Molecular phenotypes of DCIS predict overall and invasive recurrence.

BACKGROUND: Molecular phenotypes of invasive breast cancer predict early recurrence. Ductal carcinoma in situ (DCIS) exhibits similar phenotypes, but their frequency and significance remain unclear. To determine whether DCIS molecular phenotypes predict recurrence, 314 women (median age 57.7 years) with primary DCIS who were screened or entered DCIS trials in a specialist breast unit from 1990 to 2010 were studied. PATIENTS AND METHODS: Expression of Ki67, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) within primary DCIS was established using immunohistochemistry (IHC). Patients were subdivided into molecular phenotypes using IHC surrogates [Luminal A (ER/PR+HER2-), Luminal B (ER/PR+/HER2+), HER2 type (ER and PR-/HER2+) or triple negative (ER/PR/HER2)] and recurrence rates compared. RESULTS: Overall, there were 57 (18.2%) recurrences, 35 (11.2%) DCIS and 22 (7%) invasive cancer. A low rate of recurrence at 5 years was seen in Luminal A DCIS (7.6%), compared with 15.8%-36.1% in other phenotypes. Independent predictors of overall recurrence on multivariate analysis were involved (<1 mm) surgical margins (HR 4.31, P < 0.001), high-grade lesions (HR 2.28, P < 0.024) and molecular phenotype (HR 5.14, P = 0.001 for Luminal B; HR 6.46, P < 0.001 for HER2 type and HR 3.27, P = 0.028 for triple-negative disease compared with Luminal A DCIS). Independent predictors for invasive recurrence were high Ki67 expression (HR 1.04, P = 0.021) and molecular phenotype (HR 13.4, P = 0.014 for Luminal B; HR 11.4, P = 0.027 for HER2 type and HR 10.3, P = 0.031 for triple negative compared with Luminal A DCIS). CONCLUSIONS: DCIS molecular phenotype predicts for both overall and invasive recurrence. HER2 testing of DCIS could help clinicians individualise the treatment of patients with DCIS.

The Equine Movement Disorder "Shivers" Is Associated With Selective Cerebellar Purkinje Cell Axonal Degeneration.

"Shivers" is a progressive equine movement disorder of unknown etiology. Clinically, horses with shivers show difficulty walking backward, assume hyperflexed limb postures, and have hind limb tremors during backward movement that resembles shivering. At least initially, forward movements are normal. Given that neither the neurophysiologic nor the pathologic mechanisms of the disease is known, nor has a neuroanatomic locus been identified, we undertook a detailed neuroanatomic and neuropathologic analysis of the complete sensorimotor system in horses with shivers and clinically normal control horses. No abnormalities were identified in the examined hind limb and forelimb skeletal muscles nor the associated peripheral nerves. Eosinophilic segmented axonal spheroids were a common lesion. Calretinin-positive axonal spheroids were present in many regions of the central nervous system, particularly the nucleus cuneatus lateralis; however, their numbers did not differ significantly from those of control horses. When compared to controls, calretinin-negative, calbindin-positive, and glutamic acid decarboxylase-positive spheroids were increased 80-fold in Purkinje cell axons within the deep cerebellar nuclei of horses with shivers. Unusual lamellar or membranous structures resembling marked myelin decompaction were present between myelin sheaths of presumed Purkinje cell axons in the deep cerebellar nuclei of shivers but not control horses. The immunohistochemical and ultrastructural characteristics of the lesions combined with their functional neuroanatomic distribution indicate, for the first time, that shivers is characterized by end-terminal neuroaxonal degeneration in the deep cerebellar nuclei, which results in context-specific hypermetria and myoclonus.

Discovery of novel anxiolytic agents--the trials and tribulations of pre-clinical models of anxiety.

