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Background Dynamic hyperinflation is highly prevalent in moderate-to-severe asthma, which may significantly impede activities of daily life. We hypothesised that dynamic hyperinflation in asthma is due to inflammation of large and small airways and can be reduced by systemic anti-inflammatory treatment. Therefore, we investigated the effect of systemic glucocorticoids on dynamic hyperinflation in moderate-to-severe asthma patients and explored the relationships between inflammatory markers and changes in dynamic hyperinflation. Methods In this randomised placebo-controlled trial we included 32 asthma patients on inhaled glucocorticoid therapy showing dynamic hyperinflation, defined by a ≥10% reduction in inspiratory capacity measured by standardised metronome-paced tachypnea test. Patients received either triamcinolone (80 mg) or placebo intramuscularly. Before and 2 weeks after treatment, patients completed respiratory health questionnaires, had blood eosinophils and exhaled nitric oxide levels measured, and underwent lung function and dynamic hyperinflation testing. Results After adjustment for potential confounders, dynamic hyperinflation was significantly reduced by 28.1% in the triamcinolone group and increased by 9.4% in the placebo group (p=0.027). In the triamcinolone-treated patients, the reduction in dynamic hyperinflation was greater in patients with higher blood eosinophils at baseline (r=−0.592, p=0.020) and tended to be associated with a reduction in blood eosinophils (r=0.412, p=0.127) and exhaled nitric oxide (r=0.442, p=0.099). Conclusions This exploratory study suggests that dynamic hyperinflation in asthma can be reduced by systemic anti-inflammatory treatment, particularly in patients with elevated blood eosinophils. This supports the hypothesis that dynamic hyperinflation in asthma is due to airway inflammation and should be considered an important target for treatment., Dynamic hyperinflation: a target for treatment in asthma, which can be reduced by systemic anti-inflammatory treatment https://bit.ly/3gfyxYv

Purpose Cervical spine injury after blunt trauma in children is rare but can have severe consequences. Clear protocols for diagnostic workup are, therefore, needed, but currently not available. As a step in developing such a protocol, we determined the incidence of cervical spine injury and the degree of protocol adherence at our level 2 trauma centre. Methods We analysed data from all patients aged Results We included 170 children in the first study period and 83 in the second. One patient was diagnosed with cervical spine injury. Protocol adherence regarding the indication for imaging was > 80% in both periods. Adherence regarding the imaging type decreased over time, with 45.8% of the patients receiving a primary CT scan in the second study period versus 2.9% in the first. Conclusion Radiographic imaging is frequently performed when clearing the paediatric cervical spine, although cervical spine injury is rare. Particularly CT scan usage has wrongly been emerging over time. Stricter adherence to current protocols could limit overuse of radiographic imaging, but ultimately there is a need for an accurate rule predicting which children really are at risk of injury.

Real-world evidence is important to help unravel unanswered problems in severe asthma and is valuable to better understand the patient experience and common clinical practice. The Severe Heterogeneous Asthma Registry, Patient-centred (SHARP) Clinical Research Collaboration is created as a network of national registries and severe asthma centres that work together to perform registry based real-world research and clinical studies on a pan-European scale. Such collaboration requires a new, innovative design to overcome the many issues that arise with large-scale data collection across national borders. SHARP has developed a platform that offers a federated analysis approach where national registry data are transformed and integrated into a common data model (CDM). The CDM then allows a local analysis of de-identified patient data and subsequent aggregate (meta-)analysis. To facilitate an easily accessible way to set up new registries, SHARP enables new registries to take part in a central database, based on already proven technology. Next to being economical, this linkage ensures data from different SHARP central members to be comparable. Technological advancements lead to an ever-expanding rate of patient data that will be collected; with the collective effort of the pan-European severe asthma research community SHARP hopes to ensure that they are well equipped to enter a new era of medical research, with the ultimate goal to positively impact the lives of patients with severe asthma., SHARP brings together national asthma registries in Europe and enables generation of real-world evidence on severe asthma by using a common data model that aligns data from existing registries and by facilitating the development of new asthma registries https://bit.ly/3a1E42D

Background: Myelin damage is a salient feature in cerebral small vessel disease (cSVD). Of note, myelin damage extends into the normal appearing white matter (NAWM). Currently, the specific role of myelin content in cognition is poorly understood. Objective: The objective of this exploratory study was to investigate the association between NAWM myelin and cognitive function in older adults with cSVD. Methods: This exploratory study included 55 participants with cSVD. NAWM myelin was measured using myelin water imaging and was quantified as myelin water fraction (MWF). Assessment of cognitive function included processing speed (Trail Making Test Part A), set shifting (Trail Making Test Part B minus A), working memory (Verbal Digit Span Backwards Test), and inhibition (Stroop Test). Multiple linear regression analyses assessed the contribution of NAWM MWF on cognitive outcomes controlling for age, education, and total white matter hyperintensity volume. The overall alpha was set at ≤0.05. Results: After accounting for age, education, and total white matter hyperintensity volume, lower NAWM MWF was significantly associated with slower processing speed (β = –0.29, p = 0.037) and poorer working memory (β= 0.30, p = 0.048). NAWM MWF was not significantly associated with set shifting or inhibitory control (p > 0.132). Conclusion: Myelin loss in NAWM may play a role in the evolution of impaired processing speed and working memory in people with cSVD. Future studies, with a longitudinal design and larger sample sizes, are needed to fully elucidate the role of myelin as a potential biomarker for cognitive function.

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ObjectiveTo determine whether natalizumab efficacy is maintained when switching to personalized extended interval dosing based on individual natalizumab trough concentrations in patients with relapsing-remitting multiple sclerosis (RRMS).MethodsThis was a prospective multicenter single-arm trial with 1 year follow-up and a 1-year extension phase. Participants were adult persons with RRMS treated with natalizumab without disease activity in the year prior to enrollment. The natalizumab treatment interval was based on longitudinal natalizumab trough concentrations. Patients received 3 monthly MRI scans, relapse assessments, and disability scoring during follow-up. The primary endpoint was the occurrence of gadolinium-enhancing lesions on MRI. Secondary endpoints were new/enlarging T2 lesions on MRI and relapses and progression on the Expanded Disability Status Scale (EDSS) during follow-up and extension phase.ResultsSixty-one patients were included. Eighty-four percent extended the interval from a 4-week interval to a 5- to 7-week interval. No patient developed gadolinium-enhancing lesions (95% confidence interval [CI] 0%–7.4%) during follow-up. No new/enlarging T2 lesions (95% CI 0%–7.4%) or relapses (95% CI 0%–7.4%) were reported during follow-up and in the extension phase. Median EDSS was comparable at baseline (3.0, interquartile range [IQR] 2.0–5.0) and after follow-up (3.0, IQR 2.0–5.0).ConclusionPersonalized extended interval dosing did not induce recurrence of MS disease activity. Natalizumab efficacy was maintained in stable patients with RRMS receiving personalized extended interval dosing based on individual natalizumab concentrations.Classification of evidenceThis study provides Class IV evidence that personalized extended interval dosing of natalizumab does not result in recurrence of disease activity in stable patients with RRMS.

