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Objective Identifying patient characteristics predicting categories of patient adherence to Chronic Obstructive Pulmonary Disease (COPD) exacerbation action plans. Methods Data were obtained from self-treatment intervention groups of two COPD self-management trials. Patients with ≥1 exacerbation and/or ≥1 self-initiated prednisolone course during one-year follow-up were included. Optimal treatment was defined as ‘self-initiating prednisolone treatment ≤2 days from the onset of a COPD exacerbation’. Predictors of adherence categories were identified by multinomial logistic regression analysis using patient characteristics. Results 145 COPD patients were included and allocated to four adherence categories: ‘optimal treatment’ (26.2 %), ‘sub optimal treatment’ (11.7 %), ‘significant delay or no treatment’ (31.7 %), or ‘treatment outside the actual exacerbation period’ (30.3 %). One unit increase in baseline dyspnoea score (mMRC scale 0–4) increased the risk of ‘significant delay or no treatment’ (OR 1.64 (95 % CI 1.07−2.50)). Cardiac comorbidity showed a borderline significant increased risk of ‘treatment outside the actual exacerbation period’ (OR 2.40 (95 % CI 0.98−5.85)). Conclusion More severe dyspnoea and cardiac comorbidity may lower adherence to COPD exacerbation action plans. Practice implications Tailored self-management support with more focus on dyspnoea and cardiac disease symptoms may help patients to better act upon increased exacerbation symptoms and improve adherence to COPD exacerbation action plans.

We present a 6-year-old boy with unilateral retinoblastoma of the left eye. MRI showed an intraocular tumor that extended into the optic nerve beyond the lamina cribrosa. The affected eye was enucleated and the optic nerve resection margin proved to be free. Following protocol, this patient received six courses of adjuvant systemic chemotherapy. Unfortunately, after 5 months this patient returned with the leptomeningeal spread of the tumor and died quickly thereafter.Histopathologic analysis of the enucleated eye and distal optic nerve revealed that the postlaminar tumor cells occupied the entire width of the optic nerve, extending all the way up to the pia mater, whereas, more often the tumor invasion is restricted to the center of the optic nerve. This was also visible on the MR images where contrast enhancement occupied the entire nerve width. A resection margin with tumor cells is recognized as a risk factor for metastasis, but perhaps the proximity of tumor cells to the leptomeninges should also be judged with caution as a potential increased risk for metastatic spread.

COVID-19 is a pandemic with high morbidity and mortality. In an autopsy cohort of COVID-19 patients, we found extensive accumulation of the tryptophan degradation products 3-hydroxy-anthranilic acid and quinolinic acid in the lungs, heart, and brain. This was not related to the expression of the tryptophan-catabolizing indoleamine 2,3-dioxygenase (IDO)-1, but rather to that of its isoform IDO-2, which otherwise is expressed rarely. Bioavailability of tryptophan is an absolute requirement for proper cell functioning and synthesis of hormones, whereas its degradation products can cause cell death. Markers of apoptosis and severe cellular stress were associated with IDO-2 expression in large areas of lung and heart tissue, whereas affected areas in brain were more restricted. Analyses of tissue, cerebrospinal fluid, and sequential plasma samples indicate early initiation of the kynurenine/aryl-hydrocarbon receptor/IDO-2 axis as a positive feedback loop, potentially leading to severe COVID-19 pathology. © 2021 The Authors. The Journal of Pathology published by John WileySons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Background and objective Patients with coronavirus disease 2019 (COVID‐19) pneumonia present with typical findings on chest computed tomography (CT), but the underlying histopathological patterns are unknown. Through direct regional correlation of imaging findings to histopathological patterns, this study aimed to explain typical COVID‐19 CT patterns at tissue level. Methods Eight autopsy cases were prospectively selected of patients with PCR‐proven COVID‐19 pneumonia with varying clinical manifestations and causes of death. All had been subjected to chest CT imaging 24–72 h prior to death. Twenty‐seven lung areas with typical COVID‐19 patterns and two radiologically unaffected pulmonary areas were correlated to histopathological findings in the same lung regions. Results Two dominant radiological patterns were observed: ground‐glass opacity (GGO) (n = 11) and consolidation (n = 16). In seven of 11 sampled areas of GGO, diffuse alveolar damage (DAD) was observed. In four areas of GGO, the histological pattern was vascular damage and thrombosis, with (n = 2) or without DAD (n = 2). DAD was also observed in five of 16 samples derived from areas of radiological consolidation. Seven areas of consolidation were based on a combination of DAD, vascular damage and thrombosis. In four areas of consolidation, bronchopneumonia was found. Unexpectedly, in samples from radiologically unaffected lung parenchyma, evidence was found of vascular damage and thrombosis. Conclusion In COVID‐19, radiological findings of GGO and consolidation are mostly explained by DAD or a combination of DAD and vascular damage plus thrombosis. However, the different typical CT patterns in COVID‐19 are not related to specific histopathological patterns. Microvascular damage and thrombosis are even encountered in the radiologically normal lung., We present direct regional comparison of the most frequently observed pulmonary computed tomography (CT) patterns with corresponding histopathological patterns in an autopsy cohort of eight coronavirus disease 2019 (COVID‐19) patients. While different stages of diffuse alveolar damage are key tissue substrates of the CT patterns in COVID‐19, vascular damage and thrombosis contribute to these typical radiological findings as well. See related Editorial

BackgroundThe blood eosinophil count has been shown to be a promising biomarker for establishing personalised treatment strategies to reduce corticosteroid use, either inhaled or systemic, in chronic obstructive pulmonary disease (COPD). Eosinophil levels seem relatively stable over time in stable state, but little is known whether this is also true in subsequent severe acute exacerbations of COPD (AECOPD).Aims and objectivesTo determine the stability in eosinophil categorisation between two subsequent severe AECOPDs employing frequently used cut-off levels.MethodsDuring two subsequent severe AECOPDs, blood eosinophil counts were determined at admission to the hospital in 237 patients in the Cohort of Mortality and Inflammation in COPD Study. The following four cut-off levels were analysed: absolute counts of eosinophils ≥0.2×10⁹/L (200 cells/µL) and ≥0.3×10⁹/L (300 cells/µL) and relative eosinophil percentage of ≥2% and ≥3% of total leucocyte count. Categorisations were considered stable if during the second AECOPD their blood eosinophil status led to the same classification: eosinophilic or not.ResultsDepending on the used cut-off, the overall stability in eosinophil categorisation varied between 70% and 85% during two subsequent AECOPDs. From patients who were eosinophilic at the first AECOPD, 34%–45% remained eosinophilic at the subsequent AECOPD, while 9%–21% of patients being non-eosinophilic at the first AECOPD became eosinophilic at the subsequent AECOPD.ConclusionsThe eosinophil variability leads to category changes in subsequent AECOPDs, which limits the eosinophil categorisation stability. Therefore, measurement of eosinophils at each new exacerbation seems warranted.

