Performance of LED-Based Fluorescence Microscopy to Diagnose Tuberculosis in a Peripheral Health Centre in Nairobi.

Sputum microscopy is the only tuberculosis (TB) diagnostic available at peripheral levels of care in resource limited countries. Its sensitivity is low, particularly in high HIV prevalence settings. Fluorescence microscopy (FM) can improve performance of microscopy and with the new light emitting diode (LED) technologies could be appropriate for peripheral settings. The study aimed to compare the performance of LED-FM versus Ziehl-Neelsen (ZN) microscopy and to assess feasibility of LED-FM at a low level of care in a high HIV prevalence country

Identification of a Novel HIF-1α-α_{M}β_{2} Integrin-NET Axis in Fibrotic Interstitial Lung Disease

Neutrophilic inflammation correlates with mortality in fibrotic interstitial lung disease (ILD) particularly in the most severe form, idiopathic pulmonary fibrosis (IPF), although the underlying mechanisms remain unclear. Neutrophil function is modulated by numerous factors, including integrin activation, inflammatory cytokines and hypoxia. Hypoxia has an important role in inflammation and may also contribute to pulmonary disease. We aimed to determine how neutrophil activation occurs in ILD and the relative importance of hypoxia. Using lung biopsies and bronchoalveolar lavage (BAL) fluid from ILD patients we investigated the extent of hypoxia and neutrophil activation in ILD lungs. Then we used ex vivo neutrophils isolated from healthy volunteers and BAL from patients with ILD and non-ILD controls to further investigate aberrant neutrophil activation in hypoxia and ILD. We demonstrate for the first time using intracellular staining, HIF-1α stabilization in neutrophils and endothelial cells in ILD lung biopsies. Hypoxia enhanced both spontaneous (+1.31-fold, p < 0.05) and phorbol 12-myristate 13-acetate (PMA)-induced (+1.65-fold, p < 0.001) neutrophil extracellular trap (NET) release, neutrophil adhesion (+8.8-fold, <0.05), and trans-endothelial migration (+1.9-fold, p < 0.05). Hypoxia also increased neutrophil expression of the αM (+3.1-fold, p < 0.001) and αX (+1.6-fold, p < 0.01) integrin subunits. Interestingly, NET formation was induced by αMβ2 integrin activation and prevented by cation chelation. Finally, we observed NET-like structures in IPF lung sections and in the BAL from ILD patients, and quantification showed increased cell-free DNA content (+5.5-fold, p < 0.01) and MPO-citrullinated histone H3 complexes (+21.9-fold, p < 0.01) in BAL from ILD patients compared to non-ILD controls. In conclusion, HIF-1α upregulation may augment neutrophil recruitment and activation within the lung interstitium through activation of β2 integrins. Our results identify a novel HIF-1α- αMβ2 integrin axis in NET formation for future exploration in therapeutic approaches to fibrotic ILD

Rasch analysis of the Multiple Sclerosis Impact Scale (MSIS-29)

<p>Abstract</p> <p>Background</p> <p>Multiple Sclerosis (MS) is a degenerative neurological disease that causes impairments, including spasticity, pain, fatigue, and bladder dysfunction, which negatively impact on quality of life. The Multiple Sclerosis Impact Scale (MSIS-29) is a disease-specific health-related quality of life (HRQoL) instrument, developed using the patient's perspective on disease impact. It consists of two subscales assessing the physical (MSIS-29-PHYS) and psychological (MSIS-29-PSYCH) impact of MS. Although previous studies have found support for the psychometric properties of the MSIS-29 using traditional methods of scale evaluation, the scale has not been subjected to a detailed Rasch analysis. Therefore, the objective of this study was to use Rasch analysis to assess the internal validity of the scale, and its response format, item fit, targeting, internal consistency and dimensionality.</p> <p>Methods</p> <p>Ninety-two persons with definite MS residing in the community were recruited from a tertiary hospital database. Patients completed the MSIS-29 as part of a larger study. Rasch analysis was undertaken to assess the psychometric properties of the MSIS-29.</p> <p>Results</p> <p>Rasch analysis showed overall support for the psychometric properties of the two MSIS-29 subscales, however it was necessary to reduce the response format of the MSIS-29-PHYS to a 3-point response scale. Both subscales were unidimensional, had good internal consistency, and were free from item bias for sex and age. Dimensionality testing indicated it was not appropriate to combine the two subscales to form a total MSIS score.</p> <p>Conclusion</p> <p>In this first study to use Rasch analysis to fully assess the psychometric properties of the MSIS-29 support was found for the two subscales but not for the use of the total scale. Further use of Rasch analysis on the MSIS-29 in larger and broader samples is recommended to confirm these findings.</p

A review of the methodological features of systematic reviews in maternal medicine