Anxiety disorders are the most common class of mental disorders present in the general population with an estimated lifetime prevalence of any anxiety disorder being approximately 15%, while the 12-month prevalence is more than 10%. They are classified into simple phobias, social phobias, obsessive-compulsive disorder (OCD) and panic attacks. Anxiety disorders are more prevalent in females than males and respond to pharmacological and non-pharmacological (behavioral) treatments. Anxiety disorders are complex with genetic and environmental factors interacting to produce the final psychopathology. There are many tests used to detect behaviors that indicate heightened anxiety in rodents however there are few pathological models of anxiety in rodents. Most compound testing is performed on naive, non-pathologically anxious, male animals which is a potential limitation to current strategies since these animals do not reflect the anxious patient. This article briefly describes some of the most common anxiety tests used in rodent research and concludes with a short perspective on areas the field could concentrate on to improve the understanding and successful translation of novel targets into new therapies in the clinic.

Characterisation of an OCS-dependent severe asthma population treated with mepolizumab.

UNLABELLED: A subpopulation of patients with asthma treated with maximal inhaled treatments is unable to maintain asthma control and requires additional therapy with oral corticosteroids (OCS); a subset of this population continues to have frequent exacerbations. Alternate treatment options are needed as daily use of OCS is associated with significant systemic adverse effects that affect many body systems and have a direct association with the dose and duration of OCS use. We compared the population demographics, medical conditions and efficacy responses of the OCS-dependent group from the DREAM study of mepolizumab with the group not managed with daily OCS. TRIAL REGISTRATION NUMBER: NCT01000506.

A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma.

BACKGROUND: CRTH2 is a G-protein-coupled receptor that mediates the activation of Th2 lymphocytes, eosinophils and basophils in response to prostaglandin D(2) and may be involved in the pathogenesis of airway inflammation and dysfunction in asthma. OBJECTIVE: To evaluate the effects of a potent and selective CRTH2 antagonist, OC000459, on the lung function, symptoms and eosinophilic airway inflammation in a double-blind, parallel group trial in steroid-free subjects with moderate persistent asthma. METHODS: Adult subjects were randomized to oral OC000459 200 mg twice daily (N=65) or a placebo (N=67) for 28 days. The primary end-point was the change from baseline in pre-bronchodilator forced expiratory volume in 1 s (FEV(1) ); eosinophilic airway inflammation was assessed by induced sputum differential eosinophil count. The trial was registered on the clinicaltrials.gov database (Identifier NCT01057927). RESULTS: Data were analysed for both the Full Analysis (FA) population and the Per Protocol (PP) population (55 treated with OC000459 and 52 with placebo), which excluded non-compliant subjects. In the FA population, the mean change in FEV(1) was 7.1% on OC000459 compared with 4.3% on placebo (not significant); in the PP population, the mean changes were 9.2% and 1.8%, respectively (P=0.037). Improvement in quality of life was apparent in both FA and PP populations [difference from the placebo in AQLQ(S) total score of 0.29, P=0.0113 and 0.37, P=0.0022, respectively]. OC000459 also improved the night-time symptom scores (mean reduction of 0.36 vs. 0.11, P=0.008, FA population; 0.37 vs. 0.12, P=0.022, PP population). The geometric mean sputum eosinophil count reduced from 2.1% to 0.7% (P=0.03) after OC000459, but this effect was not significant when compared with the change on placebo (P=0.37). Adverse events on OC000459 were comparable to those on placebo; respiratory infections were notably less common during OC000459 than the placebo treatment. CONCLUSION AND CLINICAL RELEVANCE: This study provides the first clinical evidence that CRTH2 receptors contribute to airflow limitation, symptoms and eosinophilic airway inflammation in asthma. OC000459 shows promise as a novel oral treatment for asthma and related disorders.

Asthma control with extrafine-particle hydrofluoroalkane-beclometasone vs. large-particle chlorofluorocarbon-beclometasone: a real-world observational study.