The etiology of nonimmune hydrops fetalis is extensive and includes genetic disorders. We describe a term-born female neonate with late onset extensive nonimmune hydrops, that is, polyhydramnios, edema, and congenital bilateral chylothorax. This newborn was successfully treated with repetitive thoracocentesis, total parenteral feeding, octreotide intravenously and finally surgical pleurodesis and corticosteroids. A genetic cause seemed plausible as the maternal history revealed a fatal nonimmune hydrops fetalis. A homozygous truncating variant inGDF2(c.451C>T, p.(Arg151*)) was detected with exome sequencing. Genetic analysis of tissue obtained from the deceased fetal sibling revealed the same homozygous variant. The parents and two healthy siblings were heterozygous for theGDF2variant. Skin and lung biopsies in the index patient, as well as the revised lung biopsy of the deceased fetal sibling, showed lymphatic dysplasia and lymphangiectasia. To the best of our knowledge, this is the first report of an association between a homozygous variant inGDF2with lymphatic dysplasia, hydrothorax and nonimmune hydrops fetalis.

Introduction Women with ST-elevation myocardial infarction (STEMI) present with different symptoms compared to men. This can result in delays in diagnosis and in the timely treatment of women. The aim of this study is to examine these differences, including the short- and long-term mortality in women and men. Methods This quality registry study included all patients with STEMI who received primary percutaneous coronary intervention in 2015 or 2016 in Amsterdam and the surrounding region. Results Three PCI centres and the Emergency Medical Service in Amsterdam participated. In total, 558 men (71%) and 229 women (29%) were included. Women were on average 7 years older than men (68 vs 61 years, p p = 0.002) and monovascular disease (69% vs 57%, p = 0.002). A higher percentage of men were current smokers (41% vs 49%, p = 0.043). Patient delay, system delay and overall ischaemic times were similar in both women and men (medians: 51, 94 and 157 min, respectively). Initiation of treatment was achieved within 90 min after STEMI diagnosis in 85% of patients (87% in women, 85% in men). Thirty-day and 1‑year mortality adjusted hazard ratio for women versus men was 1.60 (95% CI 0.9–3.0) and 1.24 (95% CI 0.8–2.0), respectively. Discussion Recognition of cardiac complaints remains challenging for patients. In the Amsterdam region, time delays and mortality were not significantly different between men and women presenting with STEMI. These results are in contrast to findings in similar registries. This suggests that implementation of current knowledge and national campaigns are effective in increasing awareness of the signs and symptoms suggestive of myocardial infarction.

OBJECTIVE: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count.METHODS: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70.RESULTS: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL).CONCLUSIONS: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered.

Background The novel anti-IL-5 drug mepolizumab improves asthma outcomes in the majority but not all patients with severe eosinophilic asthma. Currently it is difficult to predict an individuals' chance of being a responder. Early changes in patient-reported outcome measures may contribute to the prediction of long-term outcomes. Aim To compare early changes in patient-reported outcome measures after 8 weeks and long-term response to mepolizumab treatment. Method 22 severe eosinophilic asthma patients starting mepolizumab therapy in a severe asthma centre in the Netherlands were evaluated on baseline, 8 weeks and 52 weeks, collecting questionnaire scores and asthma-related parameters. Well-controlled asthma was defined as an asthma control questionnaire score ≤ 0.75. Long-term treatment response was defined as continuing mepolizumab therapy at 52 weeks. Results Nine patients (41%) had well-controlled asthma at 8 weeks and all were mepolizumab responders at 52 weeks (positive predictive value = 100%, 95%CI 66-100), versus only 5 responders out of 13 patients with not well-controlled asthma at 8 weeks (negative predictive value = 62%, 95%CI 32-86). Conclusion The results in this study suggest that patients receiving mepolizumab therapy with an ACQ-score ≤ 0.75 at 8 weeks are unlikely to need extensive monitoring, for they are very likely to be long-term responders.

A patient with severe asthma on benralizumab therapy was admitted to the intensive care unit (ICU) for a coronavirus disease 2019 (COVID-19) infection. At the end of the 8 week benralizumab dosing interval, discussion arose as to whether benralizumab should be administered or if treatment should be discontinued, due to the lack of experience with benralizumab in this situation. Severe broncho-obstruction developed, and the next injection of benralizumab was administered during ICU admission without detrimental symptoms. With this case report, we would like to share our experience with the safe administration of benralizumab during COVID-19 pneumonia, guiding doctors in future decision making.

This design research was focused on developing standards covering the entire process of examination to limit the chances of security risks (e.g., the prevention of exam fraud as much as possible, and detection by means of data forensics), together these standards form the Educational Data Forensics Protocol. Two research questions guided this study. The first question was, which standards regarding preventing and detecting fraud in the process of examination need to be included into the EDF protocol? In addition, practitioners must be able to act on indications of exam fraud based on these standards. Therefore, a second research question was formulated, namely which conditions must be considered during development of the EDF protocol to support practitioners in detecting possible gaps in the security of their examination process? The EDF protocol was developed and validated in five consecutive steps. This study analyses on the theoretical base of developing the EDF protocol (Step 1) and the considerations for developing a prototype (Step 2). The prototype was being validated (e.g., establishing correctness of the content) through seven semi-structured interviews with content experts in the field of either test security or data forensics (Step 3). Statements from these interviews were used to adjust the prototype into a final version of the EDF protocol (Step 4). Finally, to determine the practical value, the final version of the EDF protocol was used to flag gaps in the security of the exam process and determine possible security risks for one of eX:plain’ s exam programs (Step 5).

Background Storage of platelet concentrates (PCs) results in reduced recovery and survival of transfused platelets (PLTs). Upon storage PLTs develop storage lesion that can be monitored by several laboratory tests. However, correlation of these descriptive tests with corrected count increments (CCIs), a marker frequently used to establish the effectiveness of PLT transfusions, is limited or unknown. This study investigated to what extent a functional test or a combined in vitro rating score improves the correlation of laboratory tests with 1-hour CCI. Study design and methods PCs were analyzed using six different laboratory tests (n = 123) before transfusion in a prophylactic setting to 74 hematooncologic patients. Linear regression and Spearman correlation were used to determine associations between descriptive (either separately or combined in an in vitro rating score) or functional test results and 1-hour CCIs obtained after transfusion. Results CD62P expression (r = -0.45), annexin V binding (r = -0.36), the updated in vitro rating score (r = 0.50), and PLT responsiveness after thrombin receptor activator for peptide-6 (TRAP) (r = 0.43-0.57) or adenosine diphosphate stimulation (r = 0.11-0.51) significantly correlated to 1-hour CCIs obtained after transfusion, whereas lactate concentration, ThromboLUX score, and thromboelastography measurements did not. The strongest correlations were observed for in vitro rating score and PLT responsiveness after TRAP stimulation and these tests could explain 24 and 33% of the observed variation in 1-hour CCI, respectively. Conclusion Combining descriptive markers in one in vitro rating score improved correlation to 1-hour CCI compared to the tests separately. Of all tests investigated, mean PLT responsiveness after TRAP stimulation showed the strongest clinical correlation and was best able to predict the 1-hour CCI.