Joanne Sloots,1 Mirthe Bakker,1 Job van der Palen,1,2 Michiel Eijsvogel,1 Paul van der Valk,1 Gerard Linssen,3 Clara van Ommeren,1 Martijn Grinovero,4 Monique Tabak,5,6 Tanja Effing,7 Anke Lenferink1,8 1Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede, the Netherlands; 2Department of Research Methodology, Measurement & Data Analysis, University of Twente, Enschede, the Netherlands; 3Department of Cardiology, Hospital Group Twente, Almelo and Hengelo, the Netherlands; 4Amiko Digital Health Limited, London, UK; 5eHealth Group, Roessingh Research and Development, Enschede, the Netherlands; 6Department of Biomedical Signals and Systems, Faculty of Electrical Engineering, Mathematics and Computer Science, University of Twente, Enschede, the Netherlands; 7College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia; 8Department of Health Technology and Services Research, Faculty of Behavioural, Management and Social sciences, Technical Medical Centre, University of Twente, Enschede, the NetherlandsCorrespondence: Joanne SlootsDepartment of Pulmonary Medicine, Medisch Spectrum Twente, Koningsplein 1, Enschede, 7512 KZ, the NetherlandsTel +31651660063Email J.Sloots@mst.nlBackground: Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) often coexist and share periods of symptom deterioration. Electronic health (eHealth) might play an important role in adherence to interventions for the self-management of COPD and CHF symptoms by facilitating and supporting home-based care.Methods: In this pilot study, an eHealth self-management intervention was developed based on paper versions of multi-morbid exacerbation action plans and evaluated in patients with both COPD and CHF. Self-reporting of increased symptoms in diaries was linked to an automated decision support system that generated self-management actions, which was communicated via an eHealth application on a tablet. After participating in self-management training sessions, patients used the intervention for a maximum of four months. Adherence to daily symptom diary completion and follow-up of actions were analyzed. An add-on sensorized (Respiro®) inhaler was used to analyze inhaled medication adherence and inhalation technique.Results: In total, 1148 (91%) of the daily diaries were completed on the same day by 11 participating patients (mean age 66.8 ± 2.9 years; moderate (55%) to severe (45%) COPD; 46% midrange left ventricular function (LVF) and 27% reduced LVF). Seven patients received a total of 24 advised actions because of increased symptoms of which 11 (46%) were followed-up. Of the 13 (54%) unperformed advised actions, six were “call the case manager”. Adherence to inhaled medication was 98.4%, but 51.9% of inhalations were performed incorrectly, with “inhaling too shortly” (< 1.25 s) being the most frequent error (79.6%).Discussion: Whereas adherence to completing daily diaries was high, advised actions were inadequately followed-up, particularly the action “call the case manager”. Inhaled medication adherence was high, but inhalations were poorly performed. Future research is needed to identify adherence barriers, further tailor the intervention to the individual patient and analyse the intervention effects on health outcomes.Keywords: telemedicine, chronic conditions, self-treatment, disease management, dry powder inhalers

COVID-19 patients commonly present with neurological signs of central nervous system (CNS) and/or peripheral nervous system dysfunction. However, which neural cells are permissive to infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been controversial. Here, we show that midbrain dopamine (DA) neurons derived from human pluripotent stem cells (hPSCs) are selectively permissive to SARS-CoV-2 infection both in vitro and upon transplantation in vivo, and that SARS-CoV-2 infection triggers a DA neuron inflammatory and cellular senescence response. A high-throughput screen in hPSC-derived DA neurons identified several FDA approved drugs, including riluzole, metformin, and imatinib, that can rescue the cellular senescence phenotype and prevent SARS-CoV-2 infection. RNA-seq analysis of human ventral midbrain tissue from COVID-19 patients, using formalin-fixed paraffin-embedded autopsy samples, confirmed the induction of an inflammatory and cellular senescence signature and identified low levels of SARS-CoV-2 transcripts. Our findings demonstrate that hPSC-derived DA neurons can serve as a disease model to study neuronal susceptibility to SARS-CoV-2 and to identify candidate neuroprotective drugs for COVID-19 patients. The susceptibility of hPSC-derived DA neurons to SARS-CoV-2 and the observed inflammatory and senescence transcriptional responses suggest the need for careful, long-term monitoring of neurological problems in COVID-19 patients.

Contains fulltext : 208776.pdf (Publisher’s version ) (Closed access) CONTEXT: Current guidelines do not consistently recommend imaging beyond the head and neck region in succinate dehydrogenase subunit D (SDHD) mutation carriers as long as catecholamine metabolite levels are within the reference range. PARTICIPANTS: We report a series of 10 patients carrying pathogenic variants in the SDHD gene from five tertiary referral centers for paraganglioma (PGL) in the Netherlands, who presented with a sympathetic PGL (sPGL), pheochromocytoma (PHEO), or metastases outside the head and neck region in the absence of excessive catecholamine production. Two of six patients with a biochemically silent sPGL/PHEO developed metastatic disease. Additionally, four patients were found to have metastases outside the head and neck region from head and neck PGL. The average interval between the initial diagnosis and discovery of the silent lesions was 10 (range, 0 to 32) years. CONCLUSIONS: The absence of excessive catecholamine production does not exclude the presence of manifestations of SDHD outside the head and neck region. These findings suggest that a more extensive imaging strategy in SDHD mutation carriers may be warranted for detection of biochemically silent lesions.

Retinoblastoma mimickers, or pseudoretinoblastoma, are conditions that show similarities with the pediatric cancer retinoblastoma. However, false-positive retinoblastoma diagnosis can cause mistreatment, while false-negative diagnosis can cause life-threatening treatment delay. The purpose of this study is to identify the MR imaging features that best differentiate between retinoblastoma and the most common pseudoretinoblastoma diagnoses: Coats&rsquo, disease and persistent fetal vasculature (PFV). Here, six expert radiologists performed retrospective assessments (blinded for diagnosis) of MR images of patients with a final diagnosis based on histopathology or clinical follow-up. Associations between 20 predefined imaging features and diagnosis were assessed with exact tests corrected for multiple hypothesis testing. Sixty-six patients were included, of which 33 (50%) were retinoblastoma and 33 (50%) pseudoretinoblastoma patients. A larger eye size, vitreous seeding, and sharp-V-shaped retinal detachment were almost exclusively found in retinoblastoma (p &lt, 0.001&ndash, 0.022, specificity 93&ndash, 97%). Features that were almost exclusively found in pseudoretinoblastoma included smaller eye size, ciliary/lens deformations, optic nerve atrophy, a central stalk between optic disc and lens, Y-shaped retinal detachment, and absence of calcifications (p &lt, 0.022, specificity 91&ndash, 100%). Additionally, three newly identified imaging features were exclusively present in pseudoretinoblastoma: intraretinal macrocysts (p &lt, 0.001, 38% [9/24] in Coats&rsquo, disease and 20% [2/10] in PFV), contrast enhancement outside the solid lesion (p &lt, 0.001, 30% [7/23] in Coats&rsquo, disease and 57% [4/7] in PFV), and enhancing subfoveal nodules (38% [9/24] in Coats&rsquo, disease). An assessment strategy was proposed for MR imaging differentiation between retinoblastoma and pseudoretinoblastoma, including three newly identified differentiating MR imaging features.

Summary: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) targets multiple organs and causes severe coagulopathy. Histopathological organ changes might not only be attributable to a direct virus-induced effect, but also the immune response. The aims of this study were to assess the duration of viral presence, identify the extent of inflammatory response, and investigate the underlying cause of coagulopathy. Methods: This prospective autopsy cohort study was done at Amsterdam University Medical Centers (UMC), the Netherlands. With informed consent from relatives, full body autopsy was done on 21 patients with COVID-19 for whom autopsy was requested between March 9 and May 18, 2020. In addition to histopathological evaluation of organ damage, the presence of SARS-CoV-2 nucleocapsid protein and the composition of the immune infiltrate and thrombi were assessed, and all were linked to disease course. Findings: Our cohort (n=21) included 16 (76%) men, and median age was 68 years (range 41–78). Median disease course (time from onset of symptoms to death) was 22 days (range 5–44 days). In 11 patients tested for SARS-CoV-2 tropism, SARS-CoV-2 infected cells were present in multiple organs, most abundantly in the lungs, but presence in the lungs became sporadic with increased disease course. Other SARS-CoV-2-positive organs included the upper respiratory tract, heart, kidneys, and gastrointestinal tract. In histological analyses of organs (sampled from nine to 21 patients per organ), an extensive inflammatory response was present in the lungs, heart, liver, kidneys, and brain. In the brain, extensive inflammation was seen in the olfactory bulbs and medulla oblongata. Thrombi and neutrophilic plugs were present in the lungs, heart, kidneys, liver, spleen, and brain and were most frequently observed late in the disease course (15 patients with thrombi, median disease course 22 days [5–44]; ten patients with neutrophilic plugs, 21 days [5–44]). Neutrophilic plugs were observed in two forms: solely composed of neutrophils with neutrophil extracellular traps (NETs), or as aggregates of NETs and platelets.. Interpretation: In patients with lethal COVID-19, an extensive systemic inflammatory response was present, with a continued presence of neutrophils and NETs. However, SARS-CoV-2-infected cells were only sporadically present at late stages of COVID-19. This suggests a maladaptive immune response and substantiates the evidence for immunomodulation as a target in the treatment of severe COVID-19. Funding: Amsterdam UMC Corona Research Fund.