BACKGROUND: The extrafine-particle formulation of hydrofluoroalkane-beclometasone (EF HFA-BDP; Qvar®) demonstrates improved total and small airway deposition compared with large-particle chlorofluorocarbon (CFC)-BDP. In some short-term studies, EF HFA-BDP provides greater effects on lung function than CFC-BDP, and hence is recommended to be prescribed at a lower dose, but whether there are differences in asthma outcomes during long-term treatment is unknown. OBJECTIVE: To compare the effectiveness of EF HFA-BDP vs. CFC-BDP over 1 year. METHODS: This retrospective matched cohort study examined outcomes in a large primary care database for patients aged 5-60 years with asthma receiving their first inhaled corticosteroid (ICS) prescription (initiation population) or first ICS dose increase (step-up population) by a pressurized metered-dose inhaler (pMDI) as EF HFA-BDP or CFC-BDP. Patients were matched on baseline demographic and asthma severity measures in EF HFA-BDP:CFC-BDP ratios of 1:3 and 1:2 for initiation and step-up populations, respectively. Step-up patients were matched also on ICS dose during a baseline year. Co-primary endpoints were asthma control (composite measure comprising no recorded hospital attendance for asthma, oral corticosteroids, or antibiotics for lower respiratory infection) and exacerbation rate during the outcome year. RESULTS: For the initiation population (EF HFA-BDP n=2882; CFC-BDP n=8646), adjusted odds of achieving asthma control with EF HFA-BDP vs. CFC-BDP was 1.15 (95% CI 1.02-1.28). For the step-up population (n=258 and 516), adjusted odds of asthma control with EF HFA-BDP was 1.72 (95% CI 1.14-2.56). EF HFA-BDP was prescribed at a median dose half that of CFC-BDP. CONCLUSION AND CLINICAL RELEVANCE: During 1 year after initiating or stepping up ICS therapy by pMDI, patients who received EF HFA-BDP were more likely to achieve asthma control than those receiving CFC-BDP. These findings suggest that ICS formulation, particle size, and deposition characteristics play important roles in real-life effectiveness of asthma therapy. This study shows that an EF-particle formulation of beclometasone can be used at half the dose of the large-particle formulation with at least as good clinical outcomes.

Patient-reported outcomes of immediate implant-based breast reconstruction with and without biological or synthetic mesh.

BACKGROUND: Biological and synthetic meshes may improve the outcomes of immediate implant-based breast reconstruction (IBBR) by facilitating single-stage procedures and improving cosmesis. Supporting evidence is, however, limited. The aim of this study was to explore the impact of biological and synthetic mesh on patient-reported outcomes (PROs) of IBBR 18 months after surgery. METHODS: Consecutive women undergoing immediate IBBR between February 2014 and June 2016 were recruited to the study. Demographic, operative, oncological and 3-month complication data were collected, and patients received validated BREAST-Q questionnaires at 18 months. The impact of different IBBR techniques on PROs were explored using mixed-effects regression models adjusted for clinically relevant confounders, and including a random effect to account for clustering by centre. RESULTS: A total of 1470 participants consented to receive the questionnaire and 891 completed it. Of these, 67 women underwent two-stage submuscular reconstructions. Some 764 patients had a submuscular reconstruction with biological mesh (495 women), synthetic mesh (95) or dermal sling (174). Fourteen patients had a prepectoral reconstruction. Compared with two-stage submuscular reconstructions, no significant differences in PROs were seen in biological or synthetic mesh-assisted or dermal sling procedures. However, patients undergoing prepectoral IBBR reported better satisfaction with breasts (adjusted mean difference +6.63, 95 per cent c.i. 1.65 to11.61; P = 0.009). PROs were similar to those in the National Mastectomy and Breast Reconstruction Audit 2008-2009 cohort, which included two-stage submuscular procedures only. CONCLUSION: This study found no difference in PROs of subpectoral IBBR with or without biological or synthetic mesh, but provides early data to suggest improved satisfaction with breasts following prepectoral reconstruction. Robust evaluation is required before this approach can be adopted as standard practice.

Morbidity and Complications of Diabetes Mellitus in Children and Adolescents in Ghana: Protocol for a Longitudinal Study.