Background In maternal medicine, research evidence is scattered making it difficult to access information for clinical decision making. Systematic reviews of good methodological quality are essential to provide valid inferences and to produce usable evidence summaries to guide management. This review assesses the methodological features of existing systematic reviews in maternal medicine, comparing Cochrane and non-Cochrane reviews in maternal medicine. Methods Medline, Embase, Database of Reviews of Effectiveness (DARE) and Cochrane Database of Systematic Reviews (CDSR) were searched for relevant reviews published between 2001 and 2006. We selected those reviews in which a minimum of two databases were searched and the primary outcome was related to the maternal condition. The selected reviews were assessed for information on framing of question, literature search and methods of review. Results Out of 2846 citations, 68 reviews were selected. Among these, 39 (57%) were Cochrane reviews. Most of the reviews (50/68, 74%) evaluated therapeutic interventions. Overall, 54/68 (79%) addressed a focussed question. Although 64/68 (94%) reviews had a detailed search description, only 17/68 (25%) searched without language restriction. 32/68 (47%) attempted to include unpublished data and 11/68 (16%) assessed for the risk of missing studies quantitatively. The reviews had deficiencies in the assessment of validity of studies and exploration for heterogeneity. When compared to Cochrane reviews, other reviews were significantly inferior in specifying questions (OR 20.3, 95% CI 1.1–381.3, p = 0.04), framing focussed questions (OR 30.9, 95% CI 3.7- 256.2, p = 0.001), use of unpublished data (OR 5.6, 95% CI 1.9–16.4, p = 0.002), assessment for heterogeneity (OR 38.1, 95%CI 2.1, 688.2, p = 0.01) and use of meta-analyses (OR 3.7, 95% CI 1.3–10.8, p = 0.02). Conclusion This study identifies areas which have a strong influence on maternal morbidity and mortality but lack good quality systematic reviews. Overall quality of the existing systematic reviews was variable. Cochrane reviews were of better quality as compared to other reviews. There is a need for good quality systematic reviews to inform practice in maternal medicine

Injection versus Decompression for Carpal Tunnel Syndrome-Pilot trial (INDICATE-P)-protocol for a randomised feasibility study

BACKGROUND: Carpal tunnel syndrome (CTS) is the commonest peripheral nerve disorder in the UK, with over 52,996 carpal tunnel decompressions performed in 2011. By 2030, this figure is estimated to double. Whilst evidence supports conservative measures for mild symptoms, and early surgery for severe symptoms, controversy remains over the most appropriate management for patients that present with moderate disease, with regard to early surgery or late surgery following steroid injection. Injection versus Decompression for Carpal Tunnel Syndrome-Pilot trial (INDICATE-P) is a feasibility study for a multicentre, randomised controlled trial (INDICATE) to determine whether patients over the age of 18 with moderate CTS should undergo early surgical decompression of the median nerve or a single steroid injection (followed by later surgery if required). METHODS/DESIGN: INDICATE-P is a feasibility study for an open (non-blinded) randomised controlled pilot trial. Eligible participants will be adults with a clinical diagnosis of moderate CTS. This is defined as symptoms disturbing sleep or restricting activities of daily living or work, despite a 2-week trial of night splints. Participants will be randomised to one of two possible interventions: surgical decompression or a single steroid injection (followed by surgery later if required). Clinical outcome measures will be captured by postal questionnaire at 1, 3, 6 and 12 months post-randomisation. In order to improve the study design for the main INDICATE trial, feasibility data will also be collected to identify difficulties in recruitment and retention, to gain patient feedback on questionnaires and to confirm the suitability of the proposed outcome measures. DISCUSSION: The INDICATE-P feasibility study will contribute to the design and execution of the INDICATE trial, which will seek to assess the safety and effectiveness of two approaches to treatment for patients over 18 years of age with moderate CTS: early carpal tunnel decompression or a single steroid injection (followed by later surgery)

Successful treatment of fusarium solani ecthyma gangrenosum in a patient affected by leukocyte adhesion deficiency type 1 with granulocytes transfusions

<p>Abstract</p> <p>Background</p> <p>Ecthyma gangrenosum (EG) manifests as a skin lesion affecting patients suffering extreme neutropenia and is commonly associated with <it>Pseudomonas aeruginosa </it>in immunocompromised patients. Leukocyte adhesion deficiency I (LAD I) which count among primary immunodeficiency syndromes of the innate immunity, is an autosomal recessive disorder characterized in its severe phenotype by a complete defect in CD18 expression on neutrophils, delayed cord separation, chronic skin ulcers mainly due to recurrent bacterial and fungal infections, leucocytosis with high numbers of circulating neutrophils and an accumulation of abnormally low number of neutrophils at sites of infection.</p> <p>Case Presentation</p> <p>We report at our knowledge the first case of a child affected by LAD-1, who experienced during her disease course a multi-bacterial and fungal EG lesion caused by <it>fusarium solani</it>. Despite targeted antibiotics and anti-fungi therapy, the lesion extended for as long as 18 months and only massive granulocytes pockets transfusions in association with G-CSF had the capacity to cure this lesion.</p> <p>Conclusion</p> <p>We propose that granulocytes pockets transfusions will be beneficial to heal EG especially in severely immunocompromised patients.</p

