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Background: cystic fibrosis (CF) is a life-threatening genetic disease, affecting around 10 500 people in the UK. Precision medicines have been developed to treat specific CF-gene mutations. The newest, elexacaftor/tezacaftor/ivacaftor (ELEX/TEZ/IVA), has been found to be highly effective in randomised controlled trials (RCTs) and became available to a large proportion of UK CF patients in 2020. Understanding the potential health economic impacts of ELEX/TEZ/IVA is vital to planning service provision.Methods: we combined observational UK CF Registry data with RCT results to project the impact of ELEX/TEZ/IVA on total days of intravenous (IV) antibiotic treatment at a population level. Registry data from 2015 to 2017 were used to develop prediction models for IV days over a 1-year period using several predictors, and to estimate 1-year population total IV days based on standards of care pre-ELEX/TEZ/IVA. We considered two approaches to imposing the impact of ELEX/TEZ/IVA on projected outcomes using effect estimates from RCTs: approach 1 based on effect estimates on FEV1% and approach 2 based on effect estimates on exacerbation rate.Results: ELEX/TEZ/IVA is expected to result in significant reductions in population-level requirements for IV antibiotics of 16.1% (~17 800 days) using approach 1 and 43.6% (~39 500 days) using approach 2. The two approaches require different assumptions. Increased understanding of the mechanisms through which ELEX/TEZ/IVA acts on these outcomes would enable further refinements to our projections.Conclusions: this work contributes to increased understanding of the changing healthcare needs of people with CF and illustrates how Registry data can be used in combination with RCT evidence to estimate population-level treatment impacts.

Objective: Conventional inhaler devices have a low efficacy in targeting small airways. Smart nebulizers can be used to increase deposition to small airways by adjusting the flow and depth of each inhalation based on patients ‘individual inspiratory capacity. We investigated whether targeting of high dose inhaled corticosteroids (ICS) to small airways with a smart nebulizer could reduce exacerbation rate in children with severe asthma (SA). Methods: We conducted a retrospective study in children with SA using a smart nebulizer (Akita® Jet nebulizer) for the administration of high dose ICS in our outpatient clinic at the Erasmus MC — Sophia Children’s Hospital. Clinical data before and after start of treatment were collected. The primary outcome was exacerbation rate, defined as: number of asthma exacerbations for which oral corticosteroid courses (OCS) were prescribed. The exacerbation rate 1 year before treatment was compared with the exacerbation rate 1 year after start of treatment. Secondary outcomes were changes in spirometry parameters, hospital admissions and medication use. Results: Data on OCS use was available for 28/31 patients. Median number of asthma exacerbations requiring OCS courses 1 year before decreased from 2 (interquartile range(IQR) 2) to 0.5 (IQR 3) 1 year after treatment (p = 0.021). Hospital admission decreased from 1 (IQR 3) to 0 (IQR 1)(p = 0.028). FEV1, FEF25-75 and FEF75 were not significantly improved after one year of treatment with the smart nebulizer (p = 0.191; p = 0.248; p = 0.572). Conclusion: Targeting small airways with high dose ICS using a smart nebulizer resulted in a significant reduction in exacerbations requiring OCS after one year of treatment.

Background: Return to work is potentially an important factor in assessing the success of treatment. However, little is known about the return to work after treatment for Dupuytren's contracture. Therefore, the primary aim of this study was to assess return to work after limited fasciectomy and percutaneous needle fasciotomy. Methods: Patients who underwent either a limited fasciectomy or percutaneous needle fasciotomy were invited to complete a return-To-work questionnaire at 6 weeks, 3 months, 6 months, and 12 months postoperatively. Median time to return to work was assessed using inverted Kaplan-Meier curves, and hazard ratios were calculated with Cox regression models. Finally, a cost analysis was carried out using the human capital method to determine indirect costs associated with loss of productivity. Results: The authors included 2698 patients in the study, of which 53 percent were employed at intake and included in the follow-up. After 1 year of follow-up, 90 percent of the patients had returned to work. Median time to return to work was 2 weeks after limited fasciectomy and within days after percutaneous needle fasciotomy. Furthermore, physically strenuous work, female sex, and higher age were associated with a longer time to return to work. Lost productivity per patient was estimated at €2614.43. Conclusions: The majority of patients returned to work after treatment for Dupuytren's disease. Return to work is much faster after percutaneous needle fasciotomy compared to limited fasciectomy. These findings can be used for more evidence-based preoperative counseling with patients with Dupuytren's disease.

Introduction: Osteoarthritis (OA) affects millions of people worldwide. In hand OA, the thumb base is the most affected single joint. The reported radiographic prevalence ranges from 0 to 100%, making the true radiographic prevalence unclear. Hence, we conducted a meta-analysis on the age and sex-specific prevalence of radiographic thumb base OA. Methods: We performed a search in Embase, Medline Ovid, Web of Science Core Collection, Cochrane Central Register of Trials, and Google Scholar. We included studies of the general population that reported thumb base OA for males and females separately based on a hand radiograph and reported the age of these groups. Using meta-regression, we estimated the odds ratio (OR) of having radiographic thumb base OA for age and sex, while adjusting for within-study correlation. Results: The initial search yielded 4,278 articles; we finally included 16 studies that reported the age- and sex-stratified prevalence. Taken together, there were 104 age and gender specific-prevalence rates that could be derived from the 16 studies. The prevalence of radiographic OA for the 50-year-old male and female participants was 5.8% and 7.3%, respectively, while the respective prevalence for 80-year-old male and female participants was 33.1% and 39.0%. We found an OR for having radiographic OA of 1.06 (95%CI [1.055–1.065], p < 0.001) per increasing year of age, and 1.30 (95%CI: 1.05–1.61], p = 0.014) for females. Conclusion: In the general population, radiographic thumb base OA is more prevalent in females and is strongly associated with age.

