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COPD is characterized by acute exacerbations (AECOPD), which drive its progression and burden. AECOPD can be caused by various factors. Better prediction of AECOPD provides opportunity for initiating preventive treatment. This systematic review provides an evidence-based overview of clinical predictors of moderate, severe AECOPD and relapse of moderate and severe AECOPD (≤28 days of a previous AECOPD). Cohort studies, case-control studies, or (cluster) randomized controlled trials published in English between January 2011-December 2023 in PubMed, CINAHL, Embase, Web of Science and the Cochrane library were assessed. Eligible studies included patients diagnosed with COPD, aged ≥40 years, and who were current or ex-smokers. Predictors of AECOPD were categorized into: patient characteristics, symptoms, biomarkers, lung function test results, and composite scores. Critical appraisal was performed with the QUIPS-tool. Out of 1261 screened articles, 30 were included. Sixty-one distinct possible predictors of AECOPD were assessed, of which 37 were statistically significant (P < 0.05). Age, AECOPD history, fibrinogen, FEV , bronchodilator response, health status measured with the COPD specific St. George's Respiratory Questionnaire (SGRQ-C) score, and COPD GOLD classification (2-4, B-D) were significant predictors of severe and/or moderate AECOPD in more than one article. Only 11 out of the 30 included studies had a low risk of bias. Based on the highest relative statistical significance, combined with the best overall risk of bias, the most promising predictors of AECOPD are history of ≥1 AECOPD, higher SGRQ-C scores, elevated fibrinogen levels, and worse COPD GOLD (2-4, B-D). Future research should focus on standardization of AECOPD and predictor definitions, including the use of clearly defined cut-off values. Given the complexity and heterogeneity of COPD, combining diverse predictor domains into composite measures may enhance predictive accuracy of AECOPD, and the integration of such composites is promising for advancing COPD management in clinical practice.

Comorbidities are known to complicate disease management in patients with Chronic Obstructive Pulmonary Disease (COPD). This is partly due to lack of insight into the interplay of acute exacerbations of COPD (AECOPD) and comorbid flare-ups. This study aimed to explore patterns of AECOPDs and comorbid flare-ups. Data of increased symptoms were extracted from a 12-month daily symptom follow-up database including patients with COPD and comorbidities (chronic heart failure (CHF), anxiety, depression) and transformed to visualizations of AECOPDs and comorbid flare-up patterns over time. Patterns were subsequently categorized using an inductive approach, based on both predominance (ie, which occurs most often) of AECOPDs or comorbid flare-ups, and their simultaneous (ie, simultaneous start in ≥ 50%) occurrence. We included 48 COPD patients (68 ± 9 years; comorbid CHF: 52%, anxiety: 40%, depression: 38%). In 25 patients with AECOPDs and CHF flare-ups, the following patterns were identified: AECOPDs predominant (n = 14), CHF flare-ups predominant (n = 5), AECOPDs nor CHF flare-ups predominant (n = 6). Of the 24 patients with AECOPDs and anxiety and/or depression flare-ups, anxiety and depression flare-ups occurred simultaneously in 15 patients. In 9 of these 24 patients, anxiety or depression flare-ups were observed independently from each other. In 31 of the included 48 patients, AECOPDs and comorbid flare-ups occurred mostly simultaneously. Patients with COPD and common comorbidities show a variety of patterns of AECOPDs and comorbid flare-ups. Some patients, however, show repetitive patterns that could potentially be used to improve personalized disease management, if recognized.

Alterations in sphingolipid metabolism are described to contribute to various neurological disorders. We here determined the expression of enzymes involved in the sphingomyelin cycle and their products in postmortem brain tissue of multiple sclerosis (MS) patients. In parallel, we investigated the effect of the sphingosine-1 receptor agonist Fingolimod (Gilenya ® ) on sphingomyelin metabolism in reactive astrocytes and determined its functional consequences for the process of neuro-inflammation. Our results demonstrate that in active MS lesions, marked by large number of infiltrated immune cells, an altered expression of enzymes involved in the sphingomyelin cycle favors enhanced ceramide production. We identified reactive astrocytes as the primary cellular source of enhanced ceramide production in MS brain samples. Astrocytes isolated from MS lesions expressed enhanced mRNA levels of the ceramide-producing enzyme acid sphingomyelinase (ASM) compared to astrocytes isolated from control white matter. In addition, TNF-α treatment induced ASM mRNA and ceramide levels in astrocytes isolated from control white matter. Incubation of astrocytes with Fingolimod prior to TNF-α treatment reduced ceramide production and mRNA expression of ASM to control levels in astrocytes. Importantly, supernatants derived from reactive astrocytes treated with Fingolimod significantly reduced transendothelial monocyte migration. Overall, the present study demonstrates that reactive astrocytes represent a possible additional cellular target for Fingolimod in MS by directly reducing the production of pro-inflammatory lipids and limiting subsequent transendothelial leukocyte migration.

