Quantifying the risk of multiple myeloma from symptoms reported in primary care patients: a large case-control study using electronic records

This is the author accepted manuscript. The final version is available from Royal College of General Practitioners via the DOI in this record.BACKGROUND: Patients with myeloma experience the longest diagnostic delays compared with patients with other cancers in the UK; 37% are diagnosed through emergency presentations. AIM: To identify and quantify the risk of myeloma from specific clinical features reported by primary care patients. DESIGN AND SETTING: Matched case-control study using General Practice Research Database primary care electronic records. METHOD: Putative clinical features of myeloma were identified and analysed using conditional logistic regression. Positive predictive values (PPVs) were calculated for the consulting population. RESULTS: A total of 2703 patients aged ≥40 years, diagnosed with myeloma between 2000 and 2009, and 12 157 age, sex, and general practice-matched controls were identified. Sixteen features were independently associated with myeloma: hypercalcaemia, odds ratio 11.4 (95% confidence interval [CI] = 7.1 to 18), cytopenia 5.4 (95% CI = 4.6 to 6.4), raised inflammatory markers 4.9 (95% CI = 4.2 to 5.8), fracture 3.1 (95% CI = 2.3 to 4.2), raised mean corpuscular volume 3.1 (95% CI = 2.4 to 4.1), weight loss 3.0 (95% CI = 2.0 to 4.5), nosebleeds 3.0 (95% CI = 1.9 to 4.7), rib pain 2.5 (95% CI = 1.5 to 4.4), back pain 2.2 (95% CI = 2.0 to 2.4), other bone pain 2.1 (95% CI = 1.4 to 3.1), raised creatinine 1.8 (95% CI = 1.5 to 2.2), chest pain 1.6 (95% CI = 1.4 to 1.8), joint pain 1.6 (95% CI = 1.2 to 2.2), nausea 1.5 (95% CI = 1.1 to 2.1), chest infection 1.4 (95% CI = 1.2 to 1.6), and shortness of breath 1.3 (95% CI = 1.1 to 1.5). Individual symptom PPVs were generally 10% for some symptoms when combined with leucopenia or hypercalcaemia. CONCLUSION: Individual symptoms of myeloma in primary care are generally low risk, probably explaining diagnostic delays. Once simple primary care blood tests are taken, risk estimates change. Hypercalcaemia and leucopenia are particularly important abnormalities, and coupled with symptoms, strongly suggest myeloma.This article presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-0608- 10045). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. Fiona M Walter is part-funded by a NIHR Clinician Scientist award. Richard D Neal is part funded by Public Health Wales and Betsi Cadwaladr University Health Board

Variations in 24-mu m morphologies among galaxies in the Spitzer Infrared Nearby Galaxies Survey: new insights into the Hubble sequence

To study the distribution of star formation and dust emission within nearby galaxies, we measured five morphological parameters in the 3.6- and 24-μm wavebands for 65 galaxies in the Spitzer Infrared Nearby Galaxies Survey (SINGS) and eight galaxies that were serendipitously observed by SINGS. The morphological parameters demonstrate strong variations along the Hubble sequence, including statistically significant differences between S0/a-Sab and Sc-Sd galaxies. Early-type galaxies are generally found to be compact, centralized, symmetric sources in the 24-μm band, while late-type galaxies are generally found to be extended, asymmetric sources. These results suggest that the processes that increase the real or apparent sizes of galaxies\u27 bulges also lead to more centralized 24-μm dust emission. Several phenomena, such as strong nuclear star formation, Seyfert activity, or outer ring structures, may cause galaxies to deviate from the general morphological trends observed at 24 μm. We also note that the 24-μm morphologies of Sdm-Im galaxies are quite varied, with some objects appearing very compact and symmetric but others appearing diffuse and asymmetric. These variations reflect the wide variation in star formation in irregular galaxies as observed at other wavelengths. The variations in the 24-μm morphological parameters across the Hubble sequence mirror many of the morphological trends seen in other tracers of the ISM and in stellar emission. However, the 24-μm morphological parameters for the galaxies in this sample do not match the morphological parameters measured in the stellar wavebands. This implies that the distribution of dust emission is related to but not equivalent to the distribution of stellar emission

Resolving the far-IR line deficit : photoelectric heating and far-IR line cooling in NGC 1097 and NGC 4559

