (25%) were polysymptomatic, with sleep problems and depressed mood. Class 2 (24%) was also polysymptomatic, with insomnia and depression, but participants were also obese with associated metabolic strain. Class 3 (20%) had more selective symptoms but was equally obese with metabolic strain. Class 4 (20%) and Class 5 (11%) consisted of nonfatigued, less symptomatic individuals, Class 4 being older and Class 5 younger. The classes were generally validated by independent variables. People with CFS fell equally into Classes 1 and 2. Similarities to the Wichita findings included the same four main defining variables of obesity, sleep problems, depression, and the multiplicity of symptoms. Four out of five classes were similar across both studies.</p> <p>Conclusion</p> <p>These data support the hypothesis that chronic medically unexplained fatigue is heterogeneous and can be delineated into discrete endophenotypes that can be replicated. The data do not support the current perception that CFS represents a unique homogeneous disease and suggests broader criteria may be more explanatory. This replication suggests that delineation of endophenotypes of CFS and associated ill health may be necessary in order to better understand etiology and provide more patient-focused treatments.</p

Psychiatric misdiagnoses in patients with chronic fatigue syndrome

OBJECTIVES: The aim of this study was to examine the accuracy of doctors at diagnosing co-morbid psychiatric disorders in patients with chronic fatigue syndrome (CFS). DESIGN: Case series comparing clinical diagnoses with a standardized structured psychiatric interview. SETTING: Secondary care specialist chronic fatigue syndrome clinic. PARTICIPANTS: One hundred and thirty-five participants of a randomized controlled trial of non-pharmacological treatments at one centre in the PACE trial. MAIN OUTCOME MEASURES: Current psychiatric diagnoses made by CFS specialist doctors, compared with current psychiatric diagnoses made independently using a structured psychiatric interview. RESULTS: Clinicians identified 59 (44%, 95% CI 39-56%) of patients as suffering from a co-morbid psychiatric disorder compared to 76 (56%, CI 53-69%) by structured interview. Depressive and anxiety disorders were most common. Clinicians were twice as likely to miss diagnoses (30 patients, 22%) than misdiagnose them (13, 10%). Psychiatrists were less likely to miss diagnoses than other clinicians, but were as likely to misdiagnose them. CONCLUSIONS: Doctors assessing patients in a chronic fatigue syndrome clinic miss psychiatric diagnoses more often than misdiagnosing them. Missed diagnoses are common. CFS clinic doctors should be trained to diagnose psychiatric disorders.East London Foundation Trust, Queen Mary University of London,and the Medical Research Counci

Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States

<p>Abstract</p> <p>Background</p> <p>XMRV, a xenotropic murine leukemia virus (MuLV)-related virus, was recently identified by PCR testing in 67% of persons with chronic fatigue syndrome (CFS) and in 3.7% of healthy persons from the United States. To investigate the association of XMRV with CFS we tested blood specimens from 51 persons with CFS and 56 healthy persons from the US for evidence of XMRV infection by using serologic and molecular assays. Blinded PCR and serologic testing were performed at the US Centers for Disease Control and Prevention (CDC) and at two additional laboratories.</p> <p>Results</p> <p>Archived blood specimens were tested from persons with CFS defined by the 1994 international research case definition and matched healthy controls from Wichita, Kansas and metropolitan, urban, and rural Georgia populations. Serologic testing at CDC utilized a Western blot (WB) assay that showed excellent sensitivity to MuLV and XMRV polyclonal or monoclonal antibodies, and no reactivity on sera from 121 US blood donors or 26 HTLV-and HIV-infected sera. Plasma from 51 CFS cases and plasma from 53 controls were all WB negative. Additional blinded screening of the 51 cases and 53 controls at the Robert Koch Institute using an ELISA employing recombinant Gag and Env XMRV proteins identified weak seroreactivity in one CFS case and a healthy control, which was not confirmed by immunofluorescence. PCR testing at CDC employed a <it>gag </it>and a <it>pol </it>nested PCR assay with a detection threshold of 10 copies in 1 ug of human DNA. DNA specimens from 50 CFS patients and 56 controls and 41 US blood donors were all PCR-negative. Blinded testing by a second nested gag PCR assay at the Blood Systems Research Institute was also negative for DNA specimens from the 50 CFS cases and 56 controls.</p> <p>Conclusions</p> <p>We did not find any evidence of infection with XMRV in our U.S. study population of CFS patients or healthy controls by using multiple molecular and serologic assays. These data do not support an association of XMRV with CFS.</p

