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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

Objective: To estimate the developmental trends of quantitative parameters obtained from chest computed tomography (CT) and to provide normative values on dimensions of bronchi and arteries, as well as bronchus-artery (BA) ratios from preschool age to young adulthood., Materials and Methods: Two independent radiologists screened a dataset of 1160 chest CT scans, initially reported as normal, from participants aged 0 to 24 years. Using an automated deep learning-based algorithm, we computed the following bronchus and artery parameters: bronchial outer diameter (B out ), bronchial inner diameter (B in ), adjacent pulmonary artery diameter (A), bronchial wall thickness (B wt ), bronchial wall area (B WA ), and bronchial outer area (B OA ). From these parameters, we computed the following ratios: B out /A, B in /A, B wt /A, B wt /B out , and B WA /B OA . Furthermore, mean lung density, total lung volume, and the square root of wall area of bronchi with a 10-mm lumen perimeter (Pi10) were obtained. The effects on CT parameters of age, sex, and iodine contrast were investigated using mixed-effects or regression model analyses., Results: 375 normal inspiratory chest CT scans (females / males = 156 / 219; mean age [SD] 12.7 [5.0] years) met the inclusion criteria. B out and B in progressively increased with age (all p < 0.05), but B wt , B out /A, B in /A, B wt /A, B wt /B out , or B WA /B OA did not. Total lung volume and mean lung density continuously increased with age (both p < 0.001), while Pi10 did not exhibit such a trend. B out , total lung volume, and mean lung density were the only parameters that differed between males and females, all higher in males than females (all p < 0.03). The presence of iodinated contrast led to greater values for B wt , B wt /B out , and B WA /B OA , but lower values for B in , B out /A, B in /A, and B wt /A (all p < 0.01)., Conclusion: Quantitative CT parameters of both lung parenchyma and bronchi exhibit growth-related changes, but from 6 to 24 years ratios between bronchus and artery dimensions remain constant. Contrast-enhanced CT scans affect the assessment of lung parenchyma and bronchial size. We propose age and technique-dependent normative values for bronchial dimensions and wall thickness., Key Points: Question What are the developmental trends of quantitative lung CT parameters in patients from childhood into young adulthood? Findings The ratio between bronchus and pulmonary artery dimensions demonstrates consistent values across age groups, indicating synchronized growth between bronchi and paired pulmonary arteries. Clinical relevance Our findings highlight the importance of standardized CT protocol and volume acquisition, and emphasize the need for ongoing collection of normal chest CT scans to refine the proposed reference values., Competing Interests: Compliance with ethical standards. Guarantor: The scientific guarantor of this publication is Dr. Pierluigi Ciet. Conflict of interest: The author of this manuscript, Harm Tiddens, declares relationships with the following companies: Insmed, TBIO, Thirona, Neupharma and Boehringer. The author of this manuscript, Jean-Paul Charbonnier, declares relationships with Thirona. Daan Caudri is director of the Erasmus MC-LungAnalysis laboratory. The author of this manuscript, Pierluigi Ciet, declares relationships with the following companies: Vertex Pharmaceutical, Chiesi Pharmaceuticals, and Siemens Healthineers. Wieying Kuo is affiliated with Voiant Clinical. The rest of the authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article. Statistics and biometry: One of the authors, Eleni-Rosalina Andrinopoulou, has significant statistical expertise. Informed consent: Written informed consent was not required for this study because this is a retrospective study. Ethical approval: Institutional Review Board approval was obtained. Study subjects or cohorts overlap: The cohort has been previously reported in Kuo et al [6]. In the previous study, the dataset consisted of 294 out of 1160 chest CT scans of children and adolescents were collected retrospectively by the international multicenter Normal Chest CT Study Group. The previous study aimed to define normative data on central airway dimensions, in particular trachea, right main bronchi, and left main bronchi, in chest CT of children. On these 294 inspiratory CT scans, central airways were semi-automatically analyzed using Myrian XP-Lung software (version 1.19.1, Intrasense). The intrathoracic tracheal length was measured from the carina to the thorax inlet manually. In the recent study, the dataset consisted of 375 out of 1160 chest CT scans of children and young adults. The primary aim of the current study is to establish normative data for the dimensions of peripheral airways extending down to the 6th bronchial generation, in chest CT of children. On these 375 inspiratory CT scans, bronchi and adjacent pulmonary arteries were automatically analyzed using LungQ (version 2.0.1, Thirona). Using this algorithm, we computed the following bronchus and artery parameters from segmental bronchi to the most peripheral detectable bronchi: bronchial outer diameter (Bout), bronchial inner diameter (Bin), adjacent pulmonary artery diameter (A), bronchial wall thickness (Bwt), bronchial wall area (BWA), and bronchial outer area (BOA). From these parameters, we computed the following ratios: Bout/A, Bin/A, Bwt/A, Bwt/Bout, and BWA/BOA. Furthermore, mean lung density, total lung volume, and the square root of wall area of bronchi with a 10-mm lumen perimeter (Pi10) were obtained by using another module from the same software package. Methodology: Retrospective Observational Multicenter study, (© 2025. The Author(s).)

Importance: Optimal data availability for secondary use is crucial for continuous improvement in healthcare. At the same time, it is imperative to uphold patients' rights to be informed, to control the use of their health data and to protect their privacy. To balance these two needs, we investigated which consent procedure (opt-in or opt-out) would be most supportive of data availability., Objective: This study explores an opt-in procedure versus an opt-out procedure as a consent procurement method for secondary use of routinely recorded health data, images and tissues for scientific research purposes., Design/setting: A randomized controlled trial was performed in Erasmus Medical Center, a large tertiary hospital in the Netherlands. New, first time patients were recruited from 16 outpatient clinics and randomily assigned to either the opt-in (intervention group) or the opt-out procedure (control group), until the equally balanced sample size of 2228 was reached., Results: Patient inclusion spanned from December 2022 to September 2023. The opt-out procedure resulted in higher consent rates compared to the opt-in procedure. Differences were found for gender, socioeconomic status and country of birth., Conclusions: An opt-out procedure appears to be more effective in ensuring optimal data availability with less bias for the secondary use of health data compared to opt-in. To uphold patient control over data, it is pivotal that patients are well-informed about the consent procedure., (Copyright © 2025 The Author(s). Published by Elsevier B.V. All rights reserved.)