Neurophysiologic correlates of motor learning that can be monitored during neurorehabilitation interventions can facilitate the development of more effective learning methods. Previous studies have focused on the role of the beta band (14–30 Hz) because of its clear response during motor activity. However, it is difficult to discriminate between beta activity related to learning a movement and performing the movement. In this study, we analysed differences in the electroencephalography (EEG) power spectra of complex and simple explicit sequential motor tasks in healthy young subjects. The complex motor task (CMT) allowed EEG measurement related to motor learning. In contrast, the simple motor task (SMT) made it possible to control for EEG activity associated with performing the movement without significant motor learning. Source reconstruction of the EEG revealed task-related activity from 5 clusters covering both primary motor cortices (M1) and 3 clusters localised to different parts of the cingulate cortex (CC). We found no association between M1 beta power and learning, but the CMT produced stronger bilateral beta suppression compared to the SMT. However, there was a positive association between contralateral M1 theta (5–8 Hz) and alpha (8–12 Hz) power and motor learning, and theta and alpha power in the posterior mid-CC and posterior CC were positively associated with greater motor learning. These findings suggest that the theta and alpha bands are more related to motor learning than the beta band, which might merely relate to the level of perceived difficulty during learning.

Objective: Spontaneous recovery is an important determinant of upper extremity recovery after stroke and has been described by the 70% proportional recovery rule for the Fugl–Meyer motor upper extremity (FM-UE) scale. However, this rule is criticized for overestimating the predictability of FM-UE recovery. Our objectives were to develop a longitudinal mixture model of FM-UE recovery, identify FM-UE recovery subgroups, and internally validate the model predictions. Methods: We developed an exponential recovery function with the following parameters: subgroup assignment probability, proportional recovery coefficient r k, time constant in weeks τ k, and distribution of the initial FM-UE scores. We fitted the model to FM-UE measurements of 412 first-ever ischemic stroke patients and cross-validated endpoint predictions and FM-UE recovery cluster assignment. Results: The model distinguished 5 subgroups with different recovery parameters (r 1 = 0.09, τ 1 = 5.3, r 2 = 0.46, τ 2 = 10.1, r 3 = 0.86, τ 3 = 9.8, r 4 = 0.89, τ 4 = 2.7, r 5 = 0.93, τ 5 = 1.2). Endpoint FM-UE was predicted with a median absolute error of 4.8 (interquartile range [IQR] = 1.3–12.8) at 1 week poststroke and 4.2 (IQR = 1.3–9.8) at 2 weeks. Overall accuracy of assignment to the poor (subgroup 1), moderate (subgroups 2 and 3), and good (subgroups 4 and 5) FM-UE recovery clusters was 0.79 (95% equal-tailed interval [ETI] = 0.78–0.80) at 1 week poststroke and 0.81 (95% ETI = 0.80–0.82) at 2 weeks. Interpretation: FM-UE recovery reflects different subgroups, each with its own recovery profile. Cross-validation indicates that FM-UE endpoints and FM-UE recovery clusters can be well predicted. Results will contribute to the understanding of upper limb recovery patterns in the first 6 months after stroke. ANN NEUROL 2020;87:383–393 Ann Neurol 2020;87:383–393.

Airway wall thickening and mucus plugging are important characteristics of cystic fibrosis (CF) lung disease in the first 5 years of life.The aim of this study is to investigate the association of lung disease in preschool children (age, 2‐6) with bronchiectasis and other clinical outcome measures in the school age (age >7). Deidentified computed tomography‐scans were annotated using Perth‐Rotterdam annotated grid morphometric analysis for CF. Preschool %disease (a composite score of %airway wall thickening, %mucus plugging, and %bronchiectasis) and %MUPAT (a composite score of %airway wall thickening and %mucus plugging) were used as predictors for %bronchiectasis and several other school‐age clinical outcomes. For statistical analysis, we used regression analysis, linear mixed‐effects models and two‐way mixed models. Sixty‐one patients were included. %Disease increased significantly with age (P .05). Cross‐sectional, %disease in school‐age was associated with a low FEV1% predicted and low quality of life (P = .01 and P = .007, respectively). %Disease can be considered an early marker of diffuse airways disease and is a risk factor for school‐age bronchiectasis.

IntroductionTwo-stage implant-based breast reconstruction is the most commonly performed postmastectomy reconstructive technique. During the first stage, a tissue expander creates a sufficiently large pocket for the definite breast implant placed in the second stage. Capsular contracture is a common long-term complication associated with implant-based breast reconstruction, causing functional complaints and often requiring reoperation. The exact aetiology is still unknown, but a relationship between the outer surface of the implant and the probability of developing capsular contracture has been suggested. The purpose of this study is to determine whether polyurethane-covered implants result in a different capsular contracture rate than textured implants.Methods and analysisThe Textured Implants versus Polyurethane-covered Implants (TIPI) trial is a multicentre randomised controlled trial with a 1:1 allocation rate and a follow-up of 10 years. A total of 321 breasts of female adults undergoing a two-stage breast reconstruction will be enrolled. The primary outcome is capsular contracture at 10-year follow-up which is graded with the modified Baker classification. It is analysed with survival analysis using a frailty model for clustered interval-censored data, with both an intention-to-treat and per-protocol approach. Secondary outcomes are other complication rates, surgical revision rate, patient satisfaction and quality of life and user-friendliness. Outcomes are measured 2 weeks, 6 months, 1, 2, 3, 5 and 10 years postoperatively. Interim analysis is performed when 1-year, 3-year and 5-year follow-up is completed.Ethics and disseminationThe trial has been reviewed and approved by the Medical Research Ethics Committee of the Erasmus MC, University Medical Centre Rotterdam (MEC-2018-126) and locally by each participating centre. Written informed consent will be obtained from each study participant. The results will be disseminated by publication in peer-reviewed journals.Trial registrationNTR7265.

Background: Environmental exposures and community characteristics (i.e. geomarkers) have been shown to influence pulmonary outcomes; however, the ability for geomarkers to predict rapid lung-functi...