Interstellar Turbulence II: Implications and Effects

Interstellar turbulence has implications for the dispersal and mixing of the elements, cloud chemistry, cosmic ray scattering, and radio wave propagation through the ionized medium. This review discusses the observations and theory of these effects. Metallicity fluctuations are summarized, and the theory of turbulent transport of passive tracers is reviewed. Modeling methods, turbulent concentration of dust grains, and the turbulent washout of radial abundance gradients are discussed. Interstellar chemistry is affected by turbulent transport of various species between environments with different physical properties and by turbulent heating in shocks, vortical dissipation regions, and local regions of enhanced ambipolar diffusion. Cosmic rays are scattered and accelerated in turbulent magnetic waves and shocks, and they generate turbulence on the scale of their gyroradii. Radio wave scintillation is an important diagnostic for small scale turbulence in the ionized medium, giving information about the power spectrum and amplitude of fluctuations. The theory of diffraction and refraction is reviewed, as are the main observations and scintillation regions.Comment: 46 pages, 2 figures, submitted to Annual Reviews of Astronomy and Astrophysic

Background risk of breast cancer and the association between physical activity and mammographic density

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Fluid intake and incidence of renal cell carcinoma in UK women

Background:It has been suggested that the apparent protective effect of alcohol intake on renal cell carcinoma may be due to the diluting effect of carcinogens by a high total fluid intake. We assessed the association between intakes of total fluids and of specific beverages on the risk of renal cell carcinoma in a large prospective cohort of UK women.Methods:Information on beverage consumption was obtained from a questionnaire sent 3 years after recruitment into the Million Women Study. Cox proportional hazards models were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for renal cell carcinoma associated with beverage consumption adjusted for age, region of residence, socioeconomic status, smoking, and body mass index.Results:After an average of 5.2 years of follow-up, 588 cases of renal cell carcinoma were identified among 779 369 women. While alcohol intake was associated with a reduced risk of renal cell carcinoma (RR for 2 vs 1 drink per day: 0.76; 95% CI: 0.61-0.96; P for trend0.02), there was no association with total fluid intake (RR for 12 vs 7 drinks per day: 1.15; 95% CI: 0.91-1.45; P for trend0.3) or with intakes of specific beverages.Conclusions:The apparent protective effect of alcohol on the risk of renal cell carcinoma is unlikely to be related to a high fluid intake. © 2011 Cancer Research UK All rights reserved

Stepwise Optimization of the Procedure for Assessment of Circulating Progenitor Cells in Patients with Myocardial Infarction

The number and functional activity of circulating progenitor cells (CPCs) is altered in diabetic patients. Furthermore, reduced CPC count has been shown to independently predict cardiovascular events. Validation of CPCs as a biomarker for cardiovascular risk stratification requires rigorous methodology. Before a standard operation protocol (SOP) can be designed for such a trial, a variety of technical issues have to be addressed fundamentally, which include the appropriate type of red blood cell lysis buffer, FMO or isotype controls to identify rare cell populations from background noise, optimal antibody dilutions and conditions of sample storage. We herein propose improvements in critical steps of CPC isolation, antigenic characterization and determination of functional competence for final application in a prospective investigation of CPCs as a biomarker of outcome following acute myocardial infarction.In this validation study, we refined the standard operating procedure (SOP) for flow cytometry characterisation and functional analysis of CPCs from the first 18 patients of the Progenitor Cell Response after Myocardial Infarction Study (ProMIS). ProMIS aims to verify the prognostic value of CPCs in patients with either ST elevation or non-ST elevation myocardial infarction with or without diabetes mellitus, using cardiac magnetic resonance imaging (MRI) for assessment of ventricular function as a primary endpoint. Results indicate crucial steps for SOP implementation, namely timely cell isolation after sampling, use of appropriate lysis buffer to separate blood cell types and minimize the acquisition events during flow cytometry, adoption of proper fluorophore combination and antibody titration for multiple antigenic detection and introduction of counting beads for precise quantification of functional CPC activity in migration assay.With systematic specification of factors influencing the enumeration of CPC by flow cytometry, the abundance and migration capacity of CPCs can be correctly assessed. Adoption of validated SOP is essential for refined comparison of patients with different comorbidities in the analysis of risk stratification

Developing a digital intervention for cancer survivors: an evidence-, theory- and person-based approach

This paper illustrates a rigorous approach to developing digital interventions using an evidence-, theory- and person-based approach. Intervention planning included a rapid scoping review which identified cancer survivors’ needs, including barriers and facilitators to intervention success. Review evidence (N=49 papers) informed the intervention’s Guiding Principles, theory-based behavioural analysis and logic model. The intervention was optimised based on feedback on a prototype intervention through interviews (N=96) with cancer survivors and focus groups with NHS staff and cancer charity workers (N=31). Interviews with cancer survivors highlighted barriers to engagement, such as concerns about physical activity worsening fatigue. Focus groups highlighted concerns about support appointment length and how to support distressed participants. Feedback informed intervention modifications, to maximise acceptability, feasibility and likelihood of behaviour change. Our systematic method for understanding user views enabled us to anticipate and address important barriers to engagement. This methodology may be useful to others developing digital interventions