In this cohort study involving 9399 current and former smokers from the Genetic Epidemiology of Chronic Obstructive Pulmonary Disease study, we assessed the relationship between artificial intelligence-quantified mucus plugs on chest CTs and all-cause mortality. Our results revealed a significant positive association, particularly for those with COPD GOLD stages 1-4, with HRs of 1.18 for 1-2 mucus-obstructed bronchial segments and 1.27 for ≥3 obstructed segments. This corroborates previous visual mucus plug counting research and demonstrates the relevance of mucus plugs in COPD pathology and as a marker for risk assessment. Automated mucus plug quantification methods may provide an efficient tool for both clinical evaluations and research., Competing Interests: Competing interests: TvdV: no conflicts of interest involving the work under consideration for publication, no relevant financial activities outside the submitted work, no other relationships or activities that readers could perceive to have influenced or that give the appearance of potentially influencing the current manuscript. E-RA: no conflicts of interest, no relevant financial activities or other relevant relationships or activities regarding the work under consideration. G-JB: honoraria for lectures and consultancy from GSK, AstraZeneca, Novartis and Sanofi Genzyme, as well as research grants from Sanofi Genzyme, GSK and AstraZeneca, not related to the work under consideration. JPC: employee and shareholder at Thirona. VK: no conflicts of interest, no relevant financial activities or other relevant relationships or activities regarding the work under consideration. RL: senior deep learning engineer at Thirona. DAL: no conflicts of interest, no relevant financial activities or other relevant relationships or activities regarding the work under consideration. HT: received in the last 3 years multiple grants from the following public and institutional grant institutions for lung structure and function research: NHMRC, NIH, CFF, ECFS, IMI and ErasmusMC Sophia Foundation; received unconditional grants for investigator-initiated research from Novartis and Insmed. Acted as consultant for Insmed, Thirona, Neupharma and Boehringer Ingelheim. Chief medical officer for Thirona since April 2022. Vice-chair and faculty for the ADVANCE course sponsored by Vertex., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background: Observed patient survival after cardiothoracic interventions should ideally be placed in the context of matched-general-population survival. This study outlines several methodologies of matching general population mortality to the study sample, subsequently calculating cumulative matched-general-population survival, highlighting their respective advantages, disadvantages, and limitations., Methods: A multicenter data set containing survival data after the Ross procedure was used for methodological illustration. General population mortality was extracted from country-specific life tables in the Human Mortality Database. The matched-general-population mortality, also known as background mortality, was obtained by matching general population mortality to the study sample using different matching strategies, iteratively considering median/individual age and median/individual calendar year, besides country and sex. The corresponding cumulative matched-general-population survival was calculated subsequently. Sensitivity analyses were performed to assess the impact of varying patient ages on survival estimates by adding and subtracting 15 years from individual patients. A web-based Shiny Application (App) was developed to easily calculate cumulative matched-general-population survival., Results: In total, 1431 hospital survivors from the Ross procedure from 5 countries (25.7% female; median age, 48.5 [interquartile range, 42.7-54.0] years) were included. Fifteen-year survival was 88.3% (95% CI, 85.3-90.6). Cumulative matched-general-population 15-year survival varied from 87.7% to 89.8% using the 3 methods of different complexities. For 15-year-older patients, the cumulative matched-general-population 15-year survival was 67.4%, 59.8%, and 63.2%, respectively, using the simplest to the most comprehensive matching methods; for 15-year-younger patients, it was 96.9%, 96.1%, and 96.7%, respectively., Conclusions: Different methodologies to match general population mortality to observed patient mortality yield variable estimates of cumulative matched-general-population survival, especially in older patients. The cumulative matched-general-population survival should ideally be calculated by considering country, sex, individual patient age, and calendar year (both updated annually). This method can be easily implemented using the web-based Shiny App enclosed in this article.

Introduction: Little is known about the effectiveness and safety of oxygen saturation (SpO2) thresholds in children admitted with respiratory distress. The current 90%-94% threshold could lead to prolonged administration of supplemental oxygen, increased duration of hospital admissions, distress for children and families, and healthcare costs. To balance reducing unnecessary oxygen administration and preventing hypoxia, a lower SpO2 threshold of 88% for oxygen supplementation in children has been suggested. This trial aims to test the hypothesis that a lower SpO2 threshold of 88% safely reduces the length of hospital stay in children admitted with respiratory distress when compared with a 92% SpO2 threshold and to assess its cost-effectiveness., Methods and Analysis: This is a multicentre, open-label, randomised controlled trial with two parallel arms. A total of 560 children aged 6 weeks to 12 years admitted with a diagnosis of bronchiolitis, viral wheeze or lower respiratory tract infection will be recruited and equally randomised into an intervention or usual care arm. Intervention arm patients will receive supplemental oxygen if SpO2 falls below 88% or above 88% if deemed necessary by clinical staff. Control arm patients will receive supplemental oxygen if SpO2 falls below 92% or above 92% if deemed necessary by staff. The primary outcome is the time from admission to the time when all prespecified discharge criteria are met. Secondary outcomes are length of stay, safety (time to recovery, readmissions and paediatric intensive care admissions), quality of life, parental anxiety and societal costs. Patients are followed up by digital questionnaires up to 90 days postdischarge., Ethics and Dissemination: This study has received approval from the research ethics committee (REC) of Leiden, Den Haag and Delft (EU CT number 2023-504817-56). Written informed consent will be obtained from parents or guardians. Parents of patients and patient representatives are involved in all stages of the study, from design to results, interpretation and dissemination. The results of this trial will be disseminated via lay publications, peer-reviewed scientific journals and academic conferences., Trial Registration Number: NCT06016244., Competing Interests: Competing interests: GK reports grants or contracts from the Netherlands Lung Foundation, TEVA the Netherlands, Zon-MW (VICI grant), European Union (H2020), GSK, Vertex and Ubbo Emmius Foundation, outside the submitted work; consulting fees from AstraZeneca and Pure IMS, outside the submitted work; payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Sanofi, Boehringer Ingelheim, exquAIro, European Respiratory Society and AstraZeneca, outside the submitted work and is chair of the ExqAIro foundation, outside the submitted work. The remaining authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ Group.)

Aim: Bronchiectasis (BE) is a disease defined by irreversible dilatation of the airway. Computed tomography (CT) plays an important role in the detection and quantification of BE. The aim of this study was three-fold: 1) to assess bronchus-artery (BA) dimensions using fully automated software in a cohort of BE disease patients; 2) to compare BA dimensions with semi-quantitative BEST-CT (Bronchiectasis Scoring Technique for CT) scores for BE and bronchial wall thickening; and 3) to explore the structure-function relationship between BA-method lumen dimensions and spirometry outcomes., Methods: Baseline CTs of BE patients who participated in a clinical trial were collected retrospectively. CTs were analysed manually with the BEST-CT scoring system and automatically using LungQ (v.2.1.0.1, Thirona, The Netherlands), which measures the following BA dimensions: diameters of bronchial outer wall (B out ), bronchial inner wall (B in ) and artery (A), and bronchial wall thickness (B wt ) and computes BA ratios (B out /A and B in /A) to assess bronchial widening. To assess bronchial wall thickness, we used the B wt /A ratio and the ratio between the bronchus wall area (B wa ) and the area defined by the outer airway (B oa ) (B wa /B oa )., Results: In total, 65 patients and 16 900 BA pairs were analysed by the automated BA method. The median (range) percentage of BA pairs defined as widened was 69 (55-84)% per CT using a cut-off value of 1.5 for B out /A, and 53 (42-65)% of bronchial wall were thickened using a cut-off value of 0.14 for B wt /A. BA dimensions were correlated with comparable outcomes for the BEST-CT scoring method with a correlation coefficient varying between 0.21 to 0.51. The major CT BA determinants of airflow obstruction were bronchial wall thickness (p=0.001) and a narrower bronchial inner diameter (p=0.003)., Conclusion: The automated BA method, which is an accurate and sensitive tool, demonstrates a stronger correlation between visual and automated assessment and lung function when using a higher cut-off value to define bronchiectasis., Competing Interests: Author contributions: A.L.P. Pieters contributed to the design of the work, data collection and drafted the manuscript up to the final version. Q. Lv contributed to the data collection, analyses and gave final approval for the manuscript. J.J. Meerburg contributed to the data collection for her previous studies. E-R. Andrinopoulou contributed to the analyses and gave final approval for the manuscript. H.A.W.M. Tiddens contributed to the design and analyses of the work and gave final approval for the manuscript. T. van der Veer, P. Ciet, J.D. Chalmers, M.R. Loebinger, C.S. Haworth and J.S. Elborn contributed to the design of the work and gave final approval for the manuscript. Conflict of interest: A.L.P. Pieters, Q. Lv, T. van der Veer, J.J. Meerburg, J.S. Elborn and E-R. Andrinopoulou declare no conflict of interest. Conflict of interest: P. Ciet has received grants or contract fees from NOW-Dutch Research Council and Horizon Pathfinder; and has received payment or honoraria for lectures, presentations etc. from Chiesi and Vertex, and travel support from the European Respiratory Society. He holds a leadership role as Chair of the Thoracic Group of the Cardiothoracic Taskforce of the European Society of Pediatric Radiology. Conflict of interest: J.D. Chalmers has received research grants from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Grifols, Novartis, Insmed and Trudell; has received consultancy or speaker fees from Antabio, AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Insmed, Janssen, Novartis, Pfizer, Trudell and Zambon; and is an associate editor of this journal. Conflict of interest: M.R. Loebinger has received consulting fees from Armata, 30T, AstraZeneca, Parion, Ismed, Chiesi, Zambon, Electromed, Recode and Boehringer Ingelheim; and has received payment or honoraria for lectures, presentations etc. from Chiesi, Insmed, Mylan and Zambon. Conflict of interest: C.S. Haworth has received consulting fees from 30 Technology, CSL Behring, Chiesi, Ismed, Janssen, LifeArc, Meiji, Mylan, Pneumagen, Shionogi, Vertex and Zambon; and has received payment or honoraria for lectures, presentations etc. from Chiesi, Ismed, Mylan and Zambon. Conflict of interest: H.A.W.M. Tiddens is professor emeritus at Erasmus MC and the CMO of Thirona; he has received consulting fees for Insmed, Chiesi and Boehringer, a provides paid courses for Vertex., (Copyright ©The authors 2024.)