BACKGROUND: Diabetes is associated with premature morbidity and mortality from its many complications. There are limited data on the chronic complications of diabetes in children and adolescents in sub-Saharan Africa. OBJECTIVE: The study aims to determine the (1) burden and related factors of chronic systemic complications of diabetes, including diabetic and nondiabetic ocular conditions in children and adolescents, and (2) quality of life (QoL) of participants compared to healthy controls. This manuscript describes the study methodology. METHODS: Demographic information, medical history, anthropometric measurements, and laboratory characteristics were collected, and the participants were screened for microvascular and macrovascular complications as well as nondiabetic ocular disease. QoL questionnaires were administered to participants, their caregivers, and controls. Participants were followed up annually up to 3 years to determine the natural history of and trends in these conditions. SPSS Version 25.0 will be used for data analysis. Continuous and categorical data will be presented as mean (SD) and as percentages (%), respectively. t tests and analysis of variance will be used to compare means, and chi-square tests will be used to compare categorical data. Correlation, regression, and logistic regression analyses will be employed to establish linear associations and causal associations as appropriate. Relative risk and odds ratios will be used to estimate risk. QoL outcomes in Ghanaian children and adolescents with diabetes mellitus compared with caregivers and healthy controls will be assessed using the Pediatric Quality of Life inventory. Significance will be set at α=.05. RESULTS: Institutional approval from the Ethical and Protocol Review Committee of the University of Ghana Medical School was received on August 22, 2014 (Protocol Identification Number: MS-Et/M.12-P4.5/2013-2014). Funding for the project was received from the University of Ghana Research Fund (#UGRF/9/LMG-013/2015-2016) in March 2016. Patient recruitment, clinical examination, and data collection commenced in August 2016 and was completed in September 2019. A total of 58 children and adolescents with diabetes mellitus have been recruited. Blood samples were stored at -80 °C for analysis, which was completed at the end of July 2020. Data analysis is ongoing and will be completed by the end of December 2020. Investigators plan to submit the results for publication by the end of February 2021. CONCLUSIONS: The prevalence, natural history, trends in diabetic complications and nondiabetic ocular disease, and QoL will be provided. Our data may inform policies and interventions to improve care given to children and adolescents with diabetes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/21440.

Development of the Fibromyalgia Burden Assessment: measuring the multifaceted burden of fibromyalgia.

OBJECTIVES: To develop a questionnaire assessing the burden of fibromyalgia's impacts on patients' lives. METHODS: A literature review was conducted to identify impacts of fibromyalgia and their consequences on patients' lives. Exploratory interviews were performed with 15 fibromyalgia patients in France, Germany and Spain. Using patients' wording, items were generated simultaneously in French, German, Spanish, and UK English. Relevance and comprehension of the resulting questionnaire versions were tested with 21 additional fibromyalgia patients; questionnaires were revised accordingly. RESULTS: Three domains, Burden associated with the impacts of fibromyalgia, Symptoms and Influencing factors, were identified from the literature review. Following patient interviews, the burden domain was further divided based on the nature of the impact: Pain, Physical impact (including tiredness, sleep problems and other symptoms), Activities of Daily Living impact (including autonomy and coping), Social and Family Life impact, Work, Studies and Personal Finances impact, Psychological impact (including cognitive impact), and Relationship to Medicine and Disease. The resulting test versions of the questionnaire contained 79 items. Comprehension tests identified problematic items and cultural differences and suggested deletions or rewording. After revision and linguistic harmonization, the pilot version of the questionnaire contained 62 items divided into 7 sections, and was named Fibromyalgia Burden Assessment (FMBA©). CONCLUSIONS: The FMBA is a self-reported questionnaire allowing the assessment and a better understanding of the impacts of fibromyalgia and the burden associated with these on patients' daily lives. It is available in UK English, French, German and Spanish. Its scoring and validation remain to be undertaken.

Experiences of implant loss after immediate implant-based breast reconstruction: qualitative study.