The water channel protein aquaporin-4 (AQP4) is required for a normal rate of water exchange across the blood&ndash, brain interface. Following the discovery that AQP4 is a possible autoantigen in neuromyelitis optica, the function of AQP4 in health and disease has become a research focus. While several studies have addressed the expression and function of AQP4 during inflammatory demyelination, relatively little is known about its expression during non-autoimmune-mediated myelin damage. In this study, we used the toxin-induced demyelination model cuprizone as well as a combination of metabolic and autoimmune myelin injury (i.e., Cup/EAE) to investigate AQP4 pathology. We show that during toxin-induced demyelination, diffuse AQP4 expression increases, while polarized AQP4 expression at the astrocyte endfeet decreases. The diffuse increased expression of AQP4 was verified in chronic-active multiple sclerosis lesions. Around inflammatory brain lesions, AQP4 expression dramatically decreased, especially at sites where peripheral immune cells penetrate the brain parenchyma. Humoral immune responses appear not to be involved in this process since no anti-AQP4 antibodies were detected in the serum of the experimental mice. We provide strong evidence that the diffuse increase in anti-AQP4 staining intensity is due to a metabolic injury to the brain, whereas the focal, perivascular loss of anti-AQP4 immunoreactivity is mediated by peripheral immune cells.

ispartof: PEDIATRIC NEPHROLOGY vol:35 issue:10 pages:1867-1870 ispartof: location:Germany status: published

Tailoring self-treatment by adding exacerbation phenotyping could be explored. Evidence on phenotyping effects, an accurate tool to identify eosinophilic exacerbations, and a validated cut-off point are needed before eosinophils can be used in practice.http://bit.ly/2L4b6SR

This international randomised controlled trial evaluated whether COPD patients with comorbidities, trained in using patient-tailored multidisease exacerbation action plans, had fewer COPD exacerbation days than usual care (UC).COPD patients (Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification II–IV) with ≥1 comorbidity (ischaemic heart disease, heart failure, diabetes, anxiety, depression) were randomised to a patient-tailored self-management intervention (n=102) or UC (n=99). Daily symptom diaries were completed for 12 months. The primary outcome “COPD exacerbation days per patient per year” was assessed using intention-to-treat analyses.No significant difference was observed in the number of COPD exacerbation days per patient per year (self-management: median 9.6 (interquartile range (IQR) 0.7–31.1); UC: median 15.6 (IQR 3.0–40.3); incidence rate ratio (IRR) 0.87 (95% CI 0.54; 1.39); p=0.546). There was a significantly shorter duration per COPD exacerbation for self-management (self-management: median 8.1 (IQR 4.8–10.1) days; UC: median 9.5 (IQR 7.0–15.1) days; p=0.021), with no between-group differences in the total number of respiratory hospitalisations (IRR 0.76 (95% CI 0.42; 1.35); p=0.348), but a lower probability of ≥1 for respiratory-related hospitalisation compared to UC (relative risk 0.55 (95% CI 0.35; 0.87); p=0.008). No between-group differences were observed in all-cause hospitalisations (IRR 1.07 (95% CI 0.66; 1.72)) or mortality (self-management: n=4 (3.9%); UC: n=7 (7.1%); relative risk 0.55 (95% CI 0.17; 1.84)).Patient-tailored exacerbation action plans for COPD patients with comorbidities did not significantly reduce exacerbation days, but reduced the duration per COPD exacerbation and the risk of having at least one respiratory-related hospitalisation during follow-up, without excess all-cause mortality.

Background: Elevated levels of midrange proadrenomedullin (MR-proADM) are associated with worse outcome in different diseases, including COPD. The association of stable-state MR-proADM with severe acute exacerbations of COPD (AECOPDs) requiring hospitalization, or with community-acquired pneumonia (CAP) in patients with COPD, has not been studied yet. The aim of this study was to evaluate the association of stable-state MR-proADM with severe AECOPD and CAP in patients with COPD. Methods: This study pooled data of 1,285 patients from the Cohort of Mortality and Inflammation in COPD (COMIC) and PRedicting Outcome using systemic Markers In Severe Exacerbations of Chronic Obstructive Pulmonary Disease (PROMISE-COPD) cohort studies. Time until first severe AECOPD was compared between patients with high (≥ 0.87 nmol/L) or low (< 0.87 nmol/L) levels of plasma MR-proADM in stable state as previously defined. For time until first CAP, only COMIC data (n = 795) were available. Results: Patients with COPD with high-level stable-state MR-proADM have a significantly higher risk for severe AECOPD compared with those with low-level MR-proADM with a corrected hazard ratio (HR) of 1.30 (95% CI, 1.01-1.68). Patients with high-level stable-state MR-proADM had a significantly higher risk for CAP compared with patients with COPD with low-level MR-proADM in univariate analysis (HR, 1.93; 95% CI, 1.24-3.01), but after correction for age, lung function, and previous AECOPD, the association was no longer significant (corrected HR, 1.10; 95% CI, 0.68-1.80). Conclusions: Stable-state high-level MR-proADM in patients with COPD is associated with severe AECOPD but not with CAP.

Neurodegenerative diseases, the leading cause of morbidity and disability, are gaining increased attention as they impose a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies, for example, infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage, but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases.

Background Retinoblastoma is the most common intraocular tumor in childhood with a good prognosis in terms of mortality, but detailed information about tumor morphology and disease extent in retinoblastoma is important for treatment decision making. Purpose To demonstrate ultrahigh-field MRI tumor morphology and tumor extent in retinoblastoma correlating with in and ex vivo images with histopathology. Study type Prospective case series. Population Six retinoblastoma patients (median age 5.5 months, range 2-14) were prospectively included in this study. Median time between diagnosis and enucleation was 8 days (range 7-19). Field strength/sequence In vivo pre-enucleation at 1.5T MRI with a circular surface coil. Ex vivo imaging (FLASH T1 -weighted and RARE T2 -weighted) was performed at field strengths of 9.4T and 17.6T. Assessment After ex vivo imaging, the eyes were histopathologically analyzed and morphologically matched with MRI findings by three authors (two with respectively 14 and 4 years of experience in ocular MRI and one with 16 years of experience in ophthalmopathology). Results Small submillimeter morphological aspects of intraocular retinoblastoma were successfully depicted with higher-resolution MRI and matched with histopathology images. With ex vivo MRI a small subretinal tumor seed (300 μm) adjacent to the choroid was morphologically matched with histopathology. Also, a characteristic geographical pattern of vital tumor tissue (400 μm) surrounding a central vessel interspersed with necrotic areas correlated with histopathology images. Tumor invasion into the optic nerve showed a higher signal intensity on T1 -weighted higher-resolution MRI. Data conclusion Higher-resolution MRI allows for small morphological aspects of intraocular retinoblastoma and extraocular disease extent not visible on currently used clinical in vivo MRI to be depicted. Level of evidence 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1487-1497.