Background: In chronic obstructive pulmonary disease (COPD), vascular alterations have been shown to contribute to hypoxia and pulmonary hypertension, but the independent contribution of small vessel abnormalities to mortality remains unclear., Methods: We quantified artery and vein dimensions on computed tomography (CT) down to 0.2 mm. Small vessel volumes (<1 mmᴓ) were normalized by body surface area. In 7903 current and former smokers of the COPDGene study (53.2% male) the independent contribution of small artery and small vein volume to all-cause mortality was tested in multivariable Cox models. Additionally, we calculated the 95 th percentile of small arteries and veins in 374 never smokers to create two groups: normal and high small artery or vein volume. We describe clinical, physiological and imaging characteristics of subjects with a high small artery and high small vein volume., Findings: Both high small artery and high small vein volumes were independently associated with mortality with an adjusted hazard ratio of 1.07 [1.01, 1.14] and 1.34 [1.21, 1.49] per mL/m 2 increase, respectively. In COPDGene, 447 (5.7%) had high small artery volume and 519 (9.1%) subjects had high small vein volume and both had more emphysema, more air trapping and more severe coronary calcium., Interpretation: In smokers, abnormally high volumes in small arteries and veins are both relevant for mortality, which urges investigations into the aetiology of small pulmonary vessels and cardiac function in smokers., Funding: Award Number U01-HL089897 and U01-HL089856 from the NHLBI. COPD Foundation with contributions from AstraZeneca, Boehringer Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, Siemens, and Sunovion., Competing Interests: Declaration of interests AK, EA, TV, EP: no conflicts relevant to this manuscript. DL and SH: the department of radiology of National Jewish Health received grant support from the NHLBI. PdJ: The Department of Radiology from the UMC Utrecht receives research support from Philips Healthcare. JPC: employee and shareholder of Thirona. LGE, HT: employee of Thirona., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: COMBAT-CF showed that children aged 0-3 years treated with azithromycin did clinically better than placebo but there was no effect on CT-scores. We reanalysed CTs using an automatic bronchus-artery (BA) analysis., Method: Inspiratory and expiratory CTs at 12 and 36 months were analysed. BA-analysis measures BA-diameters: bronchial outer wall (B out ), bronchial inner wall (B in ), artery (A), and bronchial wall thickness (B wt ) and computes BA-ratios: B out /A and B in /A for bronchial widening, B wt /A and B wa /B oa (bronchial wall area/bronchial outer area) for bronchial wall thickening. Low attenuation regions (LAR) were analysed using an automatic method. Mixed-effect model was used to compare BA-outcomes at 36 months between treatment groups., Results: 228 CTs (59 placebo; 66 azithromycin) were analysed. The azithromycin group had lower B wa /B oa (p = 0.0034) and higher B in /A (p = 0.001) relative to placebo. B out /A (p = 0.0088) was higher because of a reduction in artery diameters which correlated to a reduction in LAR., Conclusion: Azithromycin-treated infants with CF show a reduction in bronchial wall thickness and possibly a positive effect on lung perfusion., Competing Interests: Declaration of competing interest HAWMT reports grants from the Cystic Fibrosis Foundation, has a part time position as chief medical officer for Thirona, and Erasmus MC is expected to receive future license royalties for PRAGMA-CF. JPC is employee and shareholder at Thirona. SMS reports grants from the Cystic Fibrosis Foundation and National Health and Medical Research Foundation, and Telethon Kids Institute is expected to receive future license royalties for PRAGMA-CF. All other authors declare no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Rationale: Chest computed tomography (CT) scans are essential to diagnose and monitor bronchiectasis (BE). To date, few quantitative data are available about the nature and extent of structural lung abnormalities (SLAs) on CT scans of patients with BE. Objectives: To investigate SLAs on CT scans of patients with BE and the relationship of SLAs to clinical features using the EMBARC (European Multicenter Bronchiectasis Audit and Research Collaboration) registry. Methods: CT scans from patients with BE included in the EMBARC registry were analyzed using the validated Bronchiectasis Scoring Technique for CT (BEST-CT). The subscores of this instrument are expressed as percentages of total lung volume. The items scored are atelectasis/consolidation, BE with and without mucus plugging (MP), airway wall thickening, MP, ground-glass opacities, bullae, airways, and parenchyma. Four composite scores were calculated: total BE (i.e., BE with and without MP), total MP (i.e., BE with MP plus MP alone), total inflammatory changes (i.e., atelectasis/consolidation plus total MP plus ground-glass opacities), and total disease (i.e., all items but airways and parenchyma). Measurements and Main Results: CT scans of 524 patients with BE were analyzed. Mean subscores were 4.6 (range, 2.3-7.7) for total BE, 4.2 (1.2-8.1) for total MP, 8.3 (3.5-16.7) for total inflammatory changes, and 14.9 (9.1-25.9) for total disease. BE associated with primary ciliary dyskinesia was associated with more SLAs, whereas chronic obstructive pulmonary disease was associated with fewer SLAs. Lower FEV 1 , longer disease duration, Pseudomonas aeruginosa and nontuberculous mycobacterial infections, and severe exacerbations were all independently associated with worse SLAs. Conclusions: The type and extent of SLAs in patients with BE are highly heterogeneous. Strong relationships between radiological disease and clinical features suggest that CT analysis may be a useful tool for clinical phenotyping.

Introduction: Inflammation appears early in cystic fibrosis (CF) pathogenesis, with specific elevated inflammatory markers in bronchoalveolar lavage fluid (BALF) correlating with structural lung disease. Our aim was to identify markers of airway inflammation able to predict bronchiectasis progression over two years with high sensitivity and specificity., Methods: Children with CF with two chest computed tomography (CT) scans and bronchoscopies at a two-year interval were included (n= 10 at 1 and 3 years and n= 27 at 3 and 5 years). Chest CTs were scored for increase in bronchiectasis (Δ%Bx), using the PRAGMA-CF score. BALF collected with the first CT scan were analyzed for neutrophil% (n= 36), myeloperoxidase (MPO) (n= 25), neutrophil elastase (NE) (n= 26), and with a protein array for inflammatory and fibrotic markers (n= 26)., Results: MPO, neutrophil%, and inducible T-cell costimulator ligand (ICOSLG), but not clinical characteristics, correlated significantly with Δ%Bx. Evaluation of neutrophil%, NE, MPO, interleukin-8 (IL-8), ICOSLG, and hepatocyte growth factor (HGF), for predicting an increase of > 0.5% of Δ%Bx in two years, showed that IL-8 had the best sensitivity (82%) and specificity (73%). Neutrophil%, ICOSLG and HGF had sensitivities of 85, 82, and 82% and specificities of 59, 67 and 60%, respectively. The odds ratio for risk of >0.5% Δ%Bx was higher for IL-8 (12.4) than for neutrophil%, ICOSLG, and HGF (5.9, 5.3, and 6.7, respectively). Sensitivity and specificity were lower for NE and MPO)., Conclusions: High levels of IL-8, neutrophil%, ICOSGL and HGF in BALF may be good predictors for progression of bronchiectasis in young children with CF., Competing Interests: Declaration of competing interest There is no conflict of interest associated with this paper., (Copyright © 2024. Published by Elsevier B.V.)