BACKGROUND: Immediate implant-based breast reconstruction (IBBR) is the most commonly performed reconstructive procedure in the UK, but almost one in ten women experience implant loss and reconstructive failure after this technique. Little is known about how implant loss impacts on patients' quality of life. The first phase of the Loss of implant Breast Reconstruction (LiBRA) study aimed to use qualitative methods to explore women's experiences of implant loss and develop recommendations to improve care. METHODS: Semistructured interviews were conducted with a purposive sample of women who experienced implant loss after immediate IBBR, performed for malignancy or risk reduction across six centres. Interviews explored decision-making regarding IBBR, and experiences of implant loss and support received. Thematic analysis was used to explore the qualitative interview data. Sampling, data collection and analysis were undertaken concurrently and iteratively until data saturation was achieved. RESULTS: Twenty-four women were interviewed; 19 had surgery for malignancy and five for risk reduction. The median time between implant loss and interview was 42 (range 22-74) months. Ten women had undergone secondary reconstruction, two were awaiting surgery, and 12 had declined further reconstruction. Three key themes were identified: the need for accurate information about the risks and benefits of IBBR; the need for more information about 'early-warning' signs of postoperative problems, to empower women to seek help; and better support following implant loss. CONCLUSION: Implant loss is a devastating event for many women. Better preoperative information and support, along with holistic patient-centred care when complications occur, may significantly improve the experience and outcome of care.

ANTECEDENTES: La reconstrucción mamaria inmediata con prótesis (implant-based breast reconstruction, IBBR) es el procedimiento reconstructivo más utilizado en el Reino Unido, pero casi una de cada diez mujeres presentará pérdida de la prótesis y fallo del procedimiento reconstructivo tras esta técnica. Se sabe poco de cómo la pérdida de la prótesis afecta la calidad de vida de las pacientes. La primera fase del estudio LiBRA tuvo como objetivo explorar la percepción de las mujeres ante la pérdida de la prótesis, utilizando métodos cualitativos, y proponer una serie de medidas para mejorar la atención sanitaria de estas pacientes. MÉTODOS: Se realizaron entrevistas semiestructuradas en una muestra de mujeres que padecieron la pérdida de la prótesis tras una IBBR inmediata, realizada por neoplasia o como procedimiento de reducción de riesgo, en seis centros. Las entrevistas analizaron la toma de decisiones con respecto a la IBBR inmediata, así como la percepción ante la pérdida del implante y el soporte recibido. Se utilizó un análisis por temas para examinar los datos de la entrevista cualitativa. El muestreo, la recopilación de datos y el análisis se realizaron de forma simultánea e iterativa hasta que se logró la saturación de datos. RESULTADOS: Se entrevistaron 24 pacientes; 19 en las que la indicación quirúrgica fue por cáncer y 5 por reducción de riesgo. La mediana del tiempo entre la pérdida del implante y la entrevista fue de 42 (rango 22-52) meses. Diez mujeres se habían sometido a una reconstrucción secundaria; dos estaban a la espera de la cirugía y 12 habían rechazado la reconstrucción posterior. Se identificaron tres temas clave, siendo las necesidades de: i) información precisa sobre los riesgos y beneficios de la IBBR, ii) más información sobre los signos de "alarma precoz" de las complicaciones postoperatorias que permitiesen a las mujeres buscar ayuda, y iii) mejor soporte tras la pérdida de la prótesis. CONCLUSIÓN: La pérdida de una prótesis es una complicación catastrófica para muchas mujeres. Una mejor información y apoyo preoperatorios, junto con una atención holística centrada en la paciente cuando se presentan las complicaciones, podrían mejorar significativamente la experiencia y el resultado de la atención.

Pluto's Interaction With Energetic Heliospheric Ions.

Pluto energies of a few kiloelectron volts and suprathermal ions with tens of kiloelectron volts and above. We measure this population using the Pluto Energetic Particle Spectrometer Science Investigation (PEPSSI) instrument on board the New Horizons spacecraft that flew by Pluto in 2015. Even though the measured ions have gyroradii larger than the size of Pluto and the cross section of its magnetosphere, we find that the boundary of the magnetosphere is depleting the energetic ion intensities by about an order of magnitude close to Pluto. The intensity is increasing exponentially with distance to Pluto and reaches nominal levels of the interplanetary medium at about 190R P distance. Inside the wake of Pluto, we observe oscillations of the ion intensities with a periodicity of about 0.2 hr. We show that these can be quantitatively explained by the electric field of an ultralow-frequency wave and discuss possible physical drivers for such a field. We find no evidence for the presence of plutogenic ions in the considered energy range.