A considerable proportion of the world’s population is latently infected with Mycobacterium tuberculosis (MTB) complex (LTBI) but in low-incidence counties as the Netherlands (4.6 TB cases/100.000 /year) LTBI prevalence is predominantly found among the elder population and foreign-born residents. In resource-rich countries implementation of immunosuppressive therapies with “biologicals”, show a rapid rise with increased risk of LTBI progressing to, often serious forms of, active TB. Worldwide it is advised to screen all candidates for of immunosuppressive therapies for TB with a chest X-ray and LTBI with at least one test [interferon gamma release assays (IGRAs) and/or tuberculin skin tests (TSTs)]. Screening requires an acceptable balance between over-diagnosis and under-diagnosis, also because the tests are not perfect and can be false-negative and false-positive in populations almost without exposure. We developed a guideline advising a stratified pre-immunosuppression screening policy, using a questionnaire classifying candidates in three screening strategies, based upon their age, country of birth, documented TB contacts and tests in the past and other risk factors, such as profession and travel history. A very low risk group can start with immune therapy immediately and a very high risk group should receive preventive treatment for LTBI, both without the need for further testing. A medium risk group should be tested by TST and IGRA and receive preventive treatment if at least one test is positive. Since the questionnaire is not yet validated monitoring of this approach on a national level is needed to evaluate the performance of this stratified screening strategy, based upon risk analysis.

Adherence is an important contributor towards effective Chronic Obstructive Pulmonary Disease (COPD) self-treatment. Our aim was to evaluate which patient characteristics predict various categories of adherence to exacerbation action plans in COPD patients. Diary data on adherence were obtained from two COPD self-management trials. Only patients with ≥1 exacerbation or ≥1 performed self-treatment action (starting a course of prednisolone) during 1 year follow-up were included. Optimal treatment was defined as ‘self-initiating treatment within two days from the COPD exacerbation start’. A multinomial logistic regression model was developed to identify predictors of adherence to COPD exacerbation action plans. 145 COPD patients (COPE-II: n=64; COPE-III n=81; COPD exacerbations mean 3.0 (SD 2.5); self-treatment actions 4.1 (SD 2.9)) were assigned to four adherence categories: significant delay or no treatment (24.4%), some delay in treatment (15.7%), optimal treatment (27.6%), or treatment outside actual exacerbation period (32.2%). Low dyspnoea score was a significant risk factor for ‘significant delay or no treatment’ (OR 1.64 (95% CI 1.07-2.50)) and cardiac comorbidity increased the risk of ‘treatment outside actual exacerbation period’ (OR 2.40 (95% CI 0.98-5.85)) compared to ‘optimal treatment’. Our study results show that dyspnoea score and cardiac comorbidity are predictors of patient adherence to exacerbation action plans. Associations between adherence categories and health outcomes of COPD exacerbation action plans need to be explored to identify effective self-managers, define the clinical consequences of non-adherence, and further tailor support to improve adherence.

The role of antibiotics in acute exacerbations of chronic obstructive pulmonary disease (COPD) is controversial and a biomarker identifying patients who benefit from antibiotics is mandatory. We performed a randomised, controlled trial in patients with acute exacerbations of COPD, comparing C-reactive protein (CRP)-guided antibiotic treatment to patient reported symptoms in accordance with the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy, in order to show a reduction in antibiotic prescription.Patients hospitalised with acute exacerbations of COPD were randomised to receive antibiotics based either on the GOLD strategy or according to the CRP strategy (CRP ≥50 mg·L−1).In total, 101 patients were randomised to the CRP group and 119 to the GOLD group. Fewer patients in the CRP group were treated with antibiotics compared to the GOLD group (31.7% versus 46.2%, p=0.028; adjusted odds ratio (OR) 0.178, 95% CI 0.077–0.411, p=0.029). The 30-day treatment failure rate was nearly equal (44.5% in the CRP group versus 45.5% in the GOLD-group, p=0.881; adjusted OR 1.146, 95% CI 0.649–1.187, p=0.630), as was the time to next exacerbation (32 days in the CRP group versus 28 days in the GOLD group, p=0.713; adjusted hazard ratio 0.878, 95% CI 0.649–1.187, p=0.398). Length of stay was similar in both groups (7 days in the CRP group versus 6 days in the GOLD group, p=0.206). On day-30, no difference in symptom score, quality of life or serious adverse events was detected.Use of CRP as a biomarker to guide antibiotic treatment in severe acute exacerbations of COPD leads to a significant reduction in antibiotic treatment. In the present study, no differences in adverse events between both groups were found. Further research is needed for the generalisability of these findings.

Gray matter pathology is an important aspect of multiple sclerosis (MS) pathogenesis and disease progression. In a recent study, we were able to demonstrate that the higher myelin content in the white matter parts of the brain is an important variable in the neuroinflammatory response during demyelinating events. Whether higher white matter myelination contributes to lesion development and progression is not known. Here, we compared lesion size of intra-cortical vs. white matter MS lesions. Furthermore, dynamics of lesion development was compared in the cuprizone and lysophosphatidylcholine models. We provide clear evidence that in the human brain, white matter lesions are significantly increased in size as compared to intra-cortical gray matter lesions. In addition, studies using the cuprizone mouse model revealed that the autonomous progression of white matter lesions is more severe compared to that in the gray matter. Focal demyelination revealed that the application of equal amounts of lysophosphatidylcholine results in more severe demyelination in the white compared to the gray matter. In summary, lesion progression is most intense in myelin-rich white matter regions, irrespective of the initial lesion trigger mechanism. A better understanding of myelin debris-triggered lesion expansion will pave the way for the development of new protective strategies in the future.

Kirsten Koehorst-ter Huurne,1 Sharina Kort,1 Job van der Palen,1,3 Wendy JC van Beurden,1 Kris LL Movig,2 Paul van der Valk,1 Marjolein Brusse-Keizer1 1Department of Pulmonary Medicine, 2Department of Clinical Pharmacy, Medisch Spectrum Twente, 3Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, the Netherlands Background: Poor adherence to inhaled medications in COPD patients seems to be associated with an increased risk of death and hospitalization. Knowing the determinants of nonadherence to inhaled medications is important for creating interventions to improve adherence. Objectives: To identify disease-specific and health-related quality of life (HRQoL) factors, associated with adherence to inhaled corticosteroids (ICS) and tiotropium in COPD patients. Methods: Adherence of 795 patients was recorded over 3 years and was deemed optimal at >75%–≤125%, suboptimal at ≥50%–125% (overuse). Health-related quality of life was measured with the Clinical COPD Questionnaire and the EuroQol-5D questionnaire. Results: Patients with a higher forced expiratory volume in 1 second (FEV1)/vital capacity (VC) (odds ratio [OR] =1.03) and ≥1 hospitalizations in the year prior to inclusion in this study (OR =2.67) had an increased risk of suboptimal adherence to ICS instead of optimal adherence. An increased risk of underuse was predicted by a higher FEV1/VC (OR =1.05). Predictors for the risk of overuse were a lower FEV1 (OR =0.49), higher scores on Clinical COPD Questionnaire-question 3 (anxiety for dyspnea) (OR =1.26), and current smoking (OR =1.73). Regarding tiotropium, predictors for suboptimal use were a higher FEV1/VC (OR =1.03) and the inability to perform usual activities as asked by the EuroQol-5D questionnaire (OR =3.09). A higher FEV1/VC also was a predictor for the risk of underuse compared to optimal adherence (OR =1.03). The risk of overuse increased again with higher scores on Clinical COPD Questionnaire-question 3 (OR =1.46). Conclusion: Several disease-specific and quality of life factors are related to ICS and tiotropium adherence, but a clear profile of a nonadherent patient cannot yet be outlined. Overusers of ICS and tiotropium experience more anxiety. Keywords: chronic obstructive pulmonary disease, adherence, inhalation medication, quality of life