Background Pompe disease is a rare, progressive metabolic myopathy. The aim of this study is to investigate the associations of physical outcomes with patient-reported outcome measures (PROMs) in late-onset Pompe disease. Methods We included 121 Dutch adult patients with Pompe disease. Physical outcomes comprised muscle strength (manual muscle testing using Medical Research Council [MRC] grading, hand-held dynamometry [HHD]), walking ability (6-min walk test [6MWT]), and pulmonary function (forced vital capacity [FVC] in upright and supine positions). PROMs comprised quality of life (Short Form 36 health survey [SF-36]), participation (Rotterdam Handicap Scale [RHS]) and daily-life activities (Rasch-Built Pompe-Specific Activity [R-PAct] Scale). Analyses were cross-sectional: the time-point before, and closest to, start of Enzyme Replacement Therapy was chosen. Associations between PROMs and physical outcomes were investigated using linear regression models. Results RHS and R-PAct scores were better in patients with higher FVC supine and upright, HHD, MRC and 6MWT scores, accounting for the effect of sex, disease duration, use of wheelchair and ventilator support. While the SF-36 Physical Component Summary (PCS) was correlated positively with FVC upright, HHD, MRC and 6MWT scores, there was no significant relationship between the SF-36 Mental Component Summary (MCS) and any of the physical outcomes. Conclusions Participation, daily-life activities, and the physical component of quality of life of adult Pompe patients are positively correlated to physical outcomes. This work serves as a first step towards assessing how changes over time in physical outcomes are related to changes in PROMs, and to define the minimal change in physical outcomes required to make an important difference for the patient.

Objective: To investigate how satisfaction with treatment outcome is associated with patient mindset and Michigan Hand Outcome Questionnaire (MHQ) scores at baseline and 3 months in patients receiving nonoperative treatment for first carpometacarpal joint (CMC-1) osteoarthritis (OA). Design: Cohort study Setting: A total of 20 outpatient locations of a clinic for hand surgery and hand therapy in the Netherlands. Participants: Patients (N=308) receiving nonoperative treatment for CMC-1 OA, including exercise therapy, an orthosis, or both, between September 2017 and February 2019. Interventions: Nonoperative treatment (ie, exercise therapy, an orthosis, or both) Main Outcome Measures: Satisfaction with treatment outcomes was measured after 3 months of treatment. We measured total MHQ score at baseline and at 3 months. As baseline mindset factors, patients completed questionnaires on treatment outcome expectations, illness perceptions, pain catastrophizing, and psychological distress. We used multivariable logistic regression analysis and mediation analysis to identify factors associated with satisfaction with treatment outcomes. Results: More positive pretreatment outcome expectations were associated with a higher probability of being satisfied with treatment outcomes at 3 months (odds ratio, 1.15; 95% confidence interval, 1.07-1.25). Only a relatively small part (33%) of this association was because of a higher total MHQ score at 3 months. None of the other mindset and hand function variables at baseline were associated with satisfaction with treatment outcomes. Conclusions: This study demonstrates that patients with higher pretreatment outcome expectations are more likely to be satisfied with treatment outcomes after 3 months of nonoperative treatment for CMC-1 OA. This association could only partially be explained by a better functional outcome at 3 months for patients who were satisfied. Health care providers treating patients nonoperatively for CMC-1 OA should be aware of the importance of expectations and may take this into account in pretreatment counseling.

Background Attenuated decreases in lung function can signal the onset of acute respiratory events known as pulmonary exacerbations (PEs) in children and adolescents with cystic fibrosis (CF). Univariate joint modeling facilitates dynamic risk prediction of PE onset and accounts for measurement error of the lung function marker. However, CF is a multi-system disease and the extent to which simultaneously modeling growth and nutrition markers improves PE predictive accuracy is unknown. Furthermore, it is unclear which routinely collected clinical indicators of growth and nutrition in early life predict PE onset in CF. Methods Using a longitudinal cohort of 17,100 patients aged 6–20 years (US Cystic Fibrosis Foundation Patient Registry; 2003–2015), we fit a univariate joint model of lung-function decline and PE onset and contrasted its predictive performance with a class of multivariate joint models that included combinations of growth markers as additional submodels. Outcomes were longitudinal lung function (forced expiratory volume in 1 s of % predicted), percentiles of body mass index, weight-for-age and height-for-age and PE onset. Relevant demographic/clinical covariates were included in submodels. We implemented a univariate joint model of lung function and time-to-PE and four multivariate joint models including growth outcomes. Results All five joint models showed that declining lung function corresponded to slightly increased risk of PE onset (hazard ratio from univariate joint model: 0.97, P 0.70). None of the growth markers alongside lung function as outcomes in multivariate joint modeling appeared to have an association with hazard of PE. Jointly modeling only lung function and PE onset yielded the most accurate (area under the receiver-operator characteristic curve = 0.75) and precise (narrowest interquartile range) predictions. Dynamic predictions were accurate across forecast horizons (0.5, 1 and 2 years) and precision improved with age. Conclusions Including growth markers via multivariate joint models did not yield gains in prediction performance, compared to a univariate joint model with lung function. Individualized dynamic predictions from joint modeling could enhance physician monitoring of CF disease progression by providing PE risk assessment over a patient’s clinical course.

Background. Multidisciplinary intervention programs for overweight and obese children mainly focus on reducing bodyweight and body mass index (BMI), but they may also positively impact blood pressure (BP), and cardiorespiratory fitness (CRF), which is a stronger predictor for all-cause mortality than BMI. Objective. To evaluate whether Kids4Fit, a multidisciplinary weight reduction program, has a positive effect on CRF and BP in overweight and obese children in socially deprived areas. Methods. A quasi-experimental study design with a waiting list control period including children who participated in a multidisciplinary intervention program of 12 weeks was set-up. Blood pressure measurements and shuttle-run test (SRT) were performed at baseline, at the start of the intervention, at the end of intervention and after 52 weeks. The effect of Kids4Fit on BP and on SRT scores were analyzed using mixed models. Results. A total of 154 children were included [mean age 8.5 years (SD 1.8)]. No significant change was seen in systolic BP percentiles at 52 weeks after start of the Kids4Fit intervention (β 0.08, (95%CI −0.06, 0.22)). Diastolic BP percentiles increased significantly over time (β 0.20 (0.08, 0.31)). Effect plots showed an initial significant increase of the SRT scores but this effect diluted after the intervention. Conclusion. A local multidisciplinary intervention program in deprived areas had a significant positive effect on CRF, but this effect diluted after the intervention. Diastolic BP percentiles significantly increased over time. However, systolic BP did not change over time.