In the current offshore wind turbine support structure design method, the tower and foundation, which form the support structure are designed separately by the turbine and foundation designer. This method yields a suboptimal design and it results in a heavy, overdesigned and expensive support structure. This paper presents an integrated multidisciplinary approach to design the tower and foundation simultaneously. Aerodynamics, hydrodynamics, structure and soil mechanics are the modeled disciplines to capture the full dynamic behavior of the foundation and tower under different environmental conditions. The objective function to be minimized is the mass of the support structure. The model includes various design constraints: local and global buckling, modal frequencies, and fatigue damage along different stations of the structure. To show the usefulness of the method, an existing SWT-3.6-107 offshore wind turbine where its tower and foundation are designed separately is used as a case study. The result of the integrated multidisciplinary design optimization shows 12.1% reduction in the mass of the support structure, while satisfying all the design constraints.

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.

Background The sphingosine 1-phosphate (S1P) receptor modulator FTY720P (Gilenya®) potently reduces relapse rate and lesion activity in the neuroinflammatory disorder multiple sclerosis. Although most of its efficacy has been shown to be related to immunosuppression through the induction of lymphopenia, it has been suggested that a number of its beneficial effects are related to altered endothelial and blood–brain barrier (BBB) functionality. However, to date it remains unknown whether brain endothelial S1P receptors are involved in the maintenance of the function of the BBB thereby mediating immune quiescence of the brain. Here we demonstrate that the brain endothelial receptor S1P 5 largely contributes to the maintenance of brain endothelial barrier function. Methods We analyzed the expression of S1P 5 in human post-mortem tissues using immunohistochemistry. The function of S1P 5 at the BBB was assessed in cultured human brain endothelial cells (ECs) using agonists and lentivirus-mediated knockdown of S1P 5 . Subsequent analyses of different aspects of the brain EC barrier included the formation of a tight barrier, the expression of BBB proteins and markers of inflammation and monocyte transmigration. Results We show that activation of S1P 5 on cultured human brain ECs by a selective agonist elicits enhanced barrier integrity and reduced transendothelial migration of monocytes in vitro . These results were corroborated by genetically silencing S1P 5 in brain ECs. Interestingly, functional studies with these cells revealed that S1P 5 strongly contributes to brain EC barrier function and underlies the expression of specific BBB endothelial characteristics such as tight junctions and permeability. In addition, S1P 5 maintains the immunoquiescent state of brain ECs with low expression levels of leukocyte adhesion molecules and inflammatory chemokines and cytokines through lowering the activation of the transcription factor NFκB. Conclusion Our findings demonstrate that S1P 5 in brain ECs contributes to optimal barrier formation and maintenance of immune quiescence of the barrier endothelium.

While RB1 loss initiates retinoblastoma development, additional somatic copy number alterations (SCNAs) can drive tumor progression. Although SCNAs have been identified with good concordance between studies at a cytoband resolution, accurate identification of single genes for all recurrent SCNAs is still challenging. This study presents a comprehensive meta-analysis of genome-wide SCNAs integrated with gene expression profiling data, narrowing down the list of plausible retinoblastoma driver genes. We performed SCNA profiling of 45 primary retinoblastoma samples and eight retinoblastoma cell lines by high-resolution microarrays. We combined our data with genomic, clinical and histopathological data of ten published genome-wide SCNA studies, which strongly enhanced the power of our analyses (N = 310). Comprehensive recurrence analysis of SCNAs in all studies integrated with gene expression data allowed us to reduce candidate gene lists for 1q, 2p, 6p, 7q and 13q to a limited gene set. Besides the well-established driver genes RB1 (13q-loss) and MYCN (2p-gain) we identified CRB1 and NEK7 (1q-gain), SOX4 (6p-gain) and NUP205 (7q-gain) as novel retinoblastoma driver candidates. Depending on the sample subset and algorithms used, alternative candidates were identified including MIR181 (1q-gain) and DEK (6p gain). Remarkably, our study showed that copy number gains rarely exceeded change of one copy, even in pure tumor samples with 100% homozygosity at the RB1 locus (N = 34), which is indicative for intra-tumor heterogeneity. In addition, profound between-tumor variability was observed that was associated with age at diagnosis and differentiation grades. Since focal alterations at commonly altered chromosome regions were rare except for 2p24.3 (MYCN), further functional validation of the oncogenic potential of the described candidate genes is now required. For further investigations, our study provides a refined and revised set of candidate retinoblastoma driver genes.