It might seem self-evident that in the transition from a supervised trainee to an independent professional who is no longer supervised, formal assessment of whether the trainee knows his/her trade well enough to function independently is necessary. This would then constitute an end of training examination. Such examinations are practiced in several countries but a rather heterogeneous situation exists in the EU countries. In the Netherlands, the training program is not concluded by a summative examination and reasons behind this situation are discussed. Quality assurance of postgraduate medical training in the Netherlands has been developed along two tracks: (1) not a single testing moment but continuous evaluation of the performance of the trainee in ‘real time’ situations and (2) monitoring of the quality of the offered training program through regular site-visits. Regular (monthly and/or yearly) evaluations should be part of every self-respecting training program. In the Netherlands, these evaluations are formative only: their intention is to provide the trainee a tool by which he or she can see whether they are on track with their training schedule. In the system in the Netherlands, regular site-visits to training programs constitute a crucial element of quality assurance of postgraduate training. During the site-visit, the position and perceptions of the trainee are key elements. The perception by the trainee of the training program, the institution (or department) offering the training program, and the professionals involved in the training program is explicitly solicited and systematically assessed. With this two-tiered approach high-quality postgraduate training is assured without the need for an end of training examination.

Kirsten Koehorst-ter Huurne,1 Marjolein Brusse-Keizer,2 Paul van der Valk,1 Kris Movig,3 Job van der Palen,2,4 Christina Bode5 1Department of Pulmonary Medicine, Medisch Spectrum Twente, Enschede, the Netherlands; 2Department of Epidemiology, Medisch Spectrum Twente, Enschede, the Netherlands; 3Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede, the Netherlands; 4Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, the Netherlands; 5Department of Psychology, Health and Technology, University of Twente, Enschede, the Netherlands Background: Therapy adherence in COPD is crucial for treating symptoms, preventing exacerbations, and related complications. To achieve optimal adherence, it is important to recognize and understand a nonadherent patient. Objective: To study perceptions and beliefs regarding COPD and inhaled medication in COPD patients with poor adherence. Methods: Twenty patients (10 underuse, 10 overuse) were interviewed in semistructured in-depth interviews, about mental and physical health, illness perceptions, knowledge regarding COPD, and experience with, knowledge of, and acceptance of COPD medication and inhalation devices. Results: A majority of patients did not fully accept their disease, showed little disease knowledge, and many revealed signs of depressive mood and severe fatigue. Overusers reported more grief about decreased participation in daily life and were more frustrated in general. Underusers claimed using less medication because they felt well, did not want to use too much medication, and used their inhalation devices too long. Overusers reported medication “dependency”; they tended to catastrophize when being without medication and discarded inhalation devices too early because they feared running out of medication. Conclusion: Overusers and underusers showed a different pattern in perceptions and beliefs regarding inhaled medication and COPD. Practical implications: It is important to understand the reasons for under- and overuse. Is it related to practical issues regarding knowledge or is it influenced by beliefs and/or anxiety concerning COPD or medication? These issues need to be addressed for improving adherence. Keywords: COPD, adherence, illness perceptions, medication beliefs, in-depth interviews

Purpose To identify associations between magnetic resonance (MR) imaging features and gene expression in retinoblastoma. Materials and Methods A retinoblastoma MR imaging atlas was validated by using anonymized MR images from referral centers in Essen, Germany, and Paris, France. Images were from 39 patients with retinoblastoma (16 male and 18 female patients [the sex in five patients was unknown]; age range, 5-90 months; inclusion criterion: pretreatment MR imaging). This atlas was used to compare MR imaging features with genome-wide messenger RNA (mRNA) expression data from 60 consecutive patients obtained from 1995 to 2012 (35 male patients [58%]; age range, 2-69 months; inclusion criteria: pretreatment MR imaging, genome-wide mRNA expression data available). Imaging pathway associations were analyzed by means of gene enrichment. In addition, imaging features were compared with a predefined gene expression signature of photoreceptorness. Statistical analysis was performed with generalized linear modeling of radiology traits on normalized log2-transformed expression values. P values were corrected for multiple hypothesis testing. Results Radiogenomic analysis revealed 1336 differentially expressed genes for qualitative imaging features (threshold P = .05 after multiple hypothesis correction). Loss of photoreceptorness gene expression correlated with advanced stage imaging features, including multiple lesions (P = .03) and greater eye size (P < .001). The number of lesions on MR images was associated with expression of MYCN (P = .04). A newly defined radiophenotype of diffuse-growing, plaque-shaped, multifocal tumors displayed overexpression of SERTAD3 (P = .003, P = .049, and P = .06, respectively), a protein that stimulates cell growth by activating the E2F network. Conclusion Radiogenomic biomarkers can potentially help predict molecular features, such as photoreceptorness loss, that indicate tumor progression. Results imply a possible role for radiogenomics in future staging and treatment decision making in retinoblastoma.

Objective: To study differences in adherence to common inhaled medications in COPD. Methods: Adherence of 795 patients was recorded from pharmacy records over 3 years in the COMIC cohort. It was expressed as percentage and deemed good at ≥75–≤125%, sub-optimal ≥50–125% (overuse). Most patients used more than one medication, so we present 1379 medication periods. Results: The percentages of patients with good therapy adherence ranged from 43.2 (beclomethasone) –75.8% (tiotropium); suboptimal from 2.3 (budesonide) –23.3% (fluticasone); underuse from 4.4 (formoterol/budesonide) –18.2% (beclomethasone); and overuse from 5.1 (salmeterol) –38.6% (budesonide). Patients using fluticasone or salmeterol/fluticasone have a 2.3 and 2.0-fold increased risk of suboptimal versus good adherence compared to tiotropium. Patients using salmeterol/fluticasone or beclomethasone have a 2.3- and 4.6-fold increased risk of underuse versus good adherence compared to tiotropium. Patients using budesonide, salmeterol/fluticasone, formoterol/budesonide, ciclesonide and beclomethasone have an increased risk of overuse versus good adherence compared to tiotropium. Adherence to inhalation medication is inversely related to lung function. Conclusion: Therapy adherence to inhalation medication for the treatment of COPD is in our study related to the medication prescribed. Tiotropium showed the highest percentage of patients with good adherence, followed by ciclesonide, both dosed once daily. The idea of improving adherence by using combined preparations cannot be confirmed in this study. Further research is needed to investigate the possibilities of improving adherence by changing inhalation medication.

Background: Blood eosinophilia is frequently encountered in patients with AECOPD. However the impact of blood eosinophilia at admission in patients with AECOPD on outcome on the short and long term has not been extensively studied which was the objective of the present study. Methods: We used data of 207 exacerbations from a randomized clinical trial on antibiotic prescription based upon CRP-levels versus GOLD guided strategy and analyzed the impact of blood eosinophils (>2% of total white cell count and eosinophil count >= 300 cell/microliter) on clinical outcome. Results: 207 patients were included of whom 39 (18.8%) had eosinophilia >= 2%, 23 patients (11.1%) had blood eosinophil >= 300 cell/microliter. Eosinophilia was associated with shorter median length of stay in the eosinophilic groups(>= 2% and >= 300 cell/microliter) compared to the non-eosinophilic groups. Early treatment failure was reduced in the both the eosinophilic groups (>= 2% and >= 300 cell/microliter). Late treatment failure (day 11-30) did not differ between the groups. Relapse, was more frequent the eosinophilic groups >= 2% and >= 300 cell/microliter), however in the latter group this did not reach statistical significance. Eosinophilia >= 2% was a risk factor for having relapse (eosinophilia >= 2%: HR = 2.351; 95%Cl 1.335-4.139), whereas eosinophilia = 2% predicts a less favorable outcome due to an increased risk of relapse. (C) 2017 Published by Elsevier Ltd

Background: In patients hospitalised for an exacerbation of COPD (severe AECOPD), elevated blood eosinophil count was associated with a shortened length of stay. Less is known about its association with survival. Aims and objectives: The aim of this study was to evaluate the association of elevated blood eosinophil count at admission for a severe AECOPD with all-cause mortality. Methods: 450 patients of the COMIC cohort study who were admitted for a severe AECOPD were divided in normal or elevated blood eosinophil count, defined as eosinophils ≥2% of the total leukocyte count on day of admission. Outcome parameter was all-cause mortality. Minimum follow-up was 3 years. Results: Elevated blood eosinophil count (N=97) was associated with a significantly lower risk for all-cause mortality in univariate analysis (Figure 1; logrank p=0.004) (HR 1.53; 95%CI 1.15-2.04). [figure1] Patients with elevated blood eosinophil count were younger than patients with normal blood eosinophil count (66.3 (SD 10.4) versus 70.6 (SD 9.6) years, respectively (p Conclusion: The strong association of elevated blood eosinophils on admission for a severe AECOPD with lower risk for mortality in univariate analysis disappeared after correction for age. The association of age with eosinophil count needs further investigation.