Reflections on TORCH: potential mechanisms for the survival benefit of salmeterol/fluticasone propionate in COPD patients.

COPD is a disease with a multi-component pathophysiology in which inflammation plays a key role. An anti-inflammatory effect of salmeterol (S)/fluticasone propionate (FP) combination (SFC), as demonstrated in a number of biopsy studies, may be the mechanism by which it provides a potential survival benefit in COPD patients in the TORCH study. It is possible that the molecular synergy between S and FP shown in COPD results in enhanced anti-inflammatory in the airways. This may also contribute to the reduction in exacerbations and the increase in lung function seen in the TORCH study. Alternatively, SFC may prolong survival by impacting on systemic inflammation and disease co-morbidities in COPD.

Cellular localization of AT1 receptor mRNA and protein in normal placenta and its reduced expression in intrauterine growth restriction. Angiotensin II stimulates the release of vasorelaxants.

Angiotensin II (ANG II) is a potent vasoconstrictor and growth promoter. Quantitative receptor autoradiography using the nonselective radioligand [125I]ANG II and subtype-selective competing compounds demonstrated the presence of both ANG II receptor (AT)1 and AT2 receptor recognition sites. In addition, a relatively small population of apparently non-AT1/non-AT2 sites was identified that may represent a novel high affinity ANG II recognition site in human placenta. Using placental membrane preparations, the AT2 receptor antagonist PD123177 failed to compete for [3H]ANG II binding at relevant concentrations, whereas the AT1 receptor antagonist losartan competed in a monophasic manner for all the specific binding, suggesting that the non-AT1/non-AT2 recognition site identified using autoradiography may be a cytosolic binding site. AT1 receptor binding was significantly reduced (P < 0. 02) in intraeuterine growth restriction (IUGR) pregnancies. Western blot analysis confirmed this showing a reduction in AT1 receptor protein. In situ hybridization and immunocytochemistry revealed that AT1 receptor mRNA and protein were localized throughout pregnancy in the cytotrophoblast, syncytiotrophoblast, and extravillous trophoblast, as well as in or around the blood vessels of placental villi. The intensity of the hybridization signal for AT1 receptor mRNA over the syncytium was reduced in IUGR. ANG II evoked a rapid and concentration-dependent release of NO in first trimester cytotrophoblast-like cells that was abolished by the inclusion of the competitive NOS inhibitor NG-monomethyl-L-arginine. Neither losartan nor PD123177 alone significantly inhibited ANG II-evoked NO release, and when cells were stimulated with ANG II in the presence of losartan (10 microM) and PD123177 (10 microM) in combination, NO release was significantly inhibited (P < 0.05). These observations also suggest, for the first time, the existence of a cross-talk between AT1 or AT2 receptors in trophoblast and that the reduction in placental AT1 receptors in IUGR may, in part, account for poor placental function in this disorder.

Localization of the angiotensin II and its receptor subtype expression in human endometrium and identification of a novel high-affinity angiotensin II binding site.

Angiotensin (ANG) II is not only a potent vasoconstrictor but may also be involved in the regeneration of new blood vessels. In proliferative endometrium, ANG II-like immunoreactivity was detected in glandular epithelium and stroma with negligible staining around the vascular endothelium. In contrast, in secretory endometrium intense immunostaining was seen in the perivascular stromal cells around the endometrial spiral arterioles with negligible staining of the other cell types. Quantitative receptor autoradiography using the nonselective radioligand [125I]-ANG II and subtype selective competing compounds showed that endometrium contained predominantly AT2 receptors, with relatively low expression of AT1 receptors and a novel non-AT1/non-AT2 angiotensin II recognition site that was insensitive to AT1 or AT2 selective ligands. Levels of specific [125I]-ANG II receptor binding displayed cyclic changes during the menstrual cycle, reaching a maximum in early secretory endometrium and then decreasing in mid to late secretory endometrium to levels seen in early to mid proliferative endometrium. In situ hybridization showed AT1 receptor mRNA expression in the glands and in the endometrial blood vessels. The cyclic changes in ANG II-like immunoreactivity together with expression of both the known and the novel AT receptor subtypes imply that this octopeptide may play a dual role both in the control of the uterine vascular bed and also in the regeneration of the endometrium after endometrial shedding, acting as an angiogenic and mitogenic mediator.