Background Invasive pulmonary aspergillosis typically occurs in an immunocompromised host. For almost a century, influenza has been known to set up for bacterial superinfections, but recently patients with severe influenza were also reported to develop invasive pulmonary aspergillosis. We aimed to measure the incidence of invasive pulmonary aspergillosis over several seasons in patients with influenza pneumonia in the intensive care unit (ICU) and to assess whether influenza was an independent risk factor for invasive pulmonary aspergillosis. Methods We did a retrospective multicentre cohort study. Data were collected from adult patients with severe influenza admitted to seven ICUs across Belgium and The Netherlands during seven influenza seasons. Patients were older than 18 years, were admitted to the ICU for more than 24 h with acute respiratory failure, had pulmonary infiltrates on imaging, and a confirmed influenza infection based on a positive airway PCR test (influenza cohort). We used logistic regression analyses to determine if influenza was independently associated with invasive pulmonary aspergillosis in non-immunocompromised (ie, no European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group [EORTC/MSG] host factor) influenza-positive patients (influenza case group) compared with nonimmunocompromised patients with severe community-acquired pneumonia who had a negative airway influenza PCR test (control group). Findings Data were collected from patients admitted to the ICU between Jan 1, 2009, and June 30, 2016. Invasive pulmonary aspergillosis was diagnosed in 83 (19%) of 432 patients admitted with influenza (influenza cohort), a median of 3 days after admission to the ICU. The incidence was similar for influenza A and B. For patients with influenza who were immunocompromised, incidence of invasive pulmonary aspergillosis was as high as 32% (38 of 117 patients), whereas in the non-immunocompromised influenza case group, incidence was 14% (45 of 315 patients). Conversely, only 16 (5%) of 315 patients in the control group developed invasive pulmonary aspergillosis. The 90-day mortality was 51% in patients in the influenza cohort with invasive pulmonary aspergillosis and 28% in the influenza cohort without invasive pulmonary aspergillosis (p=0.0001). In this study, influenza was found to be independently associated with invasive pulmonary aspergillosis (adjusted odds ratio 5.19; 95% CI 2.63-10.26; p

Mechanical ventilation is a common procedure of life support in intensive care. Patient-ventilator asynchronies (PVAs) occur when the timing of the ventilator cycle is not simultaneous with the timing of the patient respiratory cycle. The association between severity markers and the events death or alive discharge has been acknowledged before, however, little is known about the addition of PVAs data to the analyses. We used an index of asynchronies (AI) to measure PVAs and the SOFA (sequential organ failure assessment) score to assess overall severity. To investigate the added value of including the AI, we propose a Bayesian joint model of bivariate longitudinal and competing risks data. The longitudinal process includes a mixed effects model for the SOFA score and a mixed effects beta regression model for the AI. The survival process is defined in terms of a cause-specific hazards model for the competing risks death or alive discharge. Our model indicates that the SOFA score is strongly related to vital status. PVAs are positively associated with alive discharge but there is not enough evidence that PVAs provide a more accurate indication of death prognosis than the SOFA score alone.

A phase 3 randomized double blind controlled, trial in 238 people with cystic fibrosis (CF) and at least one nonsense mutation (nmCF) investigated the effect of ataluren on FEV1. The study was of 48 weeks duration and failed to meet its primary endpoint. Unexpectedly, while FEV1 declined, chest computed tomography (CT) scores using the Brody-II score as secondary outcome measures did not show progression in the placebo group. Based on this observation it was concluded that the role of CT scans in CF randomized clinical trials was limited. However, more sensitive scoring systems were developed over the last decade warranting a reanalysis of this unique dataset. The aim of our study was to reanalyse all chest CT scans, obtained in the ataluren phase 3 study, using 2 independent scoring systems to characterize structural lung disease in this cohort and to compare progression of structural lung disease over the 48 weeks between treatment arms. 391 study CT scans from 210 patients were reanalysed in random order by 2 independent observers using the CF-CT and Perth-Rotterdam Annotated Grid Morphometric Analysis for CF (PRAGMA-CF) scoring systems. CF-CT and PRAGMA-CF subscores were expressed as %maximal score and %total lung volume, respectively. PRAGMA-CF subscores %Disease (p = 0.008) and %Mucus Plugging (p = 0.029) progressed over 48 weeks. CF-CT subscores did not show progression. There was no difference in progression of structural lung disease between treatment arm and placebo independent of tobramycin use. PRAGMA-CF Chest CT scores can be used as an outcome measure to study the effect of potential disease modifying drugs in CF on lung structure.

Purpose: To associate the change in the foveal avascular zone (FAZ) and vessel density (VD) with final best corrected visual acuity (BCVA) in eyes after macula-off rhegmatogenous retinal detachment surgery, and to investigate the evolution of FAZ and VD during 12 months of follow-up. Methods: We prospectively evaluated 47 patients with macula-off rhegmatogenous retinal detachment and healthy fellow eyes. At 1.5, 3.0, 6.0, and 12.0 months postoperatively, optical coherence tomography angiography scans were obtained from both eyes on a 3.0 × 3.0 mm macula-centered grid. En face images of the superficial vascular plexus, intermediate capillary plexus and deep capillary plexus were used to quantify FAZ and VD. BCVA was assessed with ETDRS-charts (logarithm of the minimal angle of resolution). At 12 months postoperatively, the association between the change in optical coherence tomography angiography parameters and visual function in study eyes was evaluated using the Spearman correlation coefficient. We calculated the BCVA difference and the percentage difference of FAZ and VD between the study and control eye. The evolution of FAZ and VD was investigated with linear mixed-effects models with nested random effects (eyes nested within patients). Results: At 12 months postoperatively, FAZ difference of the deep capillary plexus and BCVA difference were correlated (P = 0.0004, rs = 0.5). Furthermore, there was no evidence that FAZ and VD changed during follow-up. Conclusions: Although FAZ and VD remained stable during 12 months after surgery for macula-off rhegmatogenous retinal detachment, a smaller FAZ in the deep capillary plexus is associated with better BCVA. Translational relevance: Reduction in FAZ area may be caused by angiogenesis to counteract ischemia, therefore therapeutic stimulation of angiogenesis could be beneficial to visual recovery.