Background: Evidence suggests that computerized cognitive training (CCT) can improve cognitive function in older adults, particularly executive functions. However, the underlying mechanisms by which CCT may improve executive functions are not well established. Objective: To determine: 1) inter-network functional connectivity correlates of changes in executive functions; and 2) the effect of CCT on these functional connectivity correlates. Methods: This secondary analysis included a subset of 124 adults aged 65–85 years enrolled in an 8-week randomized controlled trial of CCT. Participants were randomized to either: 1) group-based CCT 3x/week for 1 hour plus 3x/week home-based training; 2) group-based CCT preceded by brisk walking (Ex+CCT) 3x/week for 1 hour plus 3x/week home-based training; or 3) group-based balanced and toned (BAT) classes 3x/week for 1 hour (control). At baseline and trial completion, 65 of the 124 participants completed resting-state functional magnetic resonance imaging and neuropsychological tests of executive functions, specifically the Stroop Colour-Word Test and Flanker Test. Results: Improved performance on the Stroop Colour-Word Test and Flanker Test were associated with decreased correlation between the default mode network (DMN) and the fronto-parietal network (FPN) (p

Background Patients with severe eosinophilic asthma show different responses to various anti–IL-5 biologics, ranging from super response to nonresponse. Residual disease manifestations observed in partial responders may prompt physicians to switch between biologics. More data on response, switches, and residual disease manifestations are needed to improve personalized treatment. Objective To assess (1) prevalences and predictors of super, partial, and nonresponders to long-term anti–IL-5 treatment, (2) frequency and reasons for switches between anti–IL-5 biologics, and (3) nature of residual disease manifestations. Methods In this 2-year follow-up study, patients with severe asthma were included who initiated an anti–IL-5 biologic (mepolizumab, reslizumab, benralizumab) (n = 114). Patient characteristics (clinical, functional, inflammatory) and comorbidities were collected at baseline and 2-year follow-up. “Super responders” showed no residual disease manifestations at 2-year follow-up, “partial responders” experienced residual disease manifestations, and “nonresponders” discontinued anti–IL-5 treatment after less than 2 years because of clinical worsening. Results After 2-year anti–IL-5 treatment, 14% of patients were super responders, 69% partial responders, and 11% nonresponders. Super response was predicted by shorter asthma duration and higher FEV1, and tended to be associated with adult-onset asthma, absence of nasal polyps, and lower body mass index. Switches between anti–IL-5 biologics occurred frequently (41%). After 2-year treatment, most common residual disease manifestations included impaired lung function (59%), uncontrolled sinonasal disease (58%), and uncontrolled asthma symptoms (48%). Conclusions After 2 years of anti–IL-5 treatment, a favorable response was found in 83% of patients with severe asthma, including a super response in 14%. Most partial responders show impaired lung function or uncontrolled sinonasal disease, causing physicians to switch between biologics.

Background The aim of this study was to determine long-term survival and clinical outcomes of the surface replacement trapeziometacarpal joint prosthesis (SR™TMC) and to evaluate implant migration using radiostereometric analysis (RSA). Methods In this clinical long-term follow-up study outcomes of ten patients who received the SR™TMC joint prosthesis were evaluated using DASH and Nelson scores, Visual Analogue Scale (VAS) of pain, and key pinch strength. RSA-radiographs were obtained direct postoperatively and 6 months, 1, 5 and 10 years postoperatively and were analyzed using model-based RSA software. Results During follow-up, two early revisions took place. Mean pre-operative DASH and Nelson scores were 54 (SD 15) and 54 (SD 17), improved significantly after 6 months (DASH 25 (SD 20), Nelson 75 (SD 18)) and remained excellent during long-term follow-up in all patients with a stable implant. At final follow-up, clinical scores deteriorated clearly in two patients with a loose implant in situ. Conclusions Long-term survival of the SR™TMC joint prosthesis is relatively poor. However, clinical outcomes improved significantly in the short-term and remained excellent in the long-term in those patients with a stable implant, but deteriorated clearly in case of loosening. The role of RSA in TMC joint arthroplasty is potentially valuable but needs to be further investigated. Several challenges of RSA in the TMC joint have been addressed by the authors and suggestions to optimize RSA-data are given. Trial registration This study was registered in the Netherlands Trial Register (NL7126).

Background It is unclear whether asthma and asthma medications increase or decrease the risk of severe COVID-19, and this is particularly true for patients with severe asthma receiving biologics. Objectives The aim of this study was to assess incidence and disease course of COVID-19 in patients with severe asthma on biologic therapy (omalizumab, mepolizumab, reslizumab, benralizumab, dupilumab), as compared with COVID-19 data from the general Dutch population. Methods COVID-19 cases were identified through a prospective ongoing survey between March 17 and April 30, 2020 among all severe asthma specialists from 15 hospitals of the Dutch Severe Asthma Registry RAPSODI. From these cases, data was collected on patient characteristics, including co-morbidities, COVID-19 disease progression and asthma exacerbations. Findings were then compared with COVID-19 data from the general Dutch population. Results Of 634 severe asthma patients who received biologic therapy in RAPSODI, 9 (1.4%) were diagnosed with COVID-19. Seven patients (1.1%) required hospitalization for oxygen therapy, of which 5 were admitted to the intensive care for intubation and mechanical ventilation. One patient died (0.16%). All intubated patients had ≥1 co-morbidities. Odds (95%CI) for COVID-19 related hospitalization and intubations were 14 (6.6–29.5) and 41 (16.9–98.5) times higher, respectively, compared to the Dutch population. One patient presented with an asthma exacerbation. Conclusion Patients with severe asthma using biologic therapy showed to have a more severe course of COVID-19 compared to the general population. This may be due to co-morbidities, the severity of asthmatic airway inflammation, the use of biologics, or a combination of these.

BACKGROUND: Patients with severe asthma not meeting the strict trial eligibility criteria for mepolizumab are now routinely treated with this biological in clinical practice, but it remains unclear whether these ineligible patients respond differently to mepolizumab treatment.OBJECTIVE: This study investigated the extent and reasons for trial ineligibility of real-life, mepolizumab-treated patients with severe asthma and compared the characteristics of these patients with trial populations. Subsequently, therapeutic response in ineligible patients was assessed on the basis of oral corticosteroid (OCS) reduction.METHODS: Trial eligibility, population differences, and therapeutic response were assessed using the baseline characteristics of mepolizumab-receiving patients with severe asthma treated in the Amsterdam University Medical Centres and OCS dose at 6 months for OCS-dependent patients extracted from patients' electronic health records. Eligibility criteria and population characteristics from trials investigating mepolizumab were extracted from their original publications.RESULTS: A total of 82.4% of 119 mepolizumab-receiving, reallife patients with severe asthma were ineligible for trial inclusion, wherein 42.9% and 39.5% were excluded on the basis of inclusion and exclusion criteria, respectively. The clinical care population was older, more often male and demonstrating a better lung function under lower OCS maintenance dosages in comparison with trial populations. A total of 50% of 66 ineligible, OCS-dependent mepolizumab-treated patients were able to reduce their maintenance OCS dosage to