Initiation of maintenance treatment with salmeterol/fluticasone propionate 50/100 microg bd versus fluticasone propionate 100 microg bd alone in patients with persistent asthma: integrated analysis of four randomised trials.

OBJECTIVES: To identify the asthma patients, on short-acting beta2-agonists alone, who would benefit from initial maintenance therapy (IMT) with salmeterol/fluticasone (SFC) propionate 50/100 microg bd compared with fluticasone propionate (FP) 100 microg bd alone. The results of an integrated analysis of data from four previous trials are presented. METHODS: The four original trials were randomised, double-blind, parallel group studies and included patients who had received IMT with SFC 50/100 microg bd or FP 100 microg bd. Patients were >or=12 years with a 6 month history of asthma and >or=15% reversibility in FEV1. Patients had either not received inhaled corticosteroids in the preceding month or were steroid naïve. Patients were assessed to determine whether any GINA-defined asthma characteristics or combination of asthma characteristics could predict those individuals who would achieve well controlled asthma status with IMT with SFC rather than with inhaled steroid alone. Patients with persistent asthma were assessed based on GINA-defined baseline asthma characteristics and well controlled asthma status in response to each treatment was investigated according to combinations of these baseline features. Subsequently, a further range of endpoints, including asthma symptoms, rescue medication use and asthma control, were analysed over weeks 1-12 for the combinations of features where the treatment difference in well controlled asthma status was greatest. RESULTS: The results of the initial analyses demonstrated that patients exhibiting two or three features of uncontrolled asthma at baseline were more likely to achieve well controlled asthma when treated with SFC than with FP alone, the most significant difference being observed in patients with three baseline features (odds ratio 2.60, 95% CI: 1.87, 3.62, p<0.001). Patients with one baseline feature showed no difference between the FP and SFC groups. Further analyses on data from patients with two or three baseline asthma features, showed that treatment with SFC resulted in significantly greater improvements in mean morning PEF, percentage symptom-free days, nights with no awakenings and rescue-free days compared with FP. In addition, asthma control was achieved earlier in patients in the SFC group. SFC and FP were well tolerated as shown previously in the four individual trials. CONCLUSIONS: Patients on short-acting beta2-agonists alone with two or three features of uncontrolled asthma (moderate to severe airflow limitation/daily symptoms/daily rescue medication use) are most likely to achieve better control, earlier, with SFC 50/100 microg bd initial maintenance treatment compared with FP 100 microg bd alone.

Evaluating the risk of pneumonia with inhaled corticosteroids in COPD: Retrospective database studies have their limitations SA.

An increased risk of non-fatal pneumonia has been documented in COPD patients treated with inhaled corticosteroids (ICS) in randomized clinical trials. Retrospective database analyses have been conducted to evaluate this signal in larger populations treated in the community. To understand how methodological choices may influence results in observational studies, we compared two recent Canadian studies which used health administrative databases from Quebec and Ontario and came to opposite conclusions on the risk of pneumonia in ICS treated COPD patients. Explanations for why the results of these studies diverged are explored. The Suissa analysis used RAMQ data from Quebec and showed an increased relative risk of serious pneumonia for current users of ICS compared to non users, RR = 1.69 (95% confidence interval, 1.63-1.75). The Gershon analysis used ODB data and showed no difference for pneumonia hospitalisation, RR = 1.01 (0.93-1.08). Reasons for differences in study findings include lack of validated definitions of COPD, poor selection of relevant exposure groups, channeling and confounding biases, and failure to perform on-treatment analyses for safety. CONCLUSION: Our study identifies methodological features that need consideration to increase robustness and minimize threats to internal validity of retrospective health administrative database studies.

Serological biomarker screening and host factor analysis elucidating immune response heterogeneity in active pulmonary tuberculosis.