__Background:__ Inhaled tobramycin is important in the treatment of Pseudomonas aeruginosa (Pa) infections in cystic fibrosis (CF). However, despite its use it fails to attenuate the clinical progression of CF lung disease. The bactericidal efficacy of tobramycin is known to be concentration-dependent and hence changing the dosing regimen from a twice-daily (q12h) inhalation to a once-daily (q24h) inhaled double dose could improve treatment outcomes. __Objectives:__ To predict local concentrations of nebulized tobramycin in the airways of patients with CF, delivered with the small airway-targeting AkitaVR system or standard PARI-LC® Plus system, with different inspiratory flow profiles. __Methods:__ Computational fluid dynamic (CFD) methods were applied to patient-specific airway models reconstructed from chest CT scans. The following q12h and q24h dosing regimens were evaluated: AkitaVR (150 and 300 mg) and PARI-LC® Plus (300 and 600 mg). Site-specific concentrations were calculated. __Results:__ Twelve CT scans from patients aged 12-17 years (median=15.7) were selected. Small airway concentrations were 762-2999 mg/L for the q12h dosing regimen and 1523-5997 mg/L for the q24h dosing regimen, well above the MIC for WT Pa strains. Importantly, the q24h regimen appeared to be more suitable than the q12h regimen against more resistant Pa strains and the inhibitory effects of sputum on tobramycin activity. __Conclusions:__ CFD modelling showed that high concentrations of inhaled tobramycin are indeed delivered to the airways, with the AkitaVR system being twice as efficient as the PARI-LC® system. Ultimately, the q24h dosing regimen appears more effective against subpopulations with high MICs (i.e. more resistant strains).

CF-CT and PRAGMA-CF are commonly used scoring methods to quantify the severity of bronchiectasis (BE) and airway wall thickening (AWT) on chest CTs of children with cystic fibrosis (CF). We aimed to validate CF-CT and PRAGMA-CF sub-scores for BE and AWT against quantitative airway–artery (AA) dimensions.This is a retrospective study with 23 spirometer guided inspiratory chest CTs (11 CF, 12 controls; age range 6 to 16 years old) included. AA-, and AWTA-ratios of all visible AA pairs were computed by dividing diameters of the outer airway and wall (outer-inner airway) by the accompanying artery diameter, respectively. BE, AWT and total airway disease (TAD) were scored using CF-CT (% max score) and PRAGMA-CF (% extent). Correlations were computed using Spearman rank. Akaike information criterion (AIC) from the mixed-effects models were used to investigate whether CF-CT or PRAGMA-CF was a better predictor for AA-, and AWTA-ratios (lower AIC equals a better fitted model).4861 AA pairs were measured in total. Correlations between CF-CT and PRAGMA-CF: BE (r = 0.93, P0.001); AWT (r = 0.62, P0.001); TAD (r = 0.88, P0.001). PRAGMA-CF TAD sub-score had lowest AIC in the mixed-model predicting AA-ratio. CF-CT AWT and PRAGMA-CF TAD sub-score had equal low AIC in the mixed-model predicting AWTA-ratio.PRAGMA-CF TAD sub-score was more precise predicting BE. CF-CT AWT and PRAGMA-CF TAD sub-scores predicted AWT equally well. CF-CT and PRAGMA-CF were both sensitive methods to score BE and AWT in children with CF lung disease, with PRAGMA-CT TAD sub-score being most accurate in predicting AA dimensions.

OBJECTIVE. Bronchoscopy and MDCT are routinely used to assess tracheobronchomalacia (TBM). Recently, dynamic MRI (cine MRI) has been proposed as a radiation-free alternative to MDCT. In this study, we tested cine MRI assessment of airway dynamics during various breathing conditions and compared cine MRI and MDCT measurements in healthy volunteers and patients with suspected TBM. CONCLUSION. Cine MRI was found to be a technically feasible alternative to MDCT for assessing central airway dynamics.

Background Cystic fibrosis (CF) caregivers focus on correct inhalation technique for nebulisers as this is essential to optimize efficacy of inhaled drugs. However, little is known on this nebuliser technique of patients at home. Methods Three "hidden" video registrations were made of 32 children with CF (6–18years) nebulising at home. Videos were randomly scored on inhalation technique items using nebuliser-specific checklists and a total score was calculated. Results Median nebuliser technique was 91.9% of max score. Nebuliser technique was perfect (score 100%) in 23.3% of the patients and incorrect (score 0%) in 13.3%. Most mistakes were made in the required optimal breathing pattern. Conclusion Most CF patients had good nebuliser technique on a day-to-day basis. However, errors observed likely resulted in reduced treatment efficacy and, in 13%, no treatment at all. Regular "real life" evaluation by the CF-team can improve inhaled therapy substantially.

Abacavir use has been associated with an increased risk of cardiovascular disease (CVD) and metabolic events in HIV-infected patients, although this finding was not consistently found. It is unclear whether abacavir only increases this risk in subpopulations of HIV-infected patients. It may be hypothesized that inosine 5'-triphosphate pyrophosphohydrolase (ITPase), an enzyme involved in the metabolism of purine analogues used in HIV treatment, plays a role in the risk of CVD and metabolic events in HIV-infected patients.ITPase activity and ITPA genotype were determined in 393 HIV-infected patients. ITPase activity4 mmol IMP/mmol Hb/h was considered decreased. ITPA polymorphisms tested were: c.94CA (rs1127354) and c.124 + 21AC (rs7270101). ORs were determined using generalized estimating equation models for developing CVD in patients who had ever been exposed to abacavir, tenofovir or didanosine and for developing metabolic events in patients currently using these drugs.In patients using abacavir, metabolic events were associated with ITPase activity. No association was demonstrated for tenofovir or didanosine. The OR for metabolic events was 3.11 in patients using abacavir with normal ITPase activity (95% CI 1.34-7.21; P = 0.008) compared with patients with decreased ITPase activity [adjusted for age, BMI, cumulative duration of combination ART (cART) use and the use of PI and NNRTI]. CVD was not associated with ITPase activity or ITPA genotype.This study shows, for the first time, that ITPase activity is associated with the occurrence of metabolic events in patients using abacavir. Further studies are needed to confirm this association and to elucidate the possible mechanism.