Background In brain tissues from multiple sclerosis (MS) patients, clusters of activated HLA-DR-expressing microglia, also referred to as preactive lesions, are located throughout the normal-appearing white matter. The aim of this study was to gain more insight into the frequency, distribution and cellular architecture of preactive lesions using a large cohort of well-characterized MS brain samples. Methods Here, we document the frequency of preactive lesions and their association with distinct white matter lesions in a cohort of 21 MS patients. Immunohistochemistry was used to gain further insight into the cellular and molecular composition of preactive lesions. Results Preactive lesions were observed in a majority of MS patients (67%) irrespective of disease duration, gender or subtype of disease. Microglial clusters were predominantly observed in the vicinity of active demyelinating lesions and are not associated with T cell infiltrates, axonal alterations, activated astrocytes or blood–brain barrier disruption. Microglia in preactive lesions consistently express interleukin-10 and TNF-α, but not interleukin-4, whereas matrix metalloproteases-2 and −9 are virtually absent in microglial nodules. Interestingly, key subunits of the free-radical-generating enzyme NADPH oxidase-2 were abundantly expressed in microglial clusters. Conclusions The high frequency of preactive lesions suggests that it is unlikely that most of them will progress into full-blown demyelinating lesions. Preactive lesions are not associated with blood–brain barrier disruption, suggesting that an intrinsic trigger of innate immune activation, rather than extrinsic factors crossing a damaged blood–brain barrier, induces the formation of clusters of activated microglia.

With the increased need for renewable energy, new offshore wind farms are being developed at an unprecedented scale. However, as the costs of offshore wind energy are still too high, design optimization and new innovations are required for lowering its cost. The design of modern day offshore wind turbines relies on numerical models for estimating ultimate and fatigue loads of the turbines. The dynamic behavior and the resulting structural loading of the turbines is determined for a large part by its structural properties, such as the natural frequencies and damping ratios. Hence, it is important to obtain accurate estimates of these modal properties. For this purpose stochastic subspace identification (SSI), in combination with clustering and statistical evaluation methods, is used to obtain the variance of the identified modal properties of an installed 3.6MW offshore wind turbine in idling conditions. It is found that one is able to obtain confidence intervals for the means of eigenfrequencies and damping ratios of the fore-aft and side-side modes of the wind turbine.

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 P <0.001). Most patients (57–70%) made no errors using ELLIPTA and did not require investigator instruction. Instruction was required for DISKUS (65%), MDI (85%), Turbuhaler (71%), Handihaler (62%) and Breezhaler (56%). Fewer asthma patients made critical errors with ELLIPTA after reading the PIL vs: DISKUS (3/70 (4%) vs 9/70 (13%), P =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%), P <0.001). More asthma and COPD patients preferred ELLIPTA over the other devices (all P ⩽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. Lung disease and asthma: Encouraging effective inhaler use Patients should be coached in inhaler technique by trained professionals to eliminate critical errors. Job van der Palen at the University of Twente, with scientists from across The Netherlands and the UK, tested whether 729 patients with asthma and chronic obstructive pulmonary disease (COPD) could use various inhalers correctly after reading accompanying instructions. A trained professional observed the patients and corrected critical errors before allowing patients to try the inhalers again. More COPD patients displayed errors in inhaler technique compared with asthma sufferers. The ELLIPTA inhaler proved far easier for patients to use from the outset, meaning they made fewer (if any) critical errors. Both asthma and COPD sufferers preferred the ELLIPTA inhaler to the other inhalers tested. The team emphasize the importance of training in correct inhaler use alongside careful selection of inhaler design.