Background: Patients with severe eosinophilic asthma may respond differently to various anti-IL-5 biologics. Many patients experience residual disease manifestations, causing physicians to switch between these biologics. Insight into these residual disease manifestations could increase our understanding of mechanisms of severe asthma and reveal unmet therapeutic needs in these patients. Aim: We aimed to: (1) assess the frequency and reasons for switching between anti-IL-5 biologics, and; (2) evaluate whether residual disease manifestations still exist after 2 years anti-IL-5 treatment in patients with severe eosinophilic asthma. Methods: In this real world cohort study, severe asthma patients were included who had been treated with an anti-IL-5 biologic (mepolizumab, reslizumab, benralizumab) ≥2yr (n=95). Data on disease manifestations (asthma control, exacerbations, FEV1, blood eosinophils, exhaled NO, symptoms of sinonasal disease, atopy and adrenal insufficiency) and medication history, were collected at baseline and after 2 years of anti-IL-5 treatment. Results: Switches between anti-IL-5 biologics occurred in 41% of patients, mainly because of insufficient clinical response. After 2 years anti-IL-5 treatment 79 patients (83%) experienced residual disease manifestations: uncontrolled sinonasal symptoms (49%), impaired lung function (48%) and uncontrolled asthma (41%). 26% were still OCS dependent (8% adrenal insufficient). Conclusion: Despite significant clinical improvements, the majority of severe eosinophilic asthma patients showed residual disease manifestations after 2 years anti-IL-5 treatment. This suggests that non-IL-5 driven inflammatory pathways may be activated.

Introduction: Therapeutic drug monitoring(TDM), measuring drug concentrations to adjust dosing and optimize clinical outcomes, is widely applied in monoclonal antibody(MAB) treatment of rheumatoid arthritis and inflammatory bowel disease. In asthma, however, it is unknown what long-term MAB serum levels are in real-life, and whether these levels are related to outcomes; for example the patient-reported need for a new MAB gift before the next administration. Aims: To examine the relationship between omalizumab trough levels and the patient-reported need for the next omalizumab gift. Methods: We measured omalizumab trough levels in patients treated ≥1 year at their 6-monthly evaluation (asthma control, lung function). A BORG-scale(0-10) was used to measure the patient-reported need for the next gift. Results: 27 patients (37% male, age 54(33-59)(median(IQR)), weight 89 kg(76-95), length of omalizumab treatment 38(24-58) months) were included. Omalizumab trough levels ranged 9.1-100 µg/ml (median 50), and patient-reported need for the next gift from 0 to 7 (median 2). Higher patient-reported need was significantly related to lower omalizumab trough levels(β=-5.11 µg/ml, 95%CI=-10.16 to -0.06, p=0.048). No significant correlation was found between trough levels and clinical or lung function parameters. Conclusion: In this proof of concept study in a real-world severe asthma population, we showed a wide variety of omalizumab trough levels after long-term treatment. Moreover, lower trough levels were related to increased patient-reported need for a new omalizumab gift. These results encourage to explore the potential of TDM to increase the efficacy, patient safety and cost-effectiveness of MABs in severe asthma treatment.

Background: In asthma, data on body composition, and especially muscle mass are scarce. Fat free mass was shown to be low in severe asthma, but the impact of low muscle mass on asthma outcomes is unknown. Aim: To explore associations between muscle mass and clinical outcomes in moderate to severe asthma. Methods: Muscle mass was assessed by fat free mass index (FFMI) using bio-impedance analyses, and creatinine excretion in 24h urine. Associations of muscle mass with clinical outcomes (asthma control (ACQ), quality of life (AQLQ), exacerbations, FEV1, blood eosinophils) were assessed with correlation coefficients. Results: We included 60 GINA 3-5 asthma patients (19 men, BMI 27±5 kg/m2). Different patient characteristics (e.g. age, smoking, medication use) did not affect FFMI or creatinine, except sex, with higher levels of FFMI (20.9±2.0 vs 17.1±2.0 kg/m2, p Conclusion: We found lower muscle mass to be related to poorer asthma outcomes and higher blood eosinophils in GINA 3-5 asthma. The mutual impact of systemic inflammation, muscle mass and asthma outcomes requires more research.

Background: The frequent use of regular and acute oral corticosteroid (OCS) treatment is identified as a key challenge in asthma management. To raise awareness about the burden of OCS and the potential of new treatments available, information about who prescribes OCS is useful. Aim: To explore the involvement of specialists in the prescriptions of regular OCS or frequent (≥2) OCS courses in asthma. Methods: We analysed OCS prescription data from 1430 pharmacies (Dutch IQVIA Prescription Database) focusing on adult patients receiving asthma medication in focus yr 2017. Prescribers were classified as specialist or general practitioners (GP). Regular OCS was defined as >28 days ≥2.5mg - ≤17.5mg and OCS courses as Results: Of 185.783 adults on asthma medication, 76.5% had no OCS prescription in the focus yr, 2.5% received ≥2 OCS courses and 4.6% regular OCS. Regular OCS or ≥2 OCS courses were prescribed across the whole range of ICS doses and in 38.9% of these cases OCS was prescribed by a specialist. In the subgroup of 79.274 patients on high dose ICS, 3.2% received ≥2 OCS courses and 5.8% regular OCS. Again in a minority of these patients (44.5%) a specialist prescribed the OCS. Extension of the evaluation to OCS prescriptions in the previous 3 yrs showed that 59% of these patients had a specialist OCS prescription. Conclusions: Our study showed that 7.1% of adults on asthma medication were exposed to frequent OCS courses or regular OCS in the focus yr. The majority of these patients received OCS without intervention of a specialist, suggesting that strategies to reduce the burden of OCS should be directed not only at specialists, but also at patients and non-specialists.

Thalamic deep brain stimulation (DBS) for chronic pain is performed in selected patients with a variable success rate. We report the use of recently developed directional DBS in a patient with hemibody central poststroke pain (CPSP) and its added value in the induction of pleasant, pain-distracting paresthesia’s throughout the contralateral body side. A 68-year-old man suffered from multiple strokes in the left hemisphere 11 years before presentation, resulting in medically refractory right-sided hemibody CPSP. He was implanted with a directional DBS electrode in the left ventrocaudal nucleus of the thalamus. A directional single-segment contact configuration produced a better improvement throughout the contralateral body side than ring-mode and other directional configurations. Treatment led to a reduction of almost 50% in pain. This case demonstrates the value of directional DBS in the treatment of chronic pain, as steering increases selectivity and reduces side effects in a small target area surrounded by structures with high functional diversity.