Purpose We determine the contrast-to-noise ratios (CNRs) of structural and functional measurements to assess their sensitivity to detect progression in the various stages of glaucoma. Methods We calculated the CNRs for the mean peripapillary retinal nerve fiber layer (RNFL) thickness measured by spectral domain optical coherence tomography, and the mean deviation (MD) and visual field index (VFI) determined by standard automated perimetry for the transitions between five stages. Longitudinal data from healthy and glaucomatous eyes from a prospective study were used. Contrast was defined as the change in the mean value of the parameter between two successive stages. Noise was defined as the variability of the parameter and calculated from the residuals of linear regression on the data from five subsequent visits per eye. Results We studied 205 eyes from 125 participants (46% men, 54% women). CNRs for different parameters varied considerably across the range of disease severity (0.8-12.2). The RNFL thickness had a higher CNR in the transition from normal to mild glaucoma (12.2) compared to the CNRs of the functional measures (MD 4.1, VFI 4.5). The CNRs for the functional measures were higher in the transition from moderate to advanced (MD 5.2, VFI 5.8) and advanced to severe glaucoma (MD 7.2, VFI 5.8) compared to the RNFL thickness (CNR 0.8 and 3.2, respectively). Conclusions The RNFL thickness is more sensitive for detecting glaucomatous progression at the onset of glaucoma compared to the functional measures, while the latter are more sensitive for detecting progression in the later stages of glaucoma. Translational relevance The CNR method can be used to determine which measurement is most sensitive for detecting progression in glaucoma, differentiated for the severity of the disease. Furthermore, it creates a basic toolset for determining the most sensitive measurement in detecting progression not only in glaucoma, but other (ophthalmic) diseases as well.

The purpose of this study was to acquire normative data on central airway dimensions on chest CT scans in the pediatric population.Chest CT findings reported as normal by a radiologist were collected retrospectively at 10 international centers. An experienced and independent thoracic radiologist reevaluated all CT scans for image quality and for normal findings. Semiautomated image analysis was performed to measure dimensions of the trachea and right and left main bronchi at inspiration. Intrathoracic tracheal length was measured from carina to thorax inlet. Cross-sectional area and short and long axes were measured perpendicular to the longitudinal airway axis starting from the carina every centimeter upward for the trachea and every 0.5 cm downward for the main bronchi. The effects on airway diameters of age, sex, intrathoracic tracheal length, and distance from the carina were investigated by use of mixed-effects models analysis.Among 1160 CT scans collected, 388 were evaluated as normal by the independent radiologist with sufficient image quality and adequate inspiratory volume level. Central airways were successfully semiautomatically analyzed in 294 of 388 CT studies. Age, sex, intrathoracic tracheal length, and distance from carina were all significant predictors in the models for tracheal and right and left main bronchial diameters (p0.001). The central airway dimensions increased with age up to 20 years, and dimensions were larger in male than in female adolescents.Normative data were determined for the central airways of children and adolescents. Central airway dimensions depended on distance from the carina and on intrathoracic tracheal length.

Background: The high genetic barrier to resistance of dolutegravir might allow for its use as maintenance monotherapy in patients with HIV. We investigated whether dolutegravir monotherapy was non-inferior to combination antiretroviral therapy (ART) for maintaining virological suppression in patients with HIV-1 infection successfully treated with combination ART.Methods: We did this open-label, phase 2, randomised non-inferiority trial at two medical centres in the Netherlands. Eligible patients (aged ≥18 years) were on combination ART, had been virologically suppressed (HIV RNA vs 50 000–99 999 copies per mL). Investigators and patients were not masked to group allocation. The primary endpoint was the proportion of patients with plasma HIV RNA viral loads of less than 200 copies per mL at week 24, with a non-inferiority margin of 12%. We did analyses in the on-treatment and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, NCT02401828.Findings: Between March 10, 2015, and Feb 4, 2016, we randomly assigned 51 patients to the immediate switch group and 53 patients to the delayed switch group. One patient who received immediate monotherapy discontinued treatment at week 12 because of disturbed sleep. At week 24, dolutegravir monotherapy was non-inferior to combination ART, with plasma HIV RNA loads of 200 copies per mL or higher observed in 2% (1/50) of patients in the immediate switch group and in no patients in the delayed switch group (difference 2%, 95% CI-5 to 12). Of patients assigned to the delayed switch group, 47 (89%) switched to dolutegravir monotherapy at week 24, two (4%) of whom subsequently discontinued monotherapy because of headache (n=1) and disturbed sleep (n=1). Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation.Interpretation: Dolutegravir monotherapy was non-inferior to combination ART at 24 weeks. However, virological failure continued to occur thereafter and led to dolutegravir resistance. Dolutegravir should not be used as maintenance monotherapy.

Aims of the study: This study aimed to evaluate if the microcirculation is impaired during and after therapeutic hypothermia (TH) in children with return of spontaneous circulation after cardiac arrest (CA) and to assess if microcirculatory impairment predicts mortality. This has been reported for post-CA adults, but results might be different for children because etiology, pathophysiology, and mortality rate differ. Methods: This prospective observational cohort study included consecutive, non-neonatal post-CA children receiving TH upon intensive care admission between June 2008 and June 2012. Also included were gender-matched and age-matched normothermic, control children without cardiorespiratory disease. The buccal microcirculation was non-invasively assessed with Sidestream Dark Field Imaging at the start of TH, halfway during TH, at the start of re-warming, and at normothermia. Macrocirculatory, respiratory, and biochemical parameters were also collected. Results: Twenty post-CA children were included of whom 9 died. During hypothermia, the microcirculation was impaired in the post-CA patients and did not change over time. At normothermia, the core body temperature and the microcirculation had increased and no longer differed from the controls. Microcirculatory deterioration was associated with mortality in the post-CA patients. In particular, the microcirculation was more severely impaired at TH start in the non-survivors than in the survivors - positive predictive value: 73-83, negative predictive value: 75-100, sensitivity: 63-100%, and specificity: 70-90%. Conclusions: The microcirculation is impaired in post-CA children during TH and more severe impairment at TH start was associated with mortality. After the stop of TH, the microcirculation improves rapidly irrespective of outcome. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

The aim was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) detects and monitors inflammatory and lung function changes during respiratory tract exacerbations (RTE) treatment in patients with cystic fibrosis (CF).29 patients with RTE underwent DWI pre- and post-antibiotic treatment. A control group of 27 stable patients, matched for age and sex, underwent DWI with the same time gap as those undergoing RTE treatment. Clinical status and lung function were assessed at each DWI time point. The CF-MRI scoring system was used to assess structural lung changes in both CF groups.Significant reduction in the DWI score over the course of antibiotic treatment (pDWI is a promising imaging method for noninvasive detection of pulmonary inflammation during RTE, and may be used to monitor treatment efficacy of anti-inflammatory treatment.