The physical state of interstellar gas and dust is dependent on the processes which heat and cool this medium. To probe heating and cooling of the interstellar medium over a large range of infrared surface brightness, on sub-kiloparsec scales, we employ line maps of [C II] 158 mu m, [O I] 63 mu m, and [N II] 122 mu m in NGC 1097 and NGC 4559, obtained with the Photodetector Array Camera & Spectrometer on board Herschel. We matched new observations to existing Spitzer Infrared Spectrograph data that trace the total emission of polycyclic aromatic hydrocarbons (PAHs). We confirm at small scales in these galaxies that the canonical measure of photoelectric heating efficiency, ([C II] + [O I])/TIR, decreases as the far-infrared (far-IR) color, nu f(nu)(70 mu m) nu f(nu)(100 mu m), increases. In contrast, the ratio of far-IR cooling to total PAH emission, ([C II] + [O I])/PAH, is a near constant similar to 6% over a wide range of far-IR color, 0.5 , derived from models of the IR spectral energy distribution. Emission from regions that exhibit a line deficit is characterized by an intense radiation field, indicating that small grains are susceptible to ionization effects. We note that there is a shift in the 7.7/11.3 mu m PAH ratio in regions that exhibit a deficit in ([C II] + [O I])/PAH, suggesting that small grains are ionized in these environments

The role of literacy in the association between educational attainment and depressive symptoms

There is a consistent association between education and depressive symptoms, but research on the mechanisms to explain this association remains limited. No study has formally evaluated the extent to which the association between education and depressive symptoms is mediated through a foundational skill such as literacy. Inverse odds ratio weighting (IORW) was used to estimate total, natural direct, and natural indirect effects in examining literacy as a mediator of the association between education and depressive symptoms. Health and Retirement Study participants born in the U.S. between 1900 and 1947 were interviewed biennially for up to 12 years (N = 16,718). Literacy was assessed with a brief vocabulary measure. Depressive symptoms were measured using the 8-item Centers for Epidemiologic Studies-Depression (CES-D) scale. Decomposition estimates were derived using regression analyses of repeated measures of depressive symptoms. Standard errors were obtained using a nonparametric bootstrap with the individual as the independent unit to account for dependence of observations within an individual. In a large cohort of older Americans, a one standard deviation difference in educational attainment (~ 3 years) was associated with a 0.35-point decrement in CES-D score (95% CI: -0.38, -0.32). This decrement represents a 0.22 standard deviation difference in depressive symptoms. Using IORW, the estimated effect of education on depressive symptoms mediated through literacy was -0.10 (95% CI: -0.18, -0.01), which represents 28% of the total effect. Education confers many benefits; as demonstrated by this study for depressive symptoms, one important benefit is literacy

Pioglitazone Prevents Capillary Rarefaction in Streptozotocin-Diabetic Rats Independently of Glucose Control and Vascular Endothelial Growth Factor Expression

Background/Aims: Reduction of capillary network density occurs early in the development of metabolic syndrome and may be relevant for the precipitation of diabetes. Agonists of the peroxisome proliferator-activated receptor (PPAR)-gamma transcription factor are vasculoprotective, but their capacity for structural preservation of the microcirculation is unclear. Methods: Male Wistar rats were rendered diabetic by streptozotocin and treated with pioglitazone in chow for up to 12 weeks. Capillary density was determined in heart and skeletal muscle after platelet endothelial cell adhesion molecule-1 (PECAM-1) immunostaining. Hallmarks of apoptosis and angiogenesis were determined. Results: Capillary density deteriorated progressively in the presence of hyperglycemia (from 971/mm(2) to 475/mm(2) in quadriceps muscle during 13 weeks). Pioglitazone did not influence plasma glucose, left ventricular weight, or body weight but nearly doubled absolute and relative capillary densities compared to untreated controls (1.2 vs. 0.6 capillaries/myocyte in heart and 1.5 vs. 0.9 capillaries/myocyte in quadriceps muscle) after 13 weeks of diabetes. No antiapoptotic or angiogenic influence of pioglitazone was detected while a reduced expression of hypoxia-inducible factor-3 alpha and PPAR coactivator-1 alpha (PGC-1 alpha) mRNA as well as vascular endothelial growth factor (VEGF) protein possibly occurred as a consequence of improved vascularization. Conclusion: Pioglitazone preserves microvascular structure in diabetes independently of improvements in glycemic control and by a mechanism unrelated to VEGF-mediated angiogenesis. Copyright (C) 2012 S. Karger AG, Base

Genetic and biochemical analyses of chromosome and plasmid gene homologues encoding ICL and ArCP domains in Vibrioanguillarum strain 775