Background and Purpose: Pompe disease is a rare, inheritable, progressive metabolic myopathy. This study aimed to estimate the minimal clinically important difference (MCID) for an improvement in forced vital capacity in the upright seated position (FVC up ) and the 6-min walk test (6MWT) after a year of treatment with enzyme replacement therapy., Methods: Data were obtained from two prospective follow-up studies. Between-group and within-group MCIDs were estimated using anchor-based methods. Additionally, a distribution-based method was used to generate supportive evidence. As anchors, self-reported change in health and in physical functioning, shortness of breath and a categorization of the Short-Form 36 Physical Component Summary score were used. Anchor appropriateness was assessed using Spearman correlations (absolute values ≥0.29) and a sufficient number of observations in each category., Results: In all, 102 patients had at least one FVC up or 6MWT measurement during enzyme replacement therapy. Based on the anchors assessed as appropriate, the between-group MCID for an improvement in FVC up ranged from 2.47% to 4.83% points. For the 6MWT, it ranged from 0.35% to 7.47% points which is equivalent to a distance of 2.18-46.61 m and 1.97-42.13 m for, respectively, a man and a woman of age 50, height 1.75 m and weight 80 kg. The results of the distribution-based method were within these ranges when applied to change in the outcome values., Conclusion: The MCIDs for FVC up and 6MWT derived in this study can be used to interpret differences between and within groups of patients with Pompe disease in clinical trials and cohort studies., (© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Modulator therapies that seek to correct the underlying defect in cystic fibrosis (CF) have revolutionized the clinical landscape. Given the heterogeneous nature of lung disease progression in the post-modulator era, there is a need to develop prediction models that are robust to modulator uptake., Methods: We conducted a retrospective longitudinal cohort study of the CF Foundation Patient Registry (N = 867 patients carrying the G551D mutation who were treated with ivacaftor from 2003 to 2018). The primary outcome was lung function (percent predicted forced expiratory volume in 1 s or FEV1pp). To characterize the association between ivacaftor initiation and lung function, we developed a dynamic prediction model through covariate selection of demographic and clinical characteristics. The ability of the selected model to predict a decline in lung function, clinically known as an FEV1-indicated exacerbation signal (FIES), was evaluated both at the population level and individual level., Results: Based on the final model, the estimated improvement in FEV1pp after ivacaftor initiation was 4.89% predicted (95% confidence interval [CI]: 3.90 to 5.89). The rate of decline was reduced with ivacaftor initiation by 0.14% predicted/year (95% CI: 0.01 to 0.27). More frequent outpatient visits prior to study entry and being male corresponded to a higher overall FEV1pp. Pancreatic insufficiency, older age at study entry, a history of more frequent pulmonary exacerbations, lung infections, CF-related diabetes, and use of Medicaid insurance corresponded to lower FEV1pp. The model had excellent predictive accuracy for FIES events with an area under the receiver operating characteristic curve of 0.83 (95% CI: 0.83 to 0.84) for the independent testing cohort and 0.90 (95% CI: 0.89 to 0.90) for 6-month forecasting with the masked cohort. The root-mean-square errors of the FEV1pp predictions for these cohorts were 7.31% and 6.78% predicted, respectively, with standard deviations of 0.29 and 0.20. The predictive accuracy was robust across different covariate specifications., Conclusions: The methods and applications of dynamic prediction models developed using data prior to modulator uptake have the potential to inform post-modulator projections of lung function and enhance clinical surveillance in the new era of CF care., (© 2024. The Author(s).)

Background: In adults with severe asthma (SA) bronchial wall thickening, bronchiectasis and low attenuation regions (LAR) have been described on chest computed tomography (CT) scans. The extent to which these structural abnormalities are present in children with SA is largely unknown. Our aim was to study the presence and extent of airway abnormalities on chest CT of children with SA., Methods: 161 inspiratory and expiratory CT scans, either spirometer-controlled or technician-controlled, obtained in 131 children with SA (mean±SD age 11.0±3.8 years) were collected retrospectively. Inspiratory scans were analysed manually using a semi-quantitative score and automatically using LungQ (v2.1.0.1; Thirona B.V., Nijmegen, the Netherlands). LungQ segments the bronchial tree, identifies the generation for each bronchus-artery (BA) pair and measures the following BA dimensions: outer bronchial wall diameter (B out ), adjacent artery diameter (A) and bronchial wall thickness (B wt ). Bronchiectasis was defined as B out /A ≥1.1, bronchial wall thickening as B wt /A ≥0.14. LAR, reflecting small airways disease (SAD), was measured automatically on inspiratory and expiratory scans and manually on expiratory scans. Functional SAD was defined as FEF 25-75 and/or FEF 75 z-scores <-1.645. Results are shown as median and interquartile range., Results: Bronchiectasis was present on 95.8% and bronchial wall thickening on all CTs using the automated method. Bronchiectasis was present on 28% and bronchial wall thickening on 88.8% of the CTs using the manual semi-quantitative analysis. The percentage of BA pairs defined as bronchiectasis was 24.62% (12.7-39.3%) and bronchial wall thickening was 41.7% (24.0-79.8%) per CT using the automated method. LAR was observed on all CTs using the automatic analysis and on 82.9% using the manual semi-quantitative analysis. Patients with LAR or functional SAD had more thickened bronchi than patients without., Conclusion: Despite a large discrepancy between the automated and the manual semi-quantitative analysis, bronchiectasis and bronchial wall thickening are present on most CT scans of children with SA. SAD is related to bronchial wall thickening., Competing Interests: Conflict of interest: W.B. van den Bosch reports an unconditional research grant for a PhD from Vectura Group PLC during the conduct of the study (contract was signed in 2018 for the duration of 4 years). Conflict of interest: Q. Lv and E-R. Andrinopoulou have nothing to disclose. Conflict of interest: M.W.H. Pijnenburg reports support from Sanofi and Novartis outside the submitted work. Conflict of interest: P. Ciet reports personal fees from Vertex, Chiesi Pharmaceuticals BV and Editamed SRL, and grants from the Dutch Research Council, outside the submitted work. Conflict of interest: H.M. Janssens reports grants and other support from Vertex Pharmaceuticals outside the submitted work. Conflict of interest: H.A.W.M. Tiddens reports personal fees from Thirona BV during the conduct of the study; and grants and other support from Novartis, personal fees from Vertex and Insmed, and grants from Vectura Group PLC, outside the submitted work. In addition, H.A.W.M. Tiddens has a patent for the PRAGMA-CF scoring system licensed and Sophia Research BV of the Erasmus MC–Sophia Children's Hospital has, in the past 3 years received unconditional research grants from Novartis and Vectura Group PLC, research grants from IMI, CFF, ECFS and the Sophia Foundation, and honoraria and travel expenses for lectures and participation on expert panels from Novartis, Insmed and Vertex. He heads the Erasmus MC core laboratory LungAnalysis which is a not-for-profit core image analysis laboratory. The financial aspects of the laboratory are handled by Erasmus MC., (Copyright ©The authors 2024.)