Background: The dawn of precision medicine and CFTR modulators require more detailed assessment of lung structure in cystic fibrosis (CF) clinical studies. Various imaging markers have emerged and are measurable, but clarity is needed to identify what markers should count for clinical studies. High-resolution chest computed tomography (CT) scoring has yielded sensitive markers for the study of CF disease progression. Once completed, CT scores from ongoing randomized controlled trials can be used to examine relationships between imaging endpoints and therapeutic effectiveness. Similarly, Magnetic Resonance Imaging (MRI) is in development to generate structural as well as functional markers. Results: The aim of this review is to characterize the role of currently available CT and MRI markers in clinical studies, and to discuss study design, data processing and statistical challenges unique to these endpoints in CF studies. Suggestions to overcome these challenges in CF studies are included. Conclusions: To maximize the potential of CT and MRI markers in clinical studies and advance treatment of CF disease progression, efforts should be made to conduct longitudinal randomized controlled trials including these modalities, develop data repositories, promote standardization and conduct reproducible research.

Wendy E Kaman,1 Eleni-Rosalina Andrinopoulou,2 John P Hays11Department of Medical Microbiology and Infectious Diseases, Erasmus Medical Center, Rotterdam, The Netherlands; 2Department of Biostatistics, Erasmus Medical Center, Rotterdam, The NetherlandsBackground: The proper development and implementation of point-of-care (POC) diagnostics requires knowledge of the perceived requirements and barriers to their implementation. To determine the current requirements and perceived barriers to the introduction of POC diagnostics in the field of medical microbiology (MM)-POC a prospective online survey (TEMPOtest-QC) was established.Methods and results: The TEMPOtest-QC survey was online between February 2011 and July 2012 and targeted the medical community, POC test diagnostic manufacturers, general practitioners, and the general public. In total, 293 individuals responded to the survey, including 91 (31%) medical microbiologists, 39 (13%) nonmedical microbiologists, 25 (9%) employees of POC test manufacturers, and 138 (47%) members of the general public. Responses were received from 18 different European countries, with the largest percentage of these living in The Netherlands (52%). The majority (>50%) of medical specialists regarded the development of MM-POC for blood culture and hospital acquired infections as “absolutely necessary”, but were much less favorable towards their use in the home environment. Significant differences in perceptions between medical specialists and the general public included the: (1) Effect on quality of patient care; (2) Ability to better monitor patients; (3) Home testing and the doctor-patient relationship; and (4) MM-POC interpretation. Only 34.7% of the general public is willing to pay more than €10 ($13) for a single MM-POC test, with 85.5% preferring to purchase their MM-POC test from a pharmacy.Conclusion: The requirements for the proper implementation of MM-POC were found to be generally similar between medical specialists and POC test kit manufacturers. The general public was much more favorable with respect to a perceived improvement in the quality of healthcare that these tests would bring to the hospital and home environment.Keywords: Survey, questionnaire, point-of-care, microbial diagnosis

An important target of many clinical studies is to identify biomarkers, including risk scores, with strong prognostic capabilities. While biomarker evaluations are commonly utilized to predict the progress of the disease at single time points, appropriate statistical tools to assess the prognostic value of serial biomarker evaluation are rarely used. The goal of this paper is to demonstrate flexible and appropriate statistical methodology to assess the predictive capability of serial echocardiographic measurements of allograft aortic valve function. Moreover, the concept of joint modeling of longitudinal and survival data to optimally utilize the relationship between repeated valve function measurements and time-to-death or time-to-reoperation, is introduced and illustrated. Optimal and suboptimal methods are illustrated using a prospective cohort of patients who survived aortic valve or root replacement with an allograft valve and who were followed clinically and echocardiographically over time. (Ann Thorac Surg 2012;93:1765-72) (c) 2012 by The Society of Thoracic Surgeons

To explore the feasibility of diffusion-weighted imaging (DWI) to assess inflammatory lung changes in patients with Cystic Fibrosis (CF) CF patients referred for their annual check-up had spirometry, chest-CT and MRI on the same day. MRI was performed in a 1.5 T scanner with BLADE and EPI-DWI sequences (b = 0–600 s/mm2). End-inspiratory and end-expiratory scans were acquired in multi-row scanners. DWI was scored with an established semi-quantitative scoring system. DWI score was correlated to CT sub-scores for bronchiectasis (CF-CTBE), mucus (CF-CTmucus), total score (CF-CTtotal-score), FEV1, and BMI. T-test was used to assess differences between patients with and without DWI-hotspots. Thirty-three CF patients were enrolled (mean 21 years, range 6–51, 19 female). 4 % (SD 2.6, range 1.5-12.9) of total CF-CT alterations presented DWI-hotspots. DWI-hotspots coincided with mucus plugging (60 %), consolidation (30 %) and bronchiectasis (10 %). DWItotal-score correlated (all p

BACKGROUND: Physicians utilize different types of information to predict patient prognosis. For example: confronted with a new patient suffering from severe aortic stenosis (AS), the cardiologist considers not only the severity of the AS but also patient characteristics, medical history, and markers such as BNP. Intuitively, doctors adjust their prediction of prognosis over time, with the change in clinical status, aortic valve area and BNP at each outpatient clinic visit. With the help of novel statistical approaches to model outcomes, it is now possible to construct dynamic event prediction models, employing longitudinal data such as AVA and BNP, and mimicking the dynamic adjustment of prognosis as employed intuitively by cardiologists. We illustrate dynamic prediction of patient survival and freedom from intervention, using baseline patient characteristics and longitudinal BNP data that are becoming available over time, from a cohort of patients with severe aortic stenosis. METHODS: A 3-step approach was employed: (1) construction of a mixed-effects model to describe temporal BNP progression, (2) jointly modeling the mixed-effects model with time-to-event data (death and freedom from intervention), and (3) using the joint model to build subject-specific prediction risk models. The dataset used for this purpose includes 191 patients with severe aortic stenosis who were followed over a 3-year time period. RESULTS: In the mixed-effects model BNP was significantly influenced by time, baseline patient age, gender, LV fractional ejection fraction and creatinine. Additionally, the joint model showed that an increasing BNP trend over time was found to be a significant predictor of death. CONCLUSIONS: By jointly modeling longitudinal data with time-to-event outcomes it is possible to construct individualized dynamic event prediction models that renew over time with accumulating evidence. It provides a potentially valuable evidence-based tool for everyday use in medical practice. ispartof: BMC Cardiovascular Disorders vol:15 issue:1 ispartof: location:England status: published