In recent years, major developments have occurred in severe asthma management. Different asthma phenotypes and subgroups have been identified and new treatment options have become available. A total of five monoclonal antibodies are currently approved in severe asthma treatment: omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab. These drugs have been shown to reduce exacerbations and to have an oral corticosteroid-sparing effect in many severe asthma patients. However, biological treatment is not successful in all patients and should be discontinued in non-responsive patients. Treating the right patient with the right biologic, and therefore biologic response prediction, has become a major point of interest in severe asthma management. A variety of response outcomes is utilized in the different clinical trials, as well as a huge range of potential predicting factors. Also, regarding the timing of the response evaluation, there are considerable differences between studies. This review summarizes the results from studies on predicting responses and responders to biological treatment in severe asthma, taking into account clinical, functional and inflammatory parameters assessed prior to the start of treatment as well as following a few months of therapy. In addition, future perspectives are discussed, highlighting the need for more research to improve patient identification and treatment responses in the field of biological treatment in severe asthma.

Difficult-to-treat asthma affects a minority of adults and children with asthma but represents a challenging mix of misdiagnosis, multimorbidity, inadequate self-management, severe airway pathobiology, and treatment complications. Management of these patients extends beyond asthma pharmacotherapy, because multiple other patient-related domains need to be addressed as well. Such complexity can hinder adequate clinical assessment even when performed in specialist practice. Systematic assessment undertaken by specialized multidisciplinary teams brings a broad range of resources to bear on patients with difficult-to-treat asthma. Although the concept of systematic assessment is not new, practices vary considerably and implementation is not universal. Nevertheless, assessment protocols are already in place in several institutions worldwide, and outcomes after such assessments have been highly encouraging. This review discusses the rationale, components, and benefits of systematic assessment, outlining its clinical utility and the available evidence for improved outcomes. It describes a range of service configurations and assessment approaches, drawing examples from severe asthma centers around the world to highlight common essential elements. It also provides a framework for establishing such services and discusses practical considerations for implementation.

[EN]For security and justice professionals (e.g., police officers, lawyers, judges), the thousands of peer-reviewed articles on nonverbal communication represent important sources of knowledge. However, despite the scope of the scientific work carried out on this subject, professionals can turn to programs, methods, and approaches that fail to reflect the state of science. The objective of this article is to examine (i) concepts of nonverbal communication conveyed by these programs, methods, and approaches, but also (ii) the consequences of their use (e.g., on the life or liberty of individuals). To achieve this objective, we describe the scope of scientific research on nonverbal communication. A program (SPOT; Screening of Passengers by Observation Techniques), a method (the BAI; Behavior Analysis Interview) and an approach (synergology) that each run counter to the state of science are examined. Finally, we outline five hypotheses to explain why some organizations in the fields of security and justice are turning to pseudoscience and pseudoscientific techniques. We conclude the article by inviting these organizations to work with the international community of scholars who have scientific expertise in nonverbal communication and lie (and truth) detection to implement evidence-based practices., [ES]Para los profesionales de la seguridad y la justicia (policías, abogados, jueces), los miles de artículos revisados por pares sobre comunicación no verbal representan fuentes importantes de conocimiento. Sin embargo, a pesar del alcance del trabajo científico realizado sobre este tema, los profesionales pueden recurrir a programas, métodos y enfoques que no reflejan el estado real de la ciencia. El objetivo de este artículo es examinar (i) los conceptos de comunicación no verbal transmitidos por estos programas, métodos y enfoques, pero también (ii) las consecuencias de su uso (por ejemplo, sobre la vida o la libertad de las personas). Para lograr estos objetivos, describimos el alcance de la investigación científica sobre la comunicación no verbal. Se examina un programa (SPOT: Evaluación de pasajeros mediante técnicas de observación), un método (BAI: Entrevista de análisis de conducta) y un enfoque (sinergología) que contradicen el estado de la ciencia. Finalmente, presentamos cinco hipótesis para explicar por qué algunas organizaciones en los campos de la seguridad y la justicia están recurriendo a la pseudociencia y a las técnicas pseudocientíficas. Concluimos el artículo invitando a estas organizaciones a trabajar con la comunidad académica internacional especializada en la investigación sobre comunicación no verbal y detección de mentiras (y verdad) para implementar prácticas basadas en la evidencia.

Background Aseptic loosening is a main concern in elbow arthroplasty. Evaluation of implant migration using radiostereometric analysis (RSA) might increase understanding of implant loosening. Previously, 2-year RSA results of 16 Instrumented Bone Preserving (IBP) elbow prostheses showed migration of the humeral component in the first weeks but most components stabilized within 6 months postoperatively. In follow-up, the present study evaluated long-term survival, the relation between early migration and survival, and the long-term migration and clinical outcomes. Methods Sixteen patients who received an IBP prosthesis were prospectively followed with a median follow-up time of 136 months (range 82-165). Migration was measured using RSA. Clinical results were described using the Elbow Function Assessment (EFA), Broberg and Morrey elbow functional rating index, Oxford Elbow Score (OES), and visual analog scale (VAS) for pain and satisfaction. Results Four patients underwent a revision within 10 years, and 2 more were planned for revision surgery after 14 years. Five patients died with their prosthesis in situ. Early migration was not associated with survival. Long-term migration patterns varied widely. Median EFA score was 58.5, Broberg and Morrey score was 50, and OES score was 32. Median VAS score for pain was 2 and that for satisfaction was 7.5. Conclusion Ten-year survival of the IBP total elbow prosthesis was 75%, decreasing to 63% after 14 years of follow-up. Long-term implant failure could not be predicted by 2-year migration results in this study. Although short-term clinical results were promising, long-term outcomes worsened in all patients.

Deep brain stimulation (DBS) is an established treatment for advanced Parkinson’s disease (PD). The two most used targets for PD are the subthalamic nucleus and the internal globus pallidus. DBS is especially efficacious for the treatment of otherwise refractory tremor, medication-related motor response fluctuations, and dyskinesia. In general, the best motor response of DBS is as good as that of dopaminergic medication but more constant. The three cardinal pillars for successful DBS treatment comprise optimal patient selection, accurate DBS lead placement, and thorough postoperative care, which includes programming and medication adjustments.

This study aims to provide more insight into how students’ perceptions of assessment quality are related to their learning approaches and learning outcomes. Six variables associated with the construct of students’ perceptions of assessment quality are distinguished: 1) effects of assessment on learning, 2) fairness of assessment, 3) conditions of assessment, 4) interpretation of test scores, 5) authenticity of assessment, and 6) credibility of assessment. 204 higher education students completed the Students’ Perceptions of Assessment Quality Questionnaire (SPAQQ), and the Approaches to Learning and Studying Inventory (ALSI), and the students’ learning outcomes (grades) were obtained. Firstly, results indicate that the students’ perceptions of the effects of assessment on learning are positively related to the students’ deep learning approach and the strategic learning approach and negatively related to the surface learning approach. Secondly, the students’ perceptions of the conditions of assessment are positively related to their learning outcomes of the assessments.