Objective: Early-stage glottic cancer (ESGC) is a malignancy of the head and neck. Besides disease control, preservation and improvement of voice quality are essential. To enable expectation management and well-informed decision-making, patients should be sufficiently counseled with individualized information on expected voice quality. This study aims to develop an individualized dynamic prediction model for patient-reported voice quality. This model should be able to provide individualized predictions at every time point from intake to the end of follow-up., Study Design: Longitudinal cohort study., Setting: Tertiary cancer center., Methods: Patients treated for ESGC were included in this study (N = 294). The Voice Handicap Index was obtained prospectively. The framework of mixed and joint models was used. The prognostic factors used are treatment, age, gender, comorbidity, performance score, smoking, T-stage, and involvement of the anterior commissure. The overall performance of these models was assessed during an internal cross-validation procedure and presentation of absolute errors using box plots., Results: The mean age in this cohort was 67 years and 81.3% are male. Patients were treated with transoral CO 2 laser microsurgery (57.8%), single vocal cord irradiation up to (24.5), or local radiotherapy (17.5%). The mean follow-up was 43.4 months (SD 21.5). Including more measurements during prediction improves predictive performance. Including more clinical and demographic variables did not provide better predictions. Little differences in predictive performance between models were found., Conclusion: We developed a dynamic individualized prediction model for patient-reported voice quality. This model has the potential to empower patients and professionals in making well-informed decisions and enables tailor-made counseling., (© 2023 The Authors. Otolaryngology-Head and Neck Surgery published by Wiley Periodicals LLC on behalf of American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Objective: To externally validate the dynamic prediction model for prediction of upper limb (UL) function 6 months after stroke. The dynamic prediction model has been developed and cross-validated on data from 4 Dutch studies., Design: Data from a prospective Danish cohort study were used to assess prediction accuracy., Setting: A Danish neurorehabilitation hospital., Participants: In this external validation study, follow-up data for 80 patients in the subacute phase after stroke (N=80), mean age 64 (SD11), 43% women, could be obtained. They were assessed at 2 weeks, 3 months, and 6 months after stroke with the Action Research Arm Test (ARAT), Fugl-Meyer Motor Assessment upper limb (FMA), and Shoulder Abduction (SA) Finger Extension (FE), (SAFE) test., Intervention: Not applicable., Main Outcome Measures: Prediction accuracy at 6 months was examined for 3 categories of ARAT (0-57 points): mild (48-57), moderate (23-47), and severe (0-22). Two individual predictions of ARAT scores at ±6 months post-stroke were computed based on, respectively, baseline (2 weeks) and 3 months ARAT, FE, SA values. The absolute individual differences between observed and predicted ARAT scores were summarized., Results: The prediction model performed best for patients with relatively good UL motor function, with an absolute error median (IQR) of 3 (2-9), and worst for patients with severe UL impairment, with a median (IQR) of 30 (3-39) at baseline. In general, prediction accuracy substantially improved when data obtained 3 months after stroke was included compared with baseline at 2 weeks after stroke., Conclusion: We found limited clinical usability due to the lack of prediction accuracy 2 weeks after stroke and for patients with severe UL impairments. The dynamic prediction model could probably be refined with data from biomarkers., (© 2023 The Authors.)

Background: Cystic fibrosis (CF) lung disease is characterised by progressive airway wall thickening and widening. We aimed to validate an artificial intelligence-based algorithm to assess dimensions of all visible bronchus-artery (BA) pairs on chest CT scans from patients with CF., Methods: The algorithm fully automatically segments the bronchial tree; identifies bronchial generations; matches bronchi with the adjacent arteries; measures for each BA-pair bronchial outer diameter (B out ), bronchial lumen diameter (B in ), bronchial wall thickness (B wt ) and adjacent artery diameter (A); and computes B out /A, B in /A and B wt /A for each BA pair from the segmental bronchi to the last visible generation. Three datasets were used to validate the automatic BA analysis. First BA analysis was executed on 23 manually annotated CT scans (11 CF, 12 control subjects) to compare automatic with manual BA-analysis outcomes. Furthermore, the BA analysis was executed on two longitudinal datasets (Copenhagen 111 CTs, ataluren 347 CTs) to assess longitudinal BA changes and compare them with manual scoring results., Results: The automatic and manual BA analysis showed no significant differences in quantifying bronchi. For the longitudinal datasets the automatic BA analysis detected 247 and 347 BA pairs/CT in the Copenhagen and ataluren dataset, respectively. A significant increase of 0.02 of B out /A and B in /A was detected for Copenhagen dataset over an interval of 2 years, and 0.03 of B out /A and 0.02 of B in /A for ataluren dataset over an interval of 48 weeks (all p<0.001). The progression of 0.01 of B wt /A was detected only in the ataluren dataset (p<0.001). BA-analysis outcomes showed weak to strong correlations (correlation coefficient from 0.29 to 0.84) with manual scoring results for airway disease., Conclusion: The BA analysis can fully automatically analyse a large number of BA pairs on chest CTs to detect and monitor progression of bronchial wall thickening and bronchial widening in patients with CF., Competing Interests: Competing interests: HT has received in the last 5 years multiple grants from the following public and institutional grant institutions for lung structure and function research: NHMRC, NIH, CFF, ECFS, IMI, Sophia Foundation. He received unconditional grants for investigator-initiated research from Chiesi; Vectura, Novartis and Insmed. He has acted as consultant for Insmed, TBIO, Thirona, Neupharma and Boehringer. He has a part time position as chief medical officer for Thirona. He functions as vice chair and faculty for the Advance course sponsored by Vertex. He owns no shares. LG-E is a scientist working at Thirona. JPC is shareholder at Thirona. DC is director of the Erasmus MC-LungAnalysis laboratory. PC acted as consultant for Vertex and Chiesi Pharmaceuticals., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Cystic fibrosis (CF) is a genetic disease but is greatly impacted by non-genetic (social/environmental and stochastic) influences. Some people with CF experience rapid decline, a precipitous drop in lung function relative to patient- and/or center-level norms. Those who experience rapid decline in early adulthood, compared to adolescence, typically exhibit less severe clinical disease but greater loss of lung function. The extent to which timing and degree of rapid decline are informed by social and environmental determinants of health (geomarkers) is unknown., Methods: A longitudinal cohort study was performed (24,228 patients, aged 6-21 years) using the U.S. CF Foundation Patient Registry. Geomarkers at the ZIP Code Tabulation Area level measured air pollution/respiratory hazards, greenspace, crime, and socioeconomic deprivation. A composite score quantifying social-environmental adversity was created and used in covariate-adjusted functional principal component analysis, which was applied to cluster longitudinal lung function trajectories., Results: Social-environmental phenotyping yielded three primary phenotypes that corresponded to early, middle, and late timing of peak decline in lung function over age. Geographic differences were related to distinct cultural and socioeconomic regions. Extent of peak decline, estimated as forced expiratory volume in 1 s of % predicted/year, ranged from 2.8 to 4.1 % predicted/year depending on social-environmental adversity. Middle decliners with increased social-environmental adversity experienced rapid decline 14.2 months earlier than their counterparts with lower social-environmental adversity, while timing was similar within other phenotypes. Early and middle decliners experienced mortality peaks during early adolescence and adulthood, respectively., Conclusion: While early decliners had the most severe CF lung disease, middle and late decliners lost more lung function. Higher social-environmental adversity associated with increased risk of rapid decline and mortality during young adulthood among middle decliners. This sub-phenotype may benefit from enhanced lung-function monitoring and personalized secondary environmental health interventions to mitigate chemical and non-chemical stressors., Competing Interests: Declaration of Competing Interest Author RDS serves on the Cystic Fibrosis Foundation Patient Registry Committee. The remaining authors have no conflicts of interest to report.