Identification of a novel HIF-1α-αMβ2 integrin-NETosis axis in fibrotic interstitial lung disease

Neutrophilic inflammation correlates with mortality in fibrotic interstitial lung disease (ILD) particularly in the most severe form, idiopathic pulmonary fibrosis (IPF), although the underlying mechanisms remain unclear. Neutrophil function is modulated by numerous factors, including integrin activation, inflammatory cytokines and hypoxia. Hypoxia has an important role in inflammation and may also contribute to pulmonary disease. We aimed to determine how neutrophil activation occurs in ILD and the relative importance of hypoxia. Using lung biopsies and bronchoalveolar lavage (BAL) fluid from ILD patients we investigated the extent of hypoxia and neutrophil activation in ILD lungs. Then we used ex vivo neutrophils isolated from healthy volunteers and BAL from patients with ILD and non-ILD controls to further investigate aberrant neutrophil activation in hypoxia and ILD. We demonstrate for the first time using intracellular staining, HIF-1α stabilization in neutrophils and endothelial cells in ILD lung biopsies. Hypoxia enhanced both spontaneous (+1.31-fold, p < 0.05) and phorbol 12-myristate 13-acetate (PMA)-induced (+1.65-fold, p < 0.001) neutrophil extracellular trap (NET) release, neutrophil adhesion (+8.8-fold, <0.05), and trans-endothelial migration (+1.9-fold, p < 0.05). Hypoxia also increased neutrophil expression of the αM (+3.1-fold, p < 0.001) and αX (+1.6-fold, p < 0.01) integrin subunits. Interestingly, NET formation was induced by αMβ2 integrin activation and prevented by cation chelation. Finally, we observed NET-like structures in IPF lung sections and in the BAL from ILD patients, and quantification showed increased cell-free DNA content (+5.5-fold, p < 0.01) and MPO-citrullinated histone H3 complexes (+21.9-fold, p < 0.01) in BAL from ILD patients compared to non-ILD controls. In conclusion, HIF-1α upregulation may augment neutrophil recruitment and activation within the lung interstitium through activation of β2 integrins. Our results identify a novel HIF-1α- αMβ2 integrin axis in NET formation for future exploration in therapeutic approaches to fibrotic ILD

Update to the College of American Pathologists Reporting on Thyroid Carcinomas

Background The reporting of thyroid carcinomas follows the recommendations of the College of American Pathologists (CAP) protocols and includes papillary carcinoma, follicular carcinoma, anaplastic carcinoma and medullary carcinoma. Despite past and recent efforts, there are a number of controversial issues in the classification and diagnosis of thyroid carcinomas (TC) that, potentially impact on therapy and prognosis of patients with TC. Discussion The most updated version of the CAP thyroid cancer protocol incorporates recent changes in histologic classification as well as changes in the staging of thyroid cancers as per the updated American Joint Commission on Cancer staging manual. Among the more contentious issues in the pathology of thyroid carcinoma include the defining criteria for tumor invasiveness. While there are defined criteria for invasion, there is not universal agreement in what constitutes capsular invasion, angioinvasion and extrathyroidal invasion. Irrespective of the discrepant views on invasion, pathologists should report on the presence and extent (focal, widely) of capsular invasion, angioinvasion and extrathyroidal extension. These findings assist clinicians in their assessment of the recurrence risk and potential for metastatic disease. It is beyond the scope of this paper to detail the entire CAP protocol for thyroid carcinomas; rather, this paper addresses some of the more problematic issues confronting pathologists in their assessment and reporting of thyroid carcinomas. Conclusion The new CAP protocol for reporting of thyroid carcinomas is a step toward improving the clinical value of the histopathologic reporting of TC. Large meticulous clinico-pathologic and molecular studies with long term follow up are still needed in order to increase the impact of microscopic examination on the prognosis and management of TC

Acute kidney disease and renal recovery : consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Consensus definitions have been reached for both acute kidney injury (AKI) and chronic kidney disease (CKD) and these definitions are now routinely used in research and clinical practice. The KDIGO guideline defines AKI as an abrupt decrease in kidney function occurring over 7 days or less, whereas CKD is defined by the persistence of kidney disease for a period of > 90 days. AKI and CKD are increasingly recognized as related entities and in some instances probably represent a continuum of the disease process. For patients in whom pathophysiologic processes are ongoing, the term acute kidney disease (AKD) has been proposed to define the course of disease after AKI; however, definitions of AKD and strategies for the management of patients with AKD are not currently available. In this consensus statement, the Acute Disease Quality Initiative (ADQI) proposes definitions, staging criteria for AKD, and strategies for the management of affected patients. We also make recommendations for areas of future research, which aim to improve understanding of the underlying processes and improve outcomes for patients with AKD