Introduction Limited tobacco dependence treatment resources exist for smoking COPD patients not ready to quit. Smoking reduction may be a viable treatment approach if it prompts quit attempts and subsequent abstinence. This article describes the protocol of the REDUQ (REDUce and Quit) study, which examines whether smoking reduction counselling plus combination nicotine replacement therapy (NRT) is (cost-)effective in achieving long-term abstinence in smoking COPD patients not ready to quit. Methods/Design We conducted a two-centre, parallel-group, randomised controlled trial with 18 months follow-up in smoking outpatients with COPD. Patients not ready to quit within the next month but willing to reduce their smoking, were randomised to receive either intensive smoking reduction counselling plus combination NRT or a single information meeting plus self-help manual. Outcomes were assessed at baseline, 6, 12 and 18 months. The primary outcome is ≥ 1-year prolonged abstinence. Secondary outcomes are point prevalence abstinence, successful (i.e. ≥ 50%) smoking reduction, and incidence of quit attempts reported at follow-up assessments. Smoking status is biochemically verified by salivary cotinine and expired CO. Other variables include smoking-related cognitions, intention and motivation to reduce and quit smoking, withdrawal symptoms, health-related quality of life, symptoms of anxiety and depression, state of mindfulness, lung function, use of health care resources, and costs. Discussion The outcomes of the REDUQ trial will advance knowledge on treatment of smoking COPD patients not ready to quit. If (cost-)effective, the smoking reduction intervention can be offered to this difficult-to-treat target group as a valuable adjunct to smoking cessation treatment.

This self-management (SM) trial evaluated tailored action plans for exacerbations of COPD and comorbid conditions in Australian and Dutch patients. Primary outcome analyses demonstrated a reduction in COPD exacerbation duration and respiratory-related hospitalisation rate. This abstract reports secondary study endpoints. COPD patients (≥ 40 years, GOLD II-IV) with ≥ 1 comorbidity (ischemic heart disease, chronic heart failure, diabetes mellitus, anxiety, depression) were randomised to a SM intervention including individualised exacerbation action plans for COPD and comorbidities (n=102) or usual care (n=99). Health status (Chronic Respiratory Disease (CRQ) and the Hospital Anxiety and Depression Scale (HADS)), self-efficacy (COPD Self-Efficacy Scale (CSES)), and fatigue were assessed at baseline, 6 and 12 months. Between-group differences were studied with repeated measurements analyses. Compared to usual care, SM showed a significantly reduced behavioural risk factors CSES domain (difference -0.26 (95% CI -0.52;-0.01), p=0.04) and a significantly worse emotional function CRQ domain (difference -0.41 (95% CI -0.70;-0.11), p SM including exacerbation action plans for COPD and comorbidities improved patients’ self-efficacy to prevent breathing difficulty. Lower emotional function scores in the SM group were not accompanied with HADS changes and may result from more symptom awareness due to training. Further tailoring of our individualised SM action plans and associated case-manager support may enhance self-efficacy and (mental) health status.

Introduction: detection and quantification of dynamic hyperinflation (DH) in COPD patients in real-life is an intriguing issue, but hard to perform. This study assessed a smart shirt, capable of measuring breathing parameters, as a new diagnostic tool compared to standard lung function equipment. Methods: 31 healthy controls and 11 COPD patients performed basic spirometry, metronome-paced tachypnea (MPT) and an exercise test (either a six-minute-walk or a cardio-pulmonary exercise test (CPET)) wearing the smart shirt (Hexoskin, Carre Technologies, Montreal, Canada) and breathing through a sensor measuring flow. Breathing waveforms produced by the shirt were compared with mobile spirometry (Oxycon Mobile, Care Fusion, San Diego, USA) for its ability to register breathing (e.g. FEV1, IVC and breathing frequency) and detect DH. Results: Moderate-high correlations between the two devices were observed during basic spirometry (median Spearman’s rho for FEV1 (0.81), IVC (0.90) and frequency (0.95)) and during the longer MPT and exercise measurements (range 0.80 - 0.95). The agreement between the shirt and the mobile spirometry with respect to the detection of DH was poor to fair (kappa 0.2-0.3). The smart shirt detected DH more often than the spirometer. Conclusion: the smart shirt is capable of registering breathing patterns and alterations in breathing over time and DH can be detected. Several disturbing factors (such as movement, skin temperature and smart shirt sizing) need to be addressed to improve the detection algorithm. Disclosure: the authors declare no conflict of interest with any company whose equipment has been used.