Purpose: Bronchopulmonary dysplasia (BPD) is the most common complication of extreme preterm birth and structural lung abnormalities are frequently found in children with BPD. To quantify lung damage in BPD, three new Hounsfield units (HU) based chest-CT scoring methods were evaluated in terms of 1) intra- and inter-observer variability, 2) correlation with the validated Perth-Rotterdam-Annotated-Grid-Morphometric-Analysis (PRAGMA)-BPD score, and 3) correlation with clinical data., Methods: Chest CT scans of children with severe BPD were performed at a median of 7 months corrected age. Hyper- and hypo-attenuated regions were quantified using PRAGMA-BPD and three new HU based scoring methods (automated, semi-automated, and manual). Intra- and inter-observer variability was measured using intraclass correlation coefficients (ICC) and Bland-Altman plots. The correlation between the 4 scoring methods and clinical data was assessed using Spearman rank correlation., Results: Thirty-five patients (median gestational age 26.1 weeks) were included. Intra- and inter-observer variability was excellent for hyper- and hypo-attenuation regions for the manual HU method and PRAGMA-BPD (ICCs range 0.80-0.97). ICC values for the semi-automated HU method were poorer, in particular for the inter-observer variability of hypo- (0.22-0.71) and hyper-attenuation (-0.06-0.89). The manual HU method was highly correlated with PRAGMA-BPD score for both hyper- (ρs0.92, p < 0.001) and hypo-attenuation (ρs0.79, p < 0.001), while automated and semi-automated HU methods showed poor correlation for hypo- (ρs < 0.22) and good correlation for hyper-attenuation (ρs0.72-0.74, p < 0.001). Several scores of hyperattenuation correlated with the use of inhaled bronchodilators in the first year of life; two hypoattenuation scores correlated with birth weight., Conclusions: PRAGMA-BPD and the manual HU method have the best reproducibility for quantification of CT abnormalities in BPD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: SHIP-CT showed that 48-week treatment with inhaled 7% hypertonic saline (HS) reduced airway abnormalities on chest CT using the manual PRAGMA-CF method relative to isotonic saline (IS) in children aged 3-6 years with cystic fibrosis (CF). An algorithm was developed and validated to automatically measure bronchus and artery (BA) dimensions of BA-pairs on chest CT. Aim of the study was to assess the effect of HS on bronchial wall thickening and bronchial widening using the BA-analysis., Methods: The BA-analysis (LungQ, version 2.1.0.1, Thirona, Netherlands) automatically segments the bronchial tree and identifies the segmental bronchi (G 0 ) and distal generations (G 1 -G 10 ). Dimensions of each BA-pair are measured: diameters of bronchial outer wall (B out ), bronchial inner wall (B in ), bronchial wall thickness (B wt ), and artery (A). BA-ratios are computed: B out /A and B in /A to detect bronchial widening and B wt /A and B wa /B oa (=bronchial wall area/bronchial outer area) to detect bronchial wall thickening., Results: 113 baseline and 102 48-week scans of 115 SHIP-CT participants were analysed. LungQ measured at baseline and 48-weeks respectively 6,073 and 7,407 BA-pairs in the IS-group and 6,363 and 6,840 BA-pairs in the HS-group. At 48 weeks, B wt /A (mean difference 0.011; 95%CI, 0.0017 to 0.020) and B wa /B oa (mean difference 0.030; 95% 0.009 to 0.052) was significantly higher (worse) in the IS-group compared to the HS-group representing more severe bronchial wall thickening in the IS-group (p=0.025 and p=0.019 respectively). B wt /A and B wa /B oa decreased and B in /A remained stable from baseline to 48 weeks in the HS while it declined in the IS-group (all p<0.001). There was no difference in progression of B out /A between two treatment groups., Conclusion: The automatic BA-analysis showed a positive impact of inhaled HS on bronchial lumen and wall thickness, but no treatment effect on progression of bronchial widening over 48 weeks., Competing Interests: Declaration of Competing Interest HAWMT reports grants from the Cystic Fibrosis Foundation and Health Holland, has received in the last 5 years multiple grants from the following public and institutional grant institutions for lung structure and function research: NHMRC, NIH, CFF, ECFS, IMI, Sophia Foundation and unconditional grants for investigator-initiated research from Chiesi, Vectura, Novartis, and Insmed, has acted as consultant for Insmed, TBIO, Thirona, Neupharma and Boehringer, has a part time position as chief medical officer for Thirona, functions as vice chair and faculty for the Advance course sponsored by Vertex, and owns no shares. Erasmus MC and Telethon Kids Institute have licensed the use of PRAGMA-CF to Thirona and Resonance Health. LGE is a scientist working at Thirona. JPC is Co-founder and shareholder at Thirona. DC is director of the Erasmus MC- LungAnalysis laboratory. SDD reports grants from Cystic Fibrosis Foundation. MR reports grants from Cystic Fibrosis Foundation. FR serves as consultant for Vertex, Bayer, Roche, Genentech, and Proteostasis. RAK reports grants from Cystic Fibrosis Foundation. KDHS reports grants from Cystic Fibrosis Foundation. SMS reports grants from the Cystic Fibrosis Foundation and National Health and Medical Research Foundation and Erasmus MC and Telethon Kids Institute have licensed the use of PRAGMA-CF to Thirona and Resonance Health. All other authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Secondhand smoke exposure, an important environmental health factor in cystic fibrosis (CF), remains uniquely challenging to children with CF as they strive to maintain pulmonary function during early stages of growth and throughout adolescence. Despite various epidemiologic studies among CF populations, little has been done to coalesce estimates of the association between secondhand smoke exposure and lung function decline., Methods: A systematic review was performed using PRISMA guidelines. A Bayesian random-effects model was employed to estimate the association between secondhand smoke exposure and change in lung function (measured as FEV 1 % predicted)., Results: Quantitative synthesis of study estimates indicated that second-hand smoke exposure corresponded to a significant drop in FEV 1 (estimated decrease: -5.11% predicted; 95% CI: -7.20, -3.47). The estimate of between-study heterogeneity was 1.32% predicted (95% CI: 0.05, 4.26). There was moderate heterogeneity between the 6 analyzed studies that met review criteria (degree of heterogeneity: I 2 =61.9% [95% CI: 7.3-84.4%] and p = 0.022 from the frequentist method.) CONCLUSIONS: Our results quantify the impact at the pediatric population level and corroborate the assertion that secondhand smoke exposure negatively affects pulmonary function in children with CF. Findings highlight challenges and opportunities for future environmental health interventions in pediatric CF care., Competing Interests: Declaration of Competing Interest Author RS serves on the editorial board of the Journal of Cystic Fibrosis. All other authors disclose no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Rationale: Studies estimating the rate of lung function decline in cystic fibrosis have been inconsistent regarding the methods used. How the methodology used impacts the validity of the results and comparability between studies is unknown. Objectives: The Cystic Fibrosis Foundation established a work group whose tasks were to examine the impact of differing approaches to estimating the rate of decline in lung function and to provide analysis guidelines. Methods: We used a natural history cohort of 35,252 individuals with cystic fibrosis aged ⩾6 years in the Cystic Fibrosis Foundation Patient Registry (CFFPR), 2003-2016. Modeling strategies using linear and nonlinear forms of marginal and mixed-effects models, which have previously quantified the rate of forced expiratory volume in 1 second (FEV 1 ) decline (percent predicted per year), were evaluated under clinically relevant scenarios of available lung function data. Scenarios varied by sample size (overall CFFPR, medium-sized cohort of 3,000 subjects, and small-sized cohort of 150), data collection/reporting frequency (encounter, quarterly, and annual), inclusion of FEV 1 during pulmonary exacerbation, and follow-up length (<2 yr, 2-5 yr, entire duration). Results: Rate of FEV 1 decline estimates (percent predicted per year) differed between linear marginal and mixed-effects models; overall cohort estimates (95% confidence interval) were 1.26 (1.24-1.29) and 1.40 (1.38-1.42), respectively. Marginal models consistently estimated less rapid lung function decline than mixed-effects models across scenarios, except for short-term follow-up (both were ∼1.4). Rate of decline estimates from nonlinear models diverged by age 30. Among mixed-effects models, nonlinear and stochastic terms fit best, except for short-term follow-up (<2 yr). Overall CFFPR analysis from a joint longitudinal-survival model implied that an increase in rate of decline of 1% predicted per year in FEV 1 was associated with a 1.52-fold (52%) increase in the hazard of death/lung transplant, but the results exhibited immortal cohort bias. Conclusions: Differences were as high as 0.5% predicted per year between rate of decline estimates, but we found estimates were robust to lung function data availability scenarios, except short-term follow-up and older age ranges. Inconsistencies among previous study results may be attributable to inherent differences in study design, inclusion criteria, or covariate adjustment. Results-based decision points reported herein will support researchers in selecting a strategy to model lung function decline most reflective of nuanced, study-specific goals.