Vascular cognitive impairment (VCI) results from cerebrovascular disease and is the second most common type of cognitive dysfunction. Sub-cortical ischemic vascular cognitive impairment (SIVCI) is the most common form of VCI. Current evidence suggests that increased or maintained cortical thickness might be one mechanism by which aerobic exercise preserves cognitive function in older adults. Whether this is also a potential pathway among older adults with SIVCI is unknown. Therefore, the aim of this secondary analysis of a 6-month proof-of-concept single-blinded randomized controlled trial of aerobic exercise was to investigate the associations between (1) aerobic-induced improvements in aerobic fitness capacity and change in cortical thickness in older adults with mild SIVCI; and (2) change in cortical thickness and changes in executive functions. This is a secondary analysis of neuroimaging data from a randomized controlled trial with 71 older adults with SIVCI who were randomly assigned to either a 6-month thrice-weekly aerobic training program or a 6-month nutrition program (i.e., control). Outcome measures were assessed at baseline and trial completion (i.e., 6 months). Aerobic fitness capacity was assessed with the 6-min walk test (6MWT). Magnetic resonance imaging data were acquired at both measurement points from 28 participants to look at changes in cortical thickness. Executive functions were assessed using (1) the Stroop test, (2) the trail making test (part A&B), and (3) the digit symbol substitution test (DSST). At trial completion, compared with the control group, participants in the aerobic training group showed significantly improved 6MWT performance (p = .037). Improved 6MWT performance was independently and significantly associated with increased change in cortical thickness, after controlling for baseline cortical thickness, baseline age, and baseline MoCA (p = .045). Specifically, change in 6MWT performance was significantly positively associated with change in the right superior temporal gyrus thickness (r = .557, p = .002). Maintenance of cortical thickness was independently and significantly associated with improved processing speed performance on the DSST over the 6-month trial, after controlling for baseline DSST performance, baseline age, and baseline MoCA (p = .014). Specifically, change in DSST performance was significantly positively associated with change in the right superior frontal thickness (r = .595, p = .002). Thus, a 6-month aerobic training program may promote cognitive outcomes in older adults with mild SIVCI by improving aerobic fitness capacity and maintaining cortical thickness.

IgE responses against allergens have acquired much attention due to their pathogenic nature as mediators of allergic reactions. In contrast, IgE responses against vaccines like Diphtheria-Tetanus-Pertussis (DTP) and the potential persistence of IgE production have received relatively little attention, presumably because of the low prevalence of allergic symptoms. In general, common early sensitivity reactions against vaccines, including tetanus toxoid, consist of mild local reactions and are not contraindicative of future vaccinations (1, 2). This article is protected by copyright. All rights reserved

Background: Deep brain stimulation (DBS) of the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN) are established treatment option in Parkinson's disease (PD). If DBS does not provide the desired effect, re-operation to the alternative target is a treatment option, but data on the effect of re-operation are scarce. Objectives: The objective of this study is to evaluate the clinical effect of re-operation the alternative target after failure of initial STN or GPi DBS for Parkinson's disease. Materials and Methods: We descriptively analyzed the baseline characteristics, the effect of initial surgery and re-operation of eight NSTAPS (Netherlands SubThalamic and Pallidal Stimulation) patients and six previously published cases that underwent re-operation to a different target. Results: In the NSTAPS cohort, two of the eight patients showed more than 30% improvement of off-drug motor symptoms after re-operation. The initial DBS leads of these patients were off target. In the cases from the literature, 30% off-drug motor improvement was seen in all three patients re-operated from GPi to STN and none of the three patients re-operated from STN to GPi. Only one of the three cases from the literature where any improvement was seen with the operation had a confirmed on target lead location after the first surgery, while the other two patients did not undergo post-operative imaging after the first surgery. Conclusions: Re-operation to a different target due to lack of effect appears to have a limited chance of leading to objective improvement if the leads were correctly placed during initial surgery.

Background: Given the world’s aging population, it is important to identify strategies that promote healthy cognitive aging and minimize cognitive decline. Currently, no curative pharmaceutical therapy exists for cognitive impairment and dementia. As a result, there is much interest in lifestyle approaches. Specifically, complex mental activity, such as cognitive training, may be a promising method to combat cognitive decline in older adults. As such, the industry of commercial computerized cognitive training (CCT) applications has rapidly grown in the last decade. However, the efficacy of these commercial products is largely not established. Moreover, exercise is a recognized strategy for promoting cognitive outcomes in older adults and may augment the efficacy of computerized cognitive training applications. Therefore, we propose a proof-of-concept randomized controlled trial (RCT) to examine the effect of a commercial CCT program in community-dwelling older adults. Methods: An 8-week RCT to examine the effect of a commercial CCT program, alone and preceded by a 15-min brisk walk, on cognitive function and explore the underlying neural mechanisms in adults aged 65–85 years old. Participants will be randomized to one of three intervention groups: 1) Computerized cognitive training (FBT); 2) A 15-min brisk walk followed by computerized cognitive training (Ex-FBT); or 3) A combination of educational classes, sham cognitive training, and balanced and tone exercises (active control, BAT). Participants in all intervention groups will attend three one-hour classes per week over the course of the intervention. Participants will be assessed at baseline, trial completion, and 1-year post study completion (1-year follow-up). Discussion: If results from this study show benefits for cognition at trial completion, CCT programs, alone or in combination with walking, might be a strategy to promote healthy cognitive aging in older adults. In addition, results from the 1-year follow-up measurement could provide important information regarding the long-term benefits of these CCT programs. Trial registration ClinicalTrials.gov Protocol Registration System: NCT02564809; registered September 1, 2015.

In het tertiair onderwijs is de kwaliteit van inferieure beoordelingen een probleem dat ernstige gevolgen heeft voor studenten, leraren, de overheid en de samenleving. Het ontbreken van een duidelijke en overkoepelende conceptualisering van de kwaliteit van de beoordeling kan problemen veroorzaken bij het garanderen van de beoordelingskwaliteit. Het doel van deze studie is om de beoordelingskwaliteit in het tertiair onderwijs te conceptualiseren door een overzicht te geven van de kwaliteitscriteria voor de beoordeling, hun invloeden, de evaluatie van de beoordelingskwaliteitscriteria en de perspectieven waarmee rekening moet worden gehouden bij de beoordeling van de beoordelingskwaliteit. Deze studie verzamelde 78 peer-reviewed tijdschriftartikelen in een kader met behulp van MAXQDA en een tekstanalyse werd uitgevoerd met Leximancer. De resultaten wezen op validiteit, transparantie en betrouwbaarheid als beoordelingskwaliteitscriteria; standaardisatie, belanghebbenden, duidelijkheid, en construeren irrelevante variantie als invloeden op de beoordelingskwaliteitscriteria; validatie en statistische gegevensanalyses om de evaluatiekwaliteit te evalueren; en studenten, personeel, overheid en experts als perspectieven waarmee rekening moet worden gehouden bij het evalueren van de beoordelingskwaliteit. Deze inzichten zijn belangrijk voor docenten, educatieve adviseurs en managers die deze informatie kunnen gebruiken om te bepalen welke beoordelingskwaliteit voor hun onderwijsorganisatie is en waar ze rekening mee moeten houden bij het garanderen van de beoordelingskwaliteit. Bovendien geeft het onderzoek onderzoekers inzicht in de huidige stand van zaken van wetenschappelijk bewijs.

