SIZE study: study protocol of a multicentre, randomised controlled trial to compare the effectiveness of an interarcuair decompression versus extended decompression in patients with intermittent neurogenic claudication caused by lumbar spinal stenosis

Introduction Intermittent neurogenic claudication (INC) is often caused by lumbar spinal stenosis (LSS). Laminectomy is considered a frequently used surgical technique for LSS. Previous studies have shown that laminectomy can potentially cause lumbar instability. Less invasive techniques, preserving midline structures including the bilateral small size interarcuair decompression, are currently applied. Due to lack of evidence and consensus, surgeons have to rely on their training and own experiences to choose the best surgical techniques for their patients. Hence, an observer and patient blinded multicentre, randomised controlled trial was designed to determine the effectiveness and cost-effectiveness of bilateral interarcuair decompression versus laminectomy for LSS. Methods and analysis 174 patients above 40 years with at least 12 weeks of INC will be recruited. Patients are eligible for inclusion if they have a clinical indication for surgery for INC with an MRI showing signs of LSS. Patients will be randomised to laminectomy or bilateral interarcuair decompression. The primary outcome is functional status measured with the Roland-Morris Disability Questionnaire at 12 months. Secondary outcomes consist of pain intensity, self-perceived recovery, functional status measured with the Oswestry Disability Index and a physical examination. Outcome measurement moments will be scheduled at 3 and 6 weeks, and at 3, 6, 12, 18, 24, 36 and 48 months after surgery. Physical examination will be performed at 6 weeks, and 12, 24 and 48 months. An economic evaluation will be performed and questionnaires will be used to collect cost data. Ethics and dissemination The Medical Ethical Committee of the Erasmus Medical Centre Rotterdam approved this study (NL.65826.078.18). The results will be published in an international peer-reviewed journal

Establishing nurse-led active surveillance for men with localised prostate cancer: development and formative evaluation of a model of care in the ProtecT trial.

Objectives To develop a nurse-led, urologist-supported model of care for men managed by active surveillance or active monitoring (AS/AM) for localised prostate cancer and provide a formative evaluation of its acceptability to patients, clinicians and nurses. Nurse-led care, comprising an explicit nurse-led protocol with support from urologists, was developed as part of the AM arm of the Prostate testing for cancer and Treatment (ProtecT) trial. Design Interviews and questionnaire surveys of clinicians, nurses and patients assessed acceptability. Setting Nurse-led clinics were established in 9 centres in the ProtecT trial and compared with 3 non-ProtecT urology centres elsewhere in UK. Participants Within ProtecT, 22 men receiving AM nurse-led care were interviewed about experiences of care; 11 urologists and 23 research nurses delivering ProtecT trial care completed a questionnaire about its acceptability; 20 men managed in urology clinics elsewhere in the UK were interviewed about models of AS/AM care; 12 urologists and three specialist nurses working in these clinics were also interviewed about management of AS/AM. Results Nurse-led care was commended by ProtecT trial participants, who valued the flexibility, accessibility and continuity of the service and felt confident about the quality of care. ProtecT consultant urologists and nurses also rated it highly, identifying continuity of care and resource savings as key attributes. Clinicians and patients outside the ProtecT trial believed that nurse-led care could relieve pressure on urology clinics without compromising patient care. Conclusions The ProtecT AM nurse-led model of care was acceptable to men with localised prostate cancer and clinical specialists in urology. The protocol is available for implementation; we aim to evaluate its impact on routine clinical practice

Prolonged activation of nasal immune cell populations and development of tissue-resident SARS-CoV-2-specific CD8(+) T cell responses following COVID-19

Systemic immune cell dynamics during coronavirus disease 2019 (COVID-19) are extensively documented, but these are less well studied in the (upper) respiratory tract, where severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates(1-6). Here, we characterized nasal and systemic immune cells in individuals with COVID-19 who were hospitalized or convalescent and compared the immune cells to those seen in healthy donors. We observed increased nasal granulocytes, monocytes, CD11c(+) natural killer (NK) cells and CD4(+) T effector cells during acute COVID-19. The mucosal proinflammatory populations positively associated with peripheral blood human leukocyte antigen (HLA)-DRlow monocytes, CD38(+)PD1(+)CD4(+) T effector (T-eff) cells and plasmablasts. However, there was no general lymphopenia in nasal mucosa, unlike in peripheral blood. Moreover, nasal neutrophils negatively associated with oxygen saturation levels in blood. Following convalescence, nasal immune cells mostly normalized, except for CD127(+) granulocytes and CD38(+)CD8(+) tissue-resident memory T cells (T-RM). SARS-CoV-2-specific CD8(+) T cells persisted at least 2 months after viral clearance in the nasal mucosa, indicating that COVID-19 has both transient and long-term effects on upper respiratory tract immune responses.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

EpiReumaPt- the study of rheumatic and musculoskeletal diseases in Portugal: a detailed view of the methodology

Rheumatic and musculoskeletal diseases (RMD) are prevalent and leading causes of disability and consumption of healthcare and social resources. EpiReumaPt is a national population-based survey developed by the Portuguese Society of Rheumatology that aimed to estimate the prevalence of RMDs and determine their impact on function, quality of life, mental health and use of healthcare resources. This article describes in detail the design, methodology and planned analyses of EpiReumaPt. Recruitment started in September 2011 and finished in December 2013. This study involved a three-stage approach. The first step was a face-to-face survey performed by trained interviewers at the household of 10,661 subjects who where randomly selected by a stratified multistage sampling. A highly sensitive screening questionnaire for RMDs was used. Secondly, participants who screened positive (64%) for at least one RMD as well as 20% of individuals with a negative screening were invited for assessment by a rheumatologist. In total, 3,877 subjects participated in this second phase, where they were also invited to donate a blood sample to be stored at the Biobanco-IMM. History and physical examination, followed by appropriate laboratory and imaging tests were performed. At the end of the visit, the rheumatologist established a diagnosis. Finally, a team of three experienced rheumatologists reviewed all the clinical data and defined the diagnoses according to previously validated criteria. The EpiReumaPt dataset, containing data from several questionnaires, various clinical measurements and information from laboratory and imaging tests, comprises an invaluable asset for research. The large amount of information collected from each participant and the large number of participants, with a wide age range covering and being representative of the adults from the entire country, makes EpiReumaPt the largest study of RMDs performed in Portugal

Genetic insights into resting heart rate and its role in cardiovascular disease.

Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development

Carlo von Landberg's letter to Ignaz Goldziher

Toll-like receptors (TLRs) participate in the defence against bacterial infections that are common in patients with Chronic Obstructive Pulmonary Disease (COPD). We studied all tagging SNPs in TLR2 and TLR4 and their associations with the level and change over time of both FEV(1) and sputum inflammatory cells in moderate-to-severe COPD. Nine TLR2 SNPs and 17 TLR4 SNPs were genotyped in 110 COPD patients. Associations of SNPs with lung function and inflammatory cells in induced sputum were analyzed cross-sectionally with linear regression and longitudinally with linear mixed-effect models. Two SNPs in TLR2 (rs1898830 and rs11938228) were associated with a lower level of FEV(1) and accelerated decline of FEV(1) and higher numbers of sputum inflammatory cells. None of the TLR4 SNPs was associated with FEV(1) level. Eleven out of 17 SNPs were associated with FEV(1) decline, including rs12377632 and rs10759931, which were additionally associated with higher numbers of sputum inflammatory cells at baseline and with increase over time. This is the first longitudinal study showing that tagging SNPs in TLR2 and TLR4 are associated with the level and decline of lung function as well as with inflammatory cell numbers in induced sputum in COPD patients, suggesting a role in the severity and progression of COPD

Multidrug resistance-associated protein 1 and lung function decline with or without long-term corticosteroids treatment in COPD

Multidrug resistance-associated protein-1 (MRP1) reduces the oxidative stress generated by smoking, a risk factor for Chronic Obstructive Pulmonary Disease (COPD). We previously showed that MRP1 variants are associated with the level and decline of annual forced expiratory volume in one second (FEV1) in the general population. Moreover, we showed that MRP1 variants are also associated with FEV1 level and inflammatory markers in COPD patients. We investigate in the current study the association of MRP1 protein expression in bronchial biopsies with FEV1 decline in COPD patients using placebo, or inhaled corticosteroids (ICS) with or without long-acting beta 2-agonists. Additionally we investigate the association of MRP1 variants with FEV1 decline. MRP1 variants (rs212093, rs4148382, rs504348, rs4781699, rs35621) were genotyped in 110 COPD patients. Associations of MRP1 variants and MRP1 protein expression in bronchial biopsies (obtained at baseline, 6 and 30 months) with FEV1 decline were analyzed using linear mixed-effect models. During 30-month ICS treatment, subjects with a moderate staining for MRP1 had less FEV1 decline than those with a weak staining. In subjects stopping ICS after 6 months followed by 24-month placebo, moderate staining for MRP1 was associated with faster FEV1 decline than in those with a weak staining. None of the variants was associated with FEV1 decline. Our unique study suggests a role of MRP1 protein expression in bronchial biopsies in FEV1 decline occurring selectively in COPD patients with long-term (30-month) ICS therapy. (C) 2012 Elsevier B.V. All rights reserved

Relapse in FEV1 Decline After Steroid Withdrawal in COPD

Pathogenesis and treatment of chronic pulmonary disease

Prediction of Long-Term Benefits of Inhaled Steroids by Phenotypic Markers in Moderate-to-Severe COPD: A Randomized Controlled Trial

Pathogenesis and treatment of chronic pulmonary disease

Airway inflammation in COPD after long-term withdrawal of inhaled corticosteroids

Long-term treatment with inhaled corticosteroids (ICS) might attenuate lung function decline and decrease airway inflammation in a subset of patients with chronic obstructive pulmonary disease (COPD), and discontinuing ICS treatment could result in further lung function decline. We hypothesised that airway inflammation increases after ICS withdrawal following long-term ICS treatment in COPD. In the GLUCOLD-1 study (GL1), 114 patients with moderate-severe COPD were randomised to 6-month or 30-month treatment with fluticasone propionate (500 mu g twice daily), 30-month treatment with fluticasone/salmeterol (500/50 mu g twice daily) or placebo. During the 5-year follow-up study (GL2), patients were followed prospectively while being treated by their physician. Bronchial biopsies and induced sputum were collected at baseline, at 30 months (end of GL1) and at 7.5 years (end of GL2) to assess inflammatory cell counts. Data were analysed using linear mixed-effects models. In patients using ICS during GL1 and using ICS 0-50% of the time during GL2 (n=61/85), there were significant increases in GL2 bronchial CD3+ (fold change per year calculated as GL2 minus GL1 2.68, 95% CI 1.87-3.84), CD4+ (1.91, 95% CI 1.33-2.75) and CD8+ cells (1.71, 95% CI 1.15-2.53), and mast cells (1.91, 95% CI 1.36-2.68). The sputum total cell counts increased significantly in GL2 (1.90, 95% CI 1.422.54), as did counts of macrophages (2.10, 95% CI 1.55-2.86), neutrophils (1.92, 95% CI 1.39-2.65) and lymphocytes (2.01, 95% CI 1.46-2.78). ICS discontinuation increases airway inflammation in patients with moderate-severe COPD, suggesting that the anti-inflammatory effects of ICS in COPD are not maintained after ICS discontinuation