Pompe disease is a rare, progressive, and metabolic myopathy. Reduced pulmonary function is one of the main problems seen in adult patients with late-onset Pompe disease (LOPD). We aimed to explore the association between changes over time in pulmonary function and in patient-reported outcome measures (PROMs), in these patients treated with enzyme replacement therapy (ERT). This is a post hoc analysis of two cohort studies. Pulmonary function was assessed as forced vital capacity in the upright position (FVC up ). As PROMs, we assessed the physical component summary score (PCS) of the Medical Outcome Study 36-item Short-Form Health Survey (SF-36) and daily life activities (Rasch-Built Pompe-Specific Activity [R-PACT] scale). We fitted Bayesian multivariate mixed-effects models. In the models of PROMs, we assumed a linear association with FVC up , and adjusted for time (nonlinear), sex, and age and disease duration at the start of ERT. One hundred and one patients were eligible for analysis. PCS and R-PAct were positively associated with FVC up , while their relation with time was nonlinear (initial increase then decrease). A 1%-point increase in FVC up is expected to increase PCS by 0.14 points (95% Credible Interval: [0.09;0.19]) and R-PACT by 0.41 points [0.33;0.49] at the same time point. In the first year of ERT, we expect a change of PCS and R-PAct scores by +0.42 and +0.80 points, and in the 5th year of +0.16 and +0.45, respectively. We conclude that the physical domain of quality of life and daily life activities improve when FVC up increases during ERT., (© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: The extent to which environmental exposures and community characteristics of the built environment collectively predict rapid lung function decline, during adolescence and early adulthood in cystic fibrosis (CF), has not been examined., Objective: To identify built environment characteristics predictive of rapid CF lung function decline., Methods: We performed a retrospective, single-center, longitudinal cohort study (n = 173 individuals with CF aged 6-20 years, 2012-2017). We used a stochastic model to predict lung function, measured as forced expiratory volume in 1 s (FEV 1 ) of % predicted. Traditional demographic/clinical characteristics were evaluated as predictors. Built environmental predictors included exposure to elemental carbon attributable to traffic sources (ECAT), neighborhood material deprivation (poverty, education, housing, and healthcare access), greenspace near the home, and residential drivetime to the CF center., Measurements and Main Results: The final model, which included ECAT, material deprivation index, and greenspace, alongside traditional demographic/clinical predictors, significantly improved fit and prediction, compared with only demographic/clinical predictors (Likelihood Ratio Test statistic: 26.78, p < 0.0001; the difference in Akaike Information Criterion: 15). An increase of 0.1 μg/m 3 of ECAT was associated with 0.104% predicted/yr (95% confidence interval: 0.024, 0.183) more rapid decline. Although not statistically significant, material deprivation was similarly associated (0.1-unit increase corresponded to additional decline of 0.103% predicted/year [-0.113, 0.319]). High-risk regional areas of rapid decline and age-related heterogeneity were identified from prediction mapping., Conclusion: Traffic-related air pollution exposure is an important predictor of rapid pulmonary decline that, coupled with community-level material deprivation and routinely collected demographic/clinical characteristics, enhance CF prognostication and enable personalized environmental health interventions., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Patients with breast cancer (BC) with low levels of human epidermal growth factor receptor 2 (HER2) expression (HER2-low) could benefit from novel antibody-drug conjugates. However, there is conflicting information regarding the characteristics of HER2-low BC and its outcome. We assessed the clinicopathologic characteristics and outcomes of HER2-low BC using real-world data from the Dutch National Pathology Registry. This retrospective study incorporated all patients with primary invasive BC, without neoadjuvant therapy, reported in the Dutch National Pathology Registry synoptic reporting module between 2014 and 2022. HER2 status was categorized as HER2-0 (defined as an immunohistochemistry score of 0 according to the current American Society of Clinical Oncology/College of American Pathologists guidelines) or HER2-low (immunohistochemistry score 1+ or 2+ without amplification). Clinicopathologic characteristics and overall survival of HER2-low BC were compared with HER2-0, adjusted for estrogen receptor (ER) status. We included 65,035 patients with BC, resulting in 69,424 tumors. The proportion of HER2-low BC was 62% in the ER+ cohort and 38% in the ER- cohort. A substantial number of patients had a different HER2 category between the needle biopsy and the corresponding surgical resection (28%) or among multiple tumors (28%). After multivariable logistic analysis, HER2-low tumors were significantly associated with histologic subtype, a higher ER, and lower progesterone receptor expression in the ER+ cohort, whereas within the ER-cohort, HER2-low tumors were associated with a lower tumor grade. However, the absolute differences were limited, and there was no significant difference in overall survival between HER2-low and HER2-0 tumors within the ER+ or ER- cohort. The classification of HER2 expression (HER2-0 vs HER2-low) varies between biopsies and corresponding resection specimens and within multiple tumors in the same patient, which could affect clinical decision making in case only HER2-low cases are eligible for novel HER2-targeting agents. The limited follow-up time and the lack of substantial clinicopathologic differences between HER2-low and HER2-0-cases could explain the lack of differences in overall survival., (Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The clinical relevance of postoperative delirium (POD) in neurosurgery remains unclear and should be investigated because these patients are vulnerable. Hence, we investigated the impact of POD, by means of incidence and health outcomes, and identified independent risk factors., Methods: Adult patients undergoing an intracranial surgical procedure in the Erasmus Medical Center Rotterdam between June 2017 and September 2020 were retrospectively included. POD incidence, defined by a Delirium Observation Screening Scale (DOSS) ≥3 or antipsychotic treatment for delirium within 5 days after surgery, was calculated. Logistic regression analysis on the full data set was conducted for the multivariable risk factor and health outcome analyses., Results: After including 2901 intracranial surgical procedures, POD was present in 19.4% with a mean onset in days of 2.62 (standard deviation, 1.22) and associated with more intensive care unit admissions and more discharge toward residential care. Onset of POD was not associated with increased length of hospitalization or mortality. We identified several independent nonmodifiable risk factors such as age, preexisting memory problems, emergency operations, craniotomy compared with burr-hole surgery, and severe blood loss. Moreover, we identified modifiable risk factors such as low preoperative potassium and opioid and dexamethasone administration., Conclusions: Our POD incidence rates and correlation with more intensive care unit admission and discharge toward residential care suggest a significant impact of POD on neurosurgical patients. We identified several modifiable and nonmodifiable risk factors, which shed light on the pathophysiologic mechanisms of POD in this cohort and could be targeted for future intervention studies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Since lung adenocarcinoma (LUAD) biopsies are usually small, it is questionable if their prognostic and predictive information is comparable to what is offered by large resection specimens. This study compares LUAD biopsies and resection specimens for their ability to provide prognostic and predictive parameters., Methods: We selected 187 biopsy specimens with stage I and II LUAD. In 123 cases, subsequent resection specimens were also available. All specimens were evaluated for growth pattern, nuclear grade, fibrosis, inflammation, and genomic alterations. Findings were compared using non-parametric testing for categorical variables. Model performance was assessed using the area under the curve for both biopsies and resection specimens, and overall (OS) and disease-free survival (DFS) was calculated., Results: The overall growth pattern concordance between biopsies and resections was 73.9%. The dominant growth pattern correlated with OS and DFS in resected adenocarcinomas and for high-grade growth pattern in biopsies. Multivariate analysis of biopsy specimens revealed that T2-tumors, N1-status, KRAS mutations and a lack of other driver mutations were associated with poorer survival. Model performance using clinical, histological and genetic data from biopsy specimens for predicting OS and DSF demonstrated an AUC of 0.72 and 0.69, respectively., Conclusions: Our data demonstrated the prognostic relevance of a high-grade growth pattern in biopsy specimens of LUAD. Combining clinical, histological and genetic information in one model demonstrated a suboptimal performance for DFS prediction and good performance for OS prediction. However, for daily practice, more robust (bio)markers are required to predict prognosis and stratify patients for therapy and follow-up., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

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, FEF 25-75 and FEF 75 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.