Background Chronic Obstructive Pulmonary Disease (COPD) self-management interventions should be structured but personalised and often multi-component, with goals of motivating, engaging and supporting the patients to positively adapt their behaviour(s) and develop skills to better manage disease. Exacerbation action plans are considered to be a key component of COPD self-management interventions. Studies assessing these interventions show contradictory results. In this Cochrane Review, we compared the effectiveness of COPD self-management interventions that include action plans for acute exacerbations of COPD (AECOPD) with usual care. Objectives To evaluate the efficacy of COPD-specific self-management interventions that include an action plan for exacerbations of COPD compared with usual care in terms of health-related quality of life, respiratory-related hospital admissions and other health outcomes. Search methods We searched the Cochrane Airways Group Specialised Register of trials, trials registries, and the reference lists of included studies to May 2016. Selection criteria We included randomised controlled trials evaluating a self-management intervention for people with COPD published since 1995. To be eligible for inclusion, the self-management intervention included a written action plan for AECOPD and an iterative process between participant and healthcare provider(s) in which feedback was provided. We excluded disease management programmes classified as pulmonary rehabilitation or exercise classes offered in a hospital, at a rehabilitation centre, or in a community-based setting to avoid overlap with pulmonary rehabilitation as much as possible. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We resolved disagreements by reaching consensus or by involving a third review author. Study authors were contacted to obtain additional information and missing outcome data where possible. When appropriate, study results were pooled using a random-effects modelling meta-analysis. The primary outcomes of the review were health-related quality of life (HRQoL) and number of respiratory-related hospital admissions. Main results We included 22 studies that involved 3,854 participants with COPD. The studies compared the effectiveness of COPD self-management interventions that included an action plan for AECOPD with usual care. The follow-up time ranged from two to 24 months and the content of the interventions was diverse. Over 12 months, there was a statistically significant beneficial effect of self-management interventions with action plans on HRQoL, as measured by the St. George's Respiratory Questionnaire (SGRQ) total score, where a lower score represents better HRQoL. We found a mean difference from usual care of -2.69 points (95% CI -4.49 to -0.90; 1,582 participants; 10 studies; high-quality evidence). Intervention participants were at a statistically significant lower risk for at least one respiratory-related hospital admission compared with participants who received usual care (OR 0.69, 95% CI 0.51 to 0.94; 3,157 participants; 14 studies; moderate-quality evidence). The number needed to treat to prevent one respiratory-related hospital admission over one year was 12 (95% CI 7 to 69) for participants with high baseline risk and 17 (95% CI 11 to 93) for participants with low baseline risk (based on the seven studies with the highest and lowest baseline risk respectively). There was no statistically significant difference in the probability of at least one all-cause hospital admission in the self-management intervention group compared to the usual care group (OR 0.74, 95% CI 0.54 to 1.03; 2467 participants; 14 studies; moderate-quality evidence). Furthermore, we observed no statistically significant difference in the number of all-cause hospitalisation days, emergency department visits, General Practitioner visits, and dyspnoea scores as measured by the (modified) Medical Research Council questionnaire for self-management intervention participants compared to usual care participants. There was no statistically significant effect observed from self-management on the number of COPD exacerbations and no difference in all-cause mortality observed (RD 0.0019, 95% CI -0.0225 to 0.0263; 3296 participants; 16 studies; moderate-quality evidence). Exploratory analysis showed a very small, but significantly higher respiratory-related mortality rate in the self-management intervention group compared to the usual care group (RD 0.028, 95% CI 0.0049 to 0.0511; 1219 participants; 7 studies; very low-quality evidence). Subgroup analyses showed significant improvements in HRQoL in self-management interventions with a smoking cessation programme (MD -4.98, 95% CI -7.17 to -2.78) compared to studies without a smoking cessation programme (MD -1.33, 95% CI -2.94 to 0.27, test for subgroup differences: Chi² = 6.89, df = 1, P = 0.009, I² = 85.5%). The number of behavioural change techniques clusters integrated in the self-management intervention, the duration of the intervention and adaptation of maintenance medication as part of the action plan did not affect HRQoL. Subgroup analyses did not detect any potential variables to explain differences in respiratory-related hospital admissions among studies. Authors' conclusions Self-management interventions that include a COPD exacerbation action plan are associated with improvements in HRQoL, as measured with the SGRQ, and lower probability of respiratory-related hospital admissions. No excess all-cause mortality risk was observed, but exploratory analysis showed a small, but significantly higher respiratory-related mortality rate for self-management compared to usual care. For future studies, we would like to urge only using action plans together with self-management interventions that meet the requirements of the most recent COPD self-management intervention definition. To increase transparency, future study authors should provide more detailed information regarding interventions provided. This would help inform further subgroup analyses and increase the ability to provide stronger recommendations regarding effective self-management interventions that include action plans for AECOPD. For safety reasons, COPD self-management action plans should take into account comorbidities when used in the wider population of people with COPD who have comorbidities. Although we were unable to evaluate this strategy in this review, it can be expected to further increase the safety of self-management interventions. We also advise to involve Data and Safety Monitoring Boards for future COPD self-management studies.

OBJECTIVETo determine the number and proportion of healthcare worker (HCW) tuberculosis (TB) cases infected while working in healthcare institutions in the Netherlands and to learn from circumstances that led to these infections.DESIGNCohort analysis.METHODSWe included all HCW TB patients reported to the Netherlands TB Register from 2000 to 2015. Using data from this register, including DNA fingerprints of the bacteria profile and additional information from public health clinics, HCW TB cases were classified into 4 categories: (1) infected during work in the Netherlands, (2) infected in the community, (3) infected outside the Netherlands, or (4) outside these 3 categories. An in-depth analysis of category 1 cases was performed to identify factors contributing to patient-to-HCW transmission.RESULTSIn total, 131 HCW TB cases were identified: 32 cases (24%) in category 1; 13 cases (10%) in category 2; 42 cases (32%) in category 3; and 44 cases (34%) in category 4. The annual number of HCW TB cases (PPP=.12) all declined over the study period. Delayed diagnosis in a TB patient was the predominant underlying factor of nosocomial transmission in 47% of category 1 HCW TB patients, most of whom were subsequently identified in a contact investigation. Performing high-risk procedures was the main contributing factor in the other 53% of cases.CONCLUSIONIn low-incidence countries, every HCW TB case should warrant timely and thorough investigation to help further define and fine-tune the HCW screening policy and to monitor its proper implementation.Infect Control Hosp Epidemiol2017;38:976–982

Errors in the use of different inhalers were investigated in patients naive to the devices under investigation in a multicentre, single-visit, randomised, open-label, cross-over study. Patients with chronic obstructive pulmonary disease (COPD) or asthma were assigned to ELLIPTA vs DISKUS (Accuhaler), metered-dose inhaler (MDI) or Turbuhaler. Patients with COPD were also assigned to ELLIPTA vs Handihaler or Breezhaler. Patients demonstrated inhaler use after reading the patient information leaflet (PIL). A trained investigator assessed critical errors (i.e., those likely to result in the inhalation of significantly reduced, minimal or no medication). If the patient made errors, the investigator demonstrated the correct use of the inhaler, and the patient demonstrated inhaler use again. Fewer COPD patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS, 9/171 (5%) vs 75/171 (44%); MDI, 10/80 (13%) vs 48/80 (60%); Turbuhaler, 8/100 (8%) vs 44/100 (44%); Handihaler, 17/118 (14%) vs 57/118 (48%); Breezhaler, 13/98 (13%) vs 45/98 (46%; all PP=0.221); MDI (2/32 (6%) vs 8/32 (25%), P=0.074) and significantly fewer vs Turbuhaler (3/60 (5%) vs 20/60 (33%), PP⩽0.002). Significantly, fewer COPD patients using ELLIPTA made critical errors after reading the PIL vs other inhalers. More asthma and COPD patients preferred ELLIPTA over comparator inhalers.

Cortical lesions (CLs) are an important component of multiple sclerosis (MS) pathology; they correlate better with physical disability and cognitive impairment than white matter lesions (WMLs). Because remyelination can be extensive in CLs, we quantified remyelination in gray matter (GM) and white matter (WM), addressing oligodendrocyte (OGD) maturation state and clinical relevance of remyelination. Brain tissue samples from 21 chronic MS patients were immunohistochemically stained for myelin proteolipid protein, Olig2, which is strongly expressed in OGD precursor cells (OPCs), but weakly expressed in mature OGDs and other OGD markers. Sections were scored for the presence of normal-appearing WM and GM, de- and remyelination, and OPC and OGD cell counts. Remyelination was significantly more extensive in CLs than in WMLs with a trend toward more GM remyelination in primary progressive MS (PPMS) vs relapse-onset MS patients. More OPCs were found in remyelinated and nonremyelinated CLs vs remyelinated WMLs and nonremyelinated WMLs. Thus, there is more remyelination in the GM than in the WM in MS patient brains, with a trend toward more remyelination in those with PPMS. There does not seem to be a significant OPC recruitment failure in the GM, which casts new light on the process of remyelination failure.

Introduction: It is still unknown how best to maintain effects of exercise programmes in COPD in the long-term. We present the long-term effects of a community-based exercise programme incorporated in a self-management programme, compared to a self-management programme only in patients with COPD.Methods: All included patients participated in four self-management sessions. Additionally, patients in the intervention group participated in an 11-month community-based exercise programme led by physiotherapists. Patients trained three times/week for six months and two times/week during the subsequent five months. To encourage a behavioural change towards exercise, one of these weekly training sessions was home-based (unsupervised). No formal exercise training was offered to intervention patients in the second year.Results: The intervention was assigned to 80 patients, and the control condition to 79 patients. 82.5% and 78.5% of the intervention and control group, respectively, completed 24 months follow-up. Modified intention-to-treat analyses were performed. Although statistically significant after 12 months (35.1 m (95%Cl: 8.4-61.8)), the between-group difference on maximal exercise capacity was not statistically significant after 24 months (12.2 m (95%Cl: -16.6 to 41.0). Nevertheless, the between-group difference in daily physical activity was maintained after 24 months (1193 steps/day (95%Cl: 203-2182)). A beneficial effect was also found on CRQ dyspnoea score but not on other CRQ domains, CCQ and HADS.Conclusions: Our intervention was effective in achieving a behavioural change reflected by a sustained increase in daily physical activity, not accompanied by a sustained increase in maximal exercise capacity after two years of follow-up (ISRCTN81447311). (C) 2014 Elsevier Ltd. All rights reserved.