Anguibactin, the siderophore produced by Vibrio anguillarum 775 is synthesized from 2,3-dihydroxybenzoic acid (DHBA), cysteine and hydroxyhistamine via a nonribosomal peptide synthetase (NRPS) mechanism. Most of the genes encoding anguibactin biosynthetic proteins are harbored by the pJM1 plasmid. In this work we report the identification of a homologue of the plasmid-encoded angB on the chromosome of strain 775. The product of both genes harbor an isochorismate lyase (ICL) domain that converts isochorismic acid to 2,3-dihydro-2,3-dihydroxybenzoic acid, one of the steps of DHBA synthesis. We show in this work that both ICL domains are functional in the production of DHBA in V. anguillarum as well as in E. coli. Substitution by alanine of the aspartic acid residue in the active site of both ICL domains completely abolishes their isochorismate lyase activity in vivo. The two proteins also carry an aryl carrier protein (ArCP) domain. In contrast with the ICL domains only the plasmid encoded ArCP can participate in anguibactin production as determined by complementation analyses and site-directed mutagenesis in the active site of the plasmid encoded protein, S248A. The site-directed mutants, D37A in the ICL domain and S248A in the ArCP domain of the plasmid encoded AngB were also tested in vitro and clearly show the importance of each residue for the domain function and that each domain operates independently.

An ongoing case-control study to evaluate the NHS Bowel Cancer Screening Programme

© 2014 Massat et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated

“Am I my genes?”: Questions of identity among individuals confronting genetic disease

Purpose: To explore many questions raised by genetics concerning personal identities that have not been fully investigated. Methods: We interviewed in depth, for 2 hours each, 64 individuals who had or were at risk for Huntington disease, breast cancer, or alpha-1 antitrypsin deficiency. Results: These individuals struggled with several difficult issues of identity. They drew on a range of genotypes and phenotypes (e.g., family history alone; mutations, but no symptoms; or symptoms). They often felt that their predicament did not fit preexisting categories well (e.g., “sick,” “healthy,” “disabled,” “predisposed”), due in part to uncertainties involved (e.g., unclear prognoses, since mutations may not produce symptoms). Hence, individuals varied in how much genetics affected their identity, in what ways, and how negatively. Factors emerged related to disease, family history, and other sources of identity. These identities may, in turn, shape disclosure, coping, and other health decisions. Conclusions: Individuals struggle to construct a genetic identity. They view genetic information in highly subjective ways, varying widely in what aspects of genetic information they focus on and how. These data have important implications for education of providers (to assist patients with these issues), patients, and family members; and for research, to understand these issues more fully

Coxiella burnetii Phagocytosis Is Regulated by GTPases of the Rho Family and the RhoA Effectors mDia1 and ROCK

The GTPases belonging to the Rho family control the actin cytoskeleton rearrangements needed for particle internalization during phagocytosis. ROCK and mDia1 are downstream effectors of RhoA, a GTPase involved in that process. Coxiella burnetii, the etiologic agent of Q fever, is internalized by the host´s cells in an actin-dependent manner. Nevertheless, the molecular mechanism involved in this process has been poorly characterized. This work analyzes the role of different GTPases of the Rho family and some downstream effectors in the internalization of C. burnetii by phagocytic and non-phagocytic cells. The internalization of C. burnetii into HeLa and RAW cells was significantly inhibited when the cells were treated with Clostridium difficile Toxin B which irreversibly inactivates members of the Rho family. In addition, the internalization was reduced in HeLa cells that overexpressed the dominant negative mutants of RhoA, Rac1 or Cdc42 or that were knocked down for the Rho GTPases. The pharmacological inhibition or the knocking down of ROCK diminished bacterium internalization. Moreover, C. burnetii was less efficiently internalized in HeLa cells overexpressing mDia1-N1, a dominant negative mutant of mDia1, while the overexpression of the constitutively active mutant mDia1-ΔN3 increased bacteria uptake. Interestingly, when HeLa and RAW cells were infected, RhoA, Rac1 and mDia1 were recruited to membrane cell fractions. Our results suggest that the GTPases of the Rho family play an important role in C. burnetii phagocytosis in both HeLa and RAW cells. Additionally, we present evidence that ROCK and mDia1, which are downstream effectors of RhoA, are involved in that processFil: Salinas Ojeda, Romina Paola. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Ortiz Flores, Rodolfo Matias. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Distel, Jesús Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Aguilera, Milton Osmar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Colombo, Maria Isabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; ArgentinaFil: Beron, Walter. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos. Universidad Nacional de Cuyo. Facultad de Cienicas Médicas. Instituto de Histología y Embriología de Mendoza Dr. Mario H. Burgos; Argentin