Objective: To study whether dopamine, norepinephrine, and epinephrine improve not only mean arterial blood pressure and heart rate but also microcirculatory perfusion in children with congenital diaphragmatic hernia. Design: Prospective observational cohort study from November 2009 to July 2012. Setting: ICU of a level III university children's hospital. Patients: Twenty-eight consecutive congenital diaphragmatic hernia newborns of whom seven did not receive any catecholaminergic support and 21 received dopamine as the drug of first choice. Fourteen of the latter also received either norepinephrine or epinephrine in addition to dopamine. Twenty-eight healthy neonates, matched for gestational age, postnatal age, and gender, served as controls. Interventions: None. Measurements and Main Results: Data were obtained before and after dopamine start and before and after norepinephrine or epinephrine start in case it was given. For the congenital diaphragmatic hernia without catecholaminergic support, data were obtained at admission days 1 and 2 and for the controls on day 1 of life. The buccal microcirculation was studied using Sidestream Dark Field imaging. Also macrocirculatory, respiratory, and biochemical variables were collected. Mean arterial blood pressure had improved after dopamine start, whereas the microcirculation had not. After the start of either norepinephrine or epinephrine, both blood pressure and heart rate had increased. However, the microcirculation failed to improve again. The microcirculation in the healthy controls was better than that in the congenital diaphragmatic hernia patients with catecholaminergic support. After cutoff values for abnormal microcirculation had been defined, abnormal microcirculation after dopamine start predicted the need for additional catecholaminergic support (area under the curve, 0.74-0.88; sensitivity, 77-77%; specificity, 69-77%). Likewise, microcirculatory impairment was associated with the need for extracorporeal membrane oxygenation. Conclusions: Catecholaminergic drug support with dopamine, norepinephrine, and/or epinephrine improved macrocirculatory function but did not improve the microcirculation in neonates with congenital diaphragmatic hernia. The microcirculation was not only impaired but it also predicted poor outcome. Copyright

Aortic gradient and aortic regurgitation are echocardiographic markers of aortic valve function. Both are biomarkers repeatedly measured in patients with valve abnormalities, and thus, it is expected that they are biologically interrelated. Loss of follow-up could be caused by multiple reasons, including valve progression related, such as an intervention or even the death of the patient. In that case, it would be of interest and appropriate to analyze these outcomes jointly. Joint models have recently received much attention because they cover a wide range of clinical applications and have promising results. We propose a joint model consisting of two longitudinal outcomes, one continuous (aortic gradient) and one ordinal (aortic regurgitation), and two time-to-events (death and reoperation). Moreover, we allow for more flexibility for the average evolution and the subject-specific profiles of the continuous repeated outcome by using B-splines. A disadvantage, however, is that when adopting a non-linear structure for the model, we may have difficulties when interpreting the results. To overcome this problem, we propose a graphical approach. In this paper, we apply the proposed joint models under the Bayesian framework, using a data set including serial echocardiographic measurements of aortic gradient and aortic regurgitation and measurements of the occurrence of death and reoperation in patients who received a human tissue valve in the aortic position. The interpretation of the results will be discussed. Copyright (C) 2014 JohnWiley & Sons, Ltd.

Item does not contain fulltext BACKGROUND: Congenital aortic stenosis (AS) is the most common obstructive left-sided cardiac lesion in young adults, however little is known about the progression in adults. Therefore, we aimed to evaluate the progression rate of AS and aortic dilatation in a large multicenter retrospective cohort of asymptomatic young adults with congenital valvular AS. METHODS: Data were obtained from chart abstraction. Linear mixed-effects models were used to evaluate the progression of AS and aortic dilatation over time. A joint model combining longitudinal echocardiographic and survival data was used for survival analysis. RESULTS: A total of 414 patients (age 29 +/- 10 years, 68% male) were included. Median follow-up duration was 4.1 (2.5-5.1) years (1587 patient-years). Peak aortic velocity was 3.4 +/- 0.7 m/s at baseline and did not change over time in the total patient population (-0.01 +/- 0.03 m/s/year). Increased left ventricular mass was significantly associated with faster AS progression (p

Objective Over the past decades, the indication for allograft implantation in aortic position has evolved. The purpose of this study is to report long-term survival, allograft durability, and potential risk factors. Methods Between 1987 and 2010, 353 patients underwent aortic valve replacements via allograft (92 subcoronary, 261 root replacement; 98% aortic allografts). Patient characteristics, survival, valve durability, and valve-related events were analyzed. Patients also were followed with standardized echocardiography. A joint modeling approach was used to detect the effect of (echocardiographic) variables on mortality and reoperation hazard. Results Mean age was 45 years (range, 1 month to 84 years); 71% were males. The etiology was endocarditis in 32% (active 22%), congenital 31%, degenerative 9%, aneurysm/dissection 12%, rheumatic 6%, and prosthetic valve failure 10%. Hospital mortality was 5.9% (n = 21). During follow-up (mean 12 years, range, 0-24; 99% complete), 113 patients died. Twenty-year cumulative survival was 41% (95% confidence interval, 32-50). Valve-related reoperations occurred in 117 patients: 100 structural valve deterioration, 9 nonstructural valve deterioration, and 8 endocarditis. Competing-risk analysis predicted that at 20 years 31% died, and 30% were alive without reoperation. Younger patient age was associated with increased reoperation. During follow-up left ventricular dilatation and severe aortic regurgitation were associated with mortality (P = .006 and .005, respectively), and grade 3 or greater aortic regurgitation during follow-up was associated with risk of reoperation (P = .001). Conclusions After almost 3 decades of experience with allografts in aortic position, the indication for use has become selective, mainly because of progressive structural valve deterioration over time. In case of complex aortic root pathology and active endocarditis allografts may still be useful.