Objective: First, to investigate the effects of a telerehabilitation intervention on health status and activity level of patients with Chronic Obstructive Pulmonary Disease (COPD), compared to usual care. Second, to investigate how patients comply with the intervention and whether compliance is related to treatment outcomes. Design: a randomized controlled pilot trial Subjects: Thirty-four patients diagnosed with COPD. Intervention: The telerehabilitation application consists of an activity coach (3D-accelerometer with smartphone) for ambulant activity registration and real-time feedback, complemented by a web portal with a symptom diary for self-treatment of exacerbations. The intervention group used the application for 4 weeks. The control group received usual care. Main measures: Activity level measured by a pedometer (in steps/day), health status by the Clinical COPD Questionnaire at baseline and after intervention. Compliance was expressed as the time the activity coach was worn. Results: Fourteen intervention and 16 control patients completed the study. Activity level (steps/day) was not significantly affected by the intervention over time. There was a non-significant difference in improvement in health status between the intervention (−0.34±0.55) and control group (0.02±0.57, p=0.10). Health status significantly improved within the intervention group (p=0.05). The activity coach was used more than prescribed (108%) and compliance was related to the increase in activity level for the first two feedback weeks (r=0.62, p=0.03). Conclusions: This pilot study shows the potential of the telerehabilitation intervention: compliance with the activity coach was high, which directly related to an improvement in activity levels.

Objectives: The objective of this randomised, cross-over study was to compare a new single-dose dry powder inhaler (Elpenhaler (EH)), with a widely used, multi-dose dry powder inhaler (Diskus (DK)) on critical errors, patient preference, and satisfaction with the inhalers. Methods: First, patients read the instructions of one device, followed by a first inhalation attempt. Inhalation errors were assessed and if mistakes were made, correct inhaler use was demonstrated. Then patients had to demonstrate again and mistakes were registered. This was repeated up to four times. After completing the first device, the same procedure was started with the second inhaler. Primary outcome was the percentage of patients making at least one critical error after reading the insert. Secondary outcomes were inhaler preference and satisfaction with the inhalers. Results: After reading the insert, 19 of 113 patients (17%) made at least one critical error with DK and 40 (35%) with EH (p = 0.001); 73% preferred the DK and 27% the EH (p < 0.001). The mean overall satisfaction score (1 = very satisfied; 5 = very dissatisfied) for DK was 1.59 and for EH 2.48 (p < 0.001). Conclusion: With DK fewer errors were made, more patients preferred DK over EH and patients were more satisfied with DK. This may enable DK to improve treatment outcomes more than EH.

BACKGROUND: Exercise training programmes for patients with COPD are effective in improving exercise capacity. The few trials that have investigated the effects of exercise programmes on daily physical activity show contradictory results. AIM: To investigate the relation between daily physical activity level and exercise capacity in patients with COPD using data of a randomised controlled trial in which the exercise intervention was aimed at improvement of both physical activity and exercise capacity (the COPE-II study). METHODS: These are secondary analyses of the COPE-II study, a randomised controlled trial in which a community-based physiotherapeutic exercise programme was evaluated. Daily physical activity was measured with a pedometer (steps/day). Exercise capacity was measured with an incremental maximal cycle ergometer test, the incremental (ISWT) and endurance shuttle walk test (ESWT). Pearson correlation coefficients were calculated. RESULTS: At baseline, correlations between steps/day and VO(2peak), ISWT (m), ESWT (m) and ESWT (s) were 0.54, 0.59, 0.44, and 0.34, respectively (all p < 0.01). In the intervention group, correlations between change in steps/day over 7 months and change in ISWT (m), ESWT (m) and ESWT (s) were 0.47, 0.41, and 0.38, respectively (all p < 0.01). In the control group, these same correlations were weak to non-existent. CONCLUSIONS: A moderate to weak relationship was found between daily physical activity and exercise capacity. These results strengthen our beliefs that exercise interventions need to target not only exercise capacity but also behaviour change with regard to daily physical activity to achieve improvements in both parameters.

Current therapies for multiple sclerosis (MS) reduce the frequency of relapses by modulating adaptive immune responses but fail to limit the irreversible neurodegeneration driving progressive disability. Experimental autoimmune encephalomyelitis (EAE) in Biozzi ABH mice recapitulates clinical features of MS including relapsing-remitting episodes and secondary-progressive disability. To address the contribution of recurrent inflammatory events and ageing as factors that amplify progressive neurological disease, we examined EAE in 8- to 12-week-old and 12-month-old ABH mice. Compared with the relapsing-remitting (RREAE) and secondary progressive (SPEAE) EAE observed in young mice, old mice developed progressive disease from onset (PEAE) associated with pronounced axonal damage and increased numbers of CD3(+) T cells and microglia/macrophages, but not B cells. Whereas the clinical neurological features of PEAE and SPEAE were comparable, the pathology was distinct. SPEAE was associated with significantly reduced perivascular infiltrates and T-cell numbers in the central nervous system (CNS) compared with PEAE and the acute phase of RREAE. In contrast to perivascular infiltrates that declined during progression from RREAE into SPEAE, the numbers of microglia clusters remained constant. Similar to what is observed during MS, the microglia clusters emerging during EAE were associated with axonal damage and oligodendrocytes expressing heat-shock protein B5, but not lymphocytes. Taken together, our data reveal that the course of EAE is dependent on the age of the mice. Younger mice show a relapsing-remitting phase followed by progressive disease, whereas old mice immediately show progression. This indicates that recurrent episodes of inflammation in the CNS, as well as age, contribute to progressive neurological disease.

COPD frequently exists with comorbidities, but inclusion of COPD patients with severe comorbidities in self-management trials is still relatively uncommon. In a randomised controlled self-management trial COPD patients with ≥ 1 comorbidity were included. We have explored possible differences in patient characteristics between a Dutch and Australian COPD sample, and evaluated associations between comorbid load and patient characteristics using multivariate logistic regression analyses. In total 201 COPD patients (mean age 68.5 ± 8.9; 64.2% male) were included (Netherlands, n=145, Australia, n=56), and 42.3% had ≥ 2 comorbidities with no differences in comorbid load between both countries (p=0.29), although there were significant baseline differences (p

Introduction: Aspergillus can cause a variety of clinical syndromes in the lung, the most common are invasive aspergillosis, aspergilloma and allergic bronchopulmonary aspergillosis. Although Aspergillus is regularly isolated in sputum samples from patients with an acute exacerbation in COPD the clinical significance remains unclear. Aim: The aim of this study was to investigate if sputum cultures positive for Aspergillus in COPD patients are a predictor for mortality. Methods: In 29 of 795 patients of the Cohort of Mortality and Inflammation in COPD (COMIC) study there was a sputum culture positive for Aspergillus . Per positive case, 4 controls (in total 116 patients) were frequency matched based on inclusion date. Outcome parameter was 5-year mortality, based on all cause mortality. Results: Baseline characteristics between the groups (e.g demographics and lung function measures) were equal. The log-rank test showed no signifance difference (p=0.323) between the COPD patients with a sputum culture positive for aspergillus and the control group (figure 1) in mortality. Conclusion: A positive sputum culture for Aspergillus is not a predictor for all-cause mortality in COPD patients.