While mortality and morbidity from pulmonary tuberculosis (PTB) have improved, diagnosis of this infectious disease remains suboptimal without a point-of-care test. Antibody/ antigen-based serodiagnostics is the most amenable for point-of-care translation but hampered by a lack of validated biomarkers and a heterogeneous patient antibody response. Using a case-control design, we assessed serodiagnostic potential of immunoglobulins G, A, and dimeric IgA responses against 18 antigenic preparations, followed by antibody-subclass responses against antigen 60 (A60), and four markers of host innate immunity by enzymelinked immunoassay using sera samples (n=110) collected from April to October 2007 in VietNam from human immunodeficiency-negative patients with provisional diagnosis of PTB. We further analyzed host variables to investigate factors driving biomarker heterogeneity observed in patients. Among active pulmonary tuberculosis patients, low correlation was observed between anti-A60 antibody-classes, and between anti-A60 immunoglobulin G subclasses, but anti-A60 immunoglobulin A subclasses were significantly correlated. The best diagnostic combination of anti-A60 immunoglobulin G/A and a C-reactive protein "ruleout" remains insufficient at 82%/92% sensitivity/specificity (95%CI: 72-92%/82-98%). Heterogeneity of anti-A60 immunoglobulins G2, G3, M, as well as C-reactive protein and serum amyloid A levels observed in this study population appeared to be significantly associated with history of previous tuberculosis, hemoptysis, age, vaccination, night sweats, smoking, chest pain, fever, alcohol, and solid culture count. Further research on tuberculosis serological biomarkers may require consideration of host factors and new approaches using multiple biomarkers.

Profiling microRNAs in individuals at risk of progression to rheumatoid arthritis.

BACKGROUND: Individuals at risk of rheumatoid arthritis (RA) demonstrate systemic autoimmunity in the form of anti-citrullinated peptide antibodies (ACPA). MicroRNAs (miRNAs) are implicated in established RA. This study aimed to (1) compare miRNA expression between healthy individuals and those at risk of and those that develop RA, (2) evaluate the change in expression of miRNA from "at-risk" to early RA and (3) explore whether these miRNAs could inform a signature predictive of progression from "at-risk" to RA. METHODS: We performed global profiling of 754 miRNAs per patient on a matched serum sample cohort of 12 anti-cyclic citrullinated peptide (CCP) + "at-risk" individuals that progressed to RA. Each individual had a serum sample from baseline and at time of detection of synovitis, forming the matched element. Healthy controls were also studied. miRNAs with a fold difference/fold change of four in expression level met our primary criterion for selection as candidate miRNAs. Validation of the miRNAs of interest was conducted using custom miRNA array cards on matched samples (baseline and follow up) in 24 CCP+ individuals; 12 RA progressors and 12 RA non-progressors. RESULTS: We report on the first study to use matched serum samples and a comprehensive miRNA array approach to identify in particular, three miRNAs (miR-22, miR-486-3p, and miR-382) associated with progression from systemic autoimmunity to RA inflammation. MiR-22 demonstrated significant fold difference between progressors and non-progressors indicating a potential biomarker role for at-risk individuals. CONCLUSIONS: This first study using a cohort with matched serum samples provides important mechanistic insights in the transition from systemic autoimmunity to inflammatory disease for future investigation, and with further evaluation, might also serve as a predictive biomarker.

Raft localisation of FcgammaRIIa and efficient signaling are dependent on palmitoylation of cysteine 208.

Ligand-dependent aggregation of FcgammaRIIa initiates multiple biochemical processes including the translocation to detergent resistant membrane domains (DRMs) and receptor tyrosine phosphorylation. Palmitoylation of cysteine residues is considered to be one process that assists in the localisation of proteins to DRMs. Within the juxtamembrane region of FcgammaRIIa there is cysteine residue (C208) that we show to be palmitoylated. Mutation of this cysteine residue results in the disruption of FcgammaRIIa translocation to DRMs as empirically defined by insolubility at high Triton X-100 concentrations. This study also demonstrates that the lack of lipid raft association diminishes FcgammaRIIa signaling as measured by receptor phosphorylation and calcium mobilisation functions suggesting that FcgammaRIIa signaling is partially dependent on lipid rafts.