Asthma and COPD are prevalent chronic inflammatory airway diseases that are responsible for a large global disease burden. Both diseases are complex and heterogeneous, and they are increasingly recognized as overlapping syndromes that may share similar pathophysiologic mechanisms and treatable traits. Eosinophilic airway inflammation is considered the most influential treatable trait of chronic airway disease, and over the last decade, several monoclonal antibodies and small molecule therapies have been developed to target this trait. These include monoclonal antibodies against IL-5 or IL-5 receptor alpha (mepolizumab, reslizumab, and benralizumab), IL-13 (lebrikizumab and tralokinumab), IL-4 receptor alpha (dupilumab), IgE (omalizumab), and anti-thymic stromal lymphopoietin (tezepelumab) and small molecule therapies such as prostaglandin D2 blockers (fevipiprant and timapiprant). Although these novel biologic agents have shown promising results in many patients with asthma and COPD who have eosinophilic airway inflammation, it is evident that not all patients respond equally well, despite similar clinical, functional, and inflammatory characteristics. This heterogeneity in treatment response is probably related to different molecular pathways or endotypes leading to eosinophilic airway inflammation, including adaptive immune pathways mediated by T helper 2 cells and innate immune pathways mediated by innate lymphoid cells. The relative contribution of these pathways in asthma and COPD is not yet clarified, and there are currently no reliable biomarkers that represent the various pathways. Therefore, there is an urgent need for easily measurable and reproducible biomarkers that are linked to underlying pathophysiologic disease mechanisms and can predict and monitor responses to novel biologic agents.

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Hemophilia A is a bleeding disorder characterized by the absence or dysfunction of blood coagulation factor VIII (FVIII). Patients are treated with regular infusions of FVIII concentrate. In response to treatment, approximately 30% of patients with severe hemophilia A develop inhibitory antibodies targeting FVIII. Both patient and treatment related risk factors for inhibitor development have been described. Multiple studies comparing the immunogenicity of recombinant and plasma-derived FVIII have yielded conflicting results. The randomized controlled SIPPET (Survey of Inhibitors in Plasma-Product Exposed Toddlers) trial demonstrated an increased risk of inhibitor development of recombinant FVIII when compared to von Willebrand factor (VWF)-containing plasma-derived FVIII. Presently, it is unclear which mechanism underlies the reduced immunogenicity of plasma-derived FVIII. In this review we address the potential role of VWF on FVIII immunogenicity and we discuss how VWF affects the immune recognition, processing and presentation of FVIII. We also briefly discuss the potential impact of glycan-composition on FVIII immunogenicity. It is well established that VWF shields the uptake of FVIII by antigen presenting cells. We have recently shown that VWF binds to the surface of dendritic cells. Here, we present a novel model in which surface bound FVIII-VWF complexes regulate the internalization of FVIII. Binding of FVIII to VWF is critically dependent on sulfation of Tyr1699 (HVGS numbering) in the light chain of FVIII. Incomplete sulfation of Tyr1699 has been suggested to occur in several recombinant FVIII products resulting in a loss of VWF binding. We hypothesize that this results in alternative pathways of FVIII internalization by antigen presenting cells which are not regulated by VWF. This hypothetical mechanism may explain the reduced immunogenicity of VWF containing plasma-derived FVIII concentrates as found in the SIPPET study.

Purpose This study compared the utility of different statistical methods in differentiating sexual crimes committed by the same person from sexual crimes committed by different persons. Methods Logistic regression, iterative classification tree (ICT), and Bayesian analysis were applied to a dataset of 3,364 solved, unsolved, serial, and apparent one-off sexual assaults committed in five countries. Receiver Operating Characteristic analysis was used to compare the statistical approaches. Results All approaches achieved statistically significant levels of discrimination accuracy. Two out of three Bayesian methods achieved a statistically higher level of accuracy (Areas Under the Curve [AUC] = 0.89 [Bayesian coding method 1]; AUC = 0.91 [Bayesian coding method 3]) than ICT analysis (AUC = 0.88), logistic regression (AUC = 0.87), and Bayesian coding method 2 (AUC = 0.86). Conclusions The ability to capture/utilize between-offender differences in behavioral consistency appear to be of benefit when linking sexual offenses. Statistical approaches that utilize individual offender behaviors when generating crime linkage predictions may be preferable to approaches that rely on a single summary score of behavioral similarity. Crime linkage decision-support tools should incorporate a range of statistical methods and future research must compare these methods in terms of accuracy, usability, and suitability for practice.

Background and purpose - Radiostereometric analysis (RSA) is an accurate method for measurement of early migration of implants. Since a relation has been shown between early migration and future loosening of total knee and hip prostheses, RSA plays an important role in the development and evaluation of prostheses. However, there have been few RSA studies of the upper limb, and the value of RSA of the upper limb is not yet clear. We therefore performed a systematic review to investigate the accuracy and precision of RSA of the upper limb. Patients and methods - PRISMA guidelines were followed and the protocol for this review was published online at PROSPERO under registration number CRD42016042014. A systematic search of the literature was performed in the databases Embase, Medline, Cochrane, Web of Science, Scopus, Cinahl, and Google Scholar on April 25, 2015 based on the keywords radiostereometric analysis, shoulder prosthesis, elbow prosthesis, wrist prosthesis, trapeziometacarpal joint prosthesis, humerus, ulna, radius, carpus. Articles concerning RSA for the analysis of early migration of prostheses of the upper limb were included. Quality assessment was performed using the MINORS score, Downs and Black checklist, and the ISO RSA Results - 23 studies were included. Precision values were in the 0.06-0.88 mm and 0.05-10.7° range for the shoulder, the 0.05-0.34 mm and 0.16-0.76° range for the elbow, and the 0.16-1.83 mm and 11-124° range for the TMC joint. Accuracy data from marker- and model-based RSA were not reported in the studies included. Interpretation - RSA is a highly precise method for measurement of early migration of orthopedic implants in the upper limb. However, the precision of rotation measurement is poor in some components. Challenges with RSA in the upper limb include the symmetrical shape of prostheses and the limited size of surrounding bone, leading to over-projection of the markers by the prosthesis. We recommend higher adherence to RSA guidelines and encourage investigators to publish long-term follow-up RSA studies.

The Dutch National Risk Assessment (NRA) is a methodology to assess the impact and likelihood of all possible threats and hazards that might hit the Netherlands, including a large-scale flood. This methodology addresses all the physical and social aspects that determine social disruption. The NRA has been applied to six European floods in Central and Western Europe. The results show that the NRA impact score for a flooding scenario can be interpreted as a measure for social disruption. Some comments can be made, however. The all hazards approach of the NRA is designed as a robust instrument that enables covering a wide array of threats and disasters. As a result, the NRA in its ‘original’ form offers little room for detailed differences in the consequences of different flooding scenarios. Tailor-made adjustments to the NRA are needed to insure that, for instance, differences in the number of casualties for different floods do not get lost in the bandwidth of the impact criteria. Socio-psychological factors significantly mark the impact of flooding. This offers opportunities to steer on avoiding or restricting social disruption by flooding by putting an adequate flood risk and crisis communication in place. The floods in Central Europe in 2002 and 2013 more or less present the lower and upper bounds of the impacts of recent large-scale river floods in Central and Western Europe. Compared with this bandwidth, the impact of a scenario of a worst-case river flood in the Netherlands is not unusual in a European context.

Laparoscopic surgery is associated with a shallow learning curve. AnubiFiX embalming technique enables laparoscopic surgical training on supple embalmed and hence insufflatable human specimens in the dissection room. Aim of the present trial is to test whether dissection-based anatomy education is superior to classical frontal classroom education on the short and long term. A total of 112 medical students were randomized in three groups. Group I attended classroom education, group II laparoscopic dissection-based education and group III received both. All groups completed an anatomy test on human specimens before, immediately after and 3 weeks after the anatomy training. Group II and III scored significantly better compared to group I immediately after the anatomy training (p I–II

Background: Asthma and bronchiectasis are 2 heterogeneous diseases that frequently coexist, particularly in severe asthma. Recognition of this co-diagnosis may importantly affect treatment decisions and outcome. Previous studies in asthma with bronchiectasis show inconsistent outcomes, probably due to the heterogeneity of the included asthma cohorts. Objectives: We hypothesized that bronchiectasis contributes to asthma severity and that patients with severe asthma and bronchiectasis present with distinct characteristics resulting in different treatable traits. In addition, we explored whether bronchiectasis in severe asthma is more common in a specific phenotype. Methods: This is a single-center study consecutively including patients with severe asthma from a tertiary referral center. Severe asthma was diagnosed according to the ATS/ERS guidelines. Asthma and infectious exacerbations were defined by the attending specialist as respiratory symptoms requiring treatment with systemic steroids or antibiotics, respectively. Two independent blinded radiologists evaluated each CT. Results: 19% of patients with severe asthma showed bronchiectasis on CT. Patients with bronchiectasis had a lower FEV1% predicted (p = 0.02) and FEV1/FVC (p = 0.004) and more infectious exacerbations (p = 0.003) compared to patients without bronchiectasis. Bronchiectasis is more common in patients with a longer duration of asthma, sensitization to A. fumigatus or a positive sputum culture. Sputum cultures of patients with severe asthma and bronchiectasis revealed more P. aeruginosa, S. maltophilia, H. parainfluenzae, and A. fumigates compared to the non-bronchiectasis group. The adult-onset, eosinophilic asthma phenotype showed the highest prevalence of bronchiectasis (29.4%). Conclusions: Patients with severe asthma and coexisting bronchiectasis were found to represent a distinct group, in terms of disease severity, microbiology, and asthma phenotype. Performing (HR)CT and sputum cultures can help to identify these patients. These results can possibly contribute to early recognition and targeted treatment of this patient group.

OBJECTIVE: Natalizumab is effective in treating relapsing-remitting multiple sclerosis (RRMS). However, many patients report an increase of multiple sclerosis symptoms at the end of the natalizumab cycle: a wearing-off effect. The objective of this study was to evaluate the prevalence of the wearing-off effect in patients with standard and extended intervals and to study possible associations with pharmacokinetic/dynamic measurements and patient characteristics in a prospective, monocenter, cross-sectional cohort study.METHODS: Patients with RRMS, with a minimum of 6 natalizumab infusions, were asked to complete 3 questionnaires: the Multiple Sclerosis Impact Scale, the 36-Item Short Form Health Survey, and a general questionnaire regarding the wearing-off effect. Natalizumab concentration and α4-integrin receptor saturation were measured before redosing.RESULTS: Ninety-three patients were included. A total of 54% experienced a wearing-off effect during natalizumab treatment and 32% experienced a current wearing-off effect at time of measurement. The self-reported wearing-off effect was not associated with natalizumab concentration nor with α4-integrin receptor saturation. The wearing-off effect was more frequently reported in the standard interval group (39%) than in the extended interval group (19%); the duration of symptoms was comparable between both groups. The wearing-off effect was not associated with number of infusions, disease duration, age, or sex.CONCLUSION: The wearing-off effect is a frequently reported phenomenon but is unlikely to reflect a nonoptimal pharmacokinetic/dynamic state. We did not find risk factors predicting the wearing-off effect.

Background: Mepolizumab treatment improves asthma outcomes in the majority but not all patients with severe eosinophilic asthma. Baseline patient characteristics may influence mepolizumab induced outcomes, but it is difficult to assess individuals’ chance of being a responder. Assessment of early treatment response may add in the prediction of long-term benefit. Aim: To examine the relationship between mepolizumab induced asthma control at 8 weeks and the chance of being mepolizumab responder at 32 weeks. Methods: 20 severe asthma patients that started with mepolizumab were evaluated on baseline and 8, 16 and 32 weeks. We compared therapy response, defined as continuing mepolizumab therapy at 32 weeks, in patients with and without good asthma control (ACQ≤0.75) at 8 weeks. Results: Of the 20 included patients (median age 52 years (range 28-76), 50% male, 70% OCS dependent), 16 patients (80%) continued mepolizumab therapy at 32 weeks after initiation (responders). Median ACQ decreased from 2.42 (0.67–4.33) at baseline to 0.75 (0.0-3.33) after 8 weeks of therapy (p 0.75 at 8 weeks(negative predictive value=40%)(RR 1.7, 95%CI 1.005-2.765; P=0.043). Conclusions: Patients who show good asthma control at 8 weeks of mepolizumab treatment have a very high chance of therapy response at 32 weeks. These data suggest that early treatment responses may be helpful to identify patients that benefit from biologicals in the long-term.

Background: Clinical trials investigating mepolizumab for eosinophilic severe asthma patients employed strict eligibility criteria. Nonetheless, patients not meeting these criteria are treated with mepolizumab in clinical practice. Aim: To investigate the extent and reasons for trial ineligibility of real-life, mepolizumab-treated severe asthma patients. To compare characteristics of these patients with trial populations. Methods: Trial criteria and patient characteristics of the SIRIUS, DREAM and MENSA trials were extracted. Baseline characteristics from mepolizumab-treated, oral glucocorticoid-dependent severe asthma patients were studied in RAPSODI (the Dutch severe asthma registry). Results: 7 of 70 mepolizumab-treated patients (10%) from RAPSODI fulfil the trial criteria, whereas 34 (48.6%) and 29 (41.4%) patients are ineligible on the basis of exclusion and inclusion criteria, respectively. Predominant deviations from criteria are summarised in table 1. Significant differences exist in age (56.5 vs 50.1 years), gender (41.4% vs 57.1% females) and FEV1 (2.49 vs 1.82 L) between the real-life and MENSA trial populations. Conclusion: Only a small part of mepolizumab-treated patients in clinical practice fulfils trial criteria and significant differences in patient characteristics exist between trial and real-life severe asthma populations, indicating limited representativeness. The RAPSODI registry was financially supported by GSK and Novartis.