Introduction: This study aims to provide an overview of outcomes after right ventricular outflow tract (RVOT) reconstruction using different valve substitutes in different age groups for different indications., Methods: The literature was systematically searched for articles published between January 2000 and June 2021 reporting on clinical and/or echocardiographic outcomes after RVOT reconstruction with valve substitutes. A random-effects meta-analysis was conducted for outcomes, and time-related outcomes were visualized by pooled Kaplan-Meier curves. Subgroup analyses were performed according to etiology, implanted valve substitute and patient age., Results: Two hundred and seventeen articles were included, comprising 37,078 patients (age: 22.86 ± 11.29 years; 31.6% female) and 240,581 patient-years of follow-up. Aortic valve disease (Ross procedure, 46.6%) and Tetralogy of Fallot (TOF, 27.0%) were the two main underlying etiologies. Homograft and xenograft accounted for 83.7 and 32.6% of the overall valve substitutes, respectively. The early mortality, late mortality, reintervention and endocarditis rates were 3.36% (2.91-3.88), 0.72%/y (95% CI: 0.62-0.82), 2.62%/y (95% CI: 2.28-3.00), and 0.38%/y (95%CI: 0.31-0.47) for all patients. The early mortality for TOF and truncus arteriosus (TA) were 1.95% (1.31-2.90) and 10.67% (7.79-14.61). Pooled late mortality and reintervention rate were 0.59%/y (0.39-0.89), 1.41%/y (0.87-2.27), and 1.20%/y (0.74-1.94), 10.15%/y (7.42-13.90) for TOF and TA, respectively. Endocarditis rate was 0.21%/y (95% CI: 0.16-0.27) for a homograft substitute and 0.80%/y (95%CI: 0.60-1.09) for a xenograft substitute. Reintervention rate for infants, children and adults was 8.80%/y (95% CI: 6.49-11.95), 4.75%/y (95% CI: 3.67-6.14), and 0.72%/y (95% CI: 0.36-1.42), respectively., Conclusion: This study shows RVOT reconstruction with valve substitutes can be performed with acceptable mortality and morbidity rates for most patients. Reinterventions after RVOT reconstruction with valve substitutes are inevitable for most patients in their life-time, emphasizing the necessity of life-long follow-up and multidisciplinary care. Follow-up protocols should be tailored to individual patients because patients with different etiologies, ages, and implanted valve substitutes have different rates of mortality and morbidity., Systematic Review Registration: [www.crd.york.ac.uk/prospero], identifier [CRD42021271622]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wang, Bakhuis, Veen, Bogers, Etnel, van Der Ven, Roos-Hesselink, Andrinopoulou and Takkenberg.)

Objectives: The emergence of big cardio-thoracic surgery datasets that include not only short-term and long-term discrete outcomes but also repeated measurements over time offers the opportunity to apply more advanced modelling of outcomes. This article presents a detailed introduction to developing and interpreting linear mixed-effects models for repeated measurements in the setting of cardiothoracic surgery outcomes research., Methods: A retrospective dataset containing serial echocardiographic measurements in patients undergoing surgical pulmonary valve replacement from 1986 to 2017 in Erasmus MC was used to illustrate the steps of developing a linear mixed-effects model for clinician researchers., Results: Essential aspects of constructing the model are illustrated with the dataset including theories of linear mixed-effects models, missing values, collinearity, interaction, nonlinearity, model specification, results interpretation and assumptions evaluation. A comparison between linear regression models and linear mixed-effects models is done to elaborate on the strengths of linear mixed-effects models. An R script is provided for the implementation of the linear mixed-effects model., Conclusions: Linear mixed-effects models can provide evolutional details of repeated measurements and give more valid estimates compared to linear regression models in the setting of cardio-thoracic surgery outcomes research., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

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 FEV 1 % 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., Competing Interests: Competing interests: SBC reports personal fees and other from Chiesi Pharmaceuticals, non-financial support and other from Vertex, other from Zambon, other from Insmed, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Supplemental oxygen is the most important treatment for preterm born infants with established bronchopulmonary dysplasia (BPD). However, it is unknown what oxygen saturation levels are optimal to improve outcomes in infants with established BPD from 36 weeks postmenstrual age (PMA) onwards. The aim of this study is to compare the use of a higher oxygen saturation limit (≥95%) to a lower oxygen saturation limit (≥90%) after 36 weeks PMA in infants diagnosed with moderate or severe BPD., Methods and Analysis: This non-blinded, multicentre, randomised controlled trial will recruit 198 preterm born infants with moderate or severe BPD between 36 and 38 weeks PMA. Infants will be randomised to either a lower oxygen saturation limit of 95% or to a lower limit of 90%; supplemental oxygen and/or respiratory support will be weaned based on the assigned lower oxygen saturation limit. Adherence to the oxygen saturation limit will be assessed by extracting oxygen saturation profiles from pulse oximeters regularly, until respiratory support is stopped. The primary outcome is the weight SD score at 6 months of corrected age. Secondary outcomes include anthropometrics collected at 6 and 12 months of corrected age, rehospitalisations, respiratory complaints, infant stress, parental quality of life and cost-effectiveness., Ethics and Dissemination: Ethical approval for the trial was obtained from the Medical Ethics Review Committee of the Erasmus University Medical Centre, Rotterdam, the Netherlands (MEC-2018-1515). Local approval for conducting the trial in the participating hospitals has been or will be obtained from the local institutional review boards. Informed consent will be obtained from the parents or legal guardians of all study participants., Trial Registration Number: NL7149/NTR7347., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Surgery for thumb carpometacarpal osteoarthritis is offered to patients who do not benefit from nonoperative treatment. Although surgery is generally successful in reducing symptoms, not all patients benefit. Predicting clinical improvement after surgery could provide decision support and enhance preoperative patient selection., Questions/purposes: This study aimed to develop and validate prediction models for clinically important improvement in (1) pain and (2) hand function 12 months after surgery for thumb carpometacarpal osteoarthritis., Methods: Between November 2011 and June 2020, 2653 patients were surgically treated for thumb carpometacarpal osteoarthritis. Patient-reported outcome measures were used to preoperatively assess pain, hand function, and satisfaction with hand function, as well as the general mental health of patients and mindset toward their condition. Patient characteristics, medical history, patient-reported symptom severity, and patient-reported mindset were considered as possible predictors. Patients who had incomplete Michigan Hand outcomes Questionnaires at baseline or 12 months postsurgery were excluded, as these scores were used to determine clinical improvement. The Michigan Hand outcomes Questionnaire provides subscores for pain and hand function. Scores range from 0 to 100, with higher scores indicating less pain and better hand function. An improvement of at least the minimum clinically important difference (MCID) of 14.4 for the pain score and 11.7 for the function score were considered "clinically relevant." These values were derived from previous reports that provided triangulated estimates of two anchor-based and one distribution-based MCID. Data collection resulted in a dataset of 1489 patients for the pain model and 1469 patients for the hand function model. The data were split into training (60%), validation (20%), and test (20%) dataset. The training dataset was used to select the predictive variables and to train our models. The performance of all models was evaluated in the validation dataset, after which one model was selected for further evaluation. Performance of this final model was evaluated on the test dataset. We trained the models using logistic regression, random forest, and gradient boosting machines and compared their performance. We chose these algorithms because of their relative simplicity, which makes them easier to implement and interpret. Model performance was assessed using discriminative ability and qualitative visual inspection of calibration curves. Discrimination was measured using area under the curve (AUC) and is a measure of how well the model can differentiate between the outcomes (improvement or no improvement), with an AUC of 0.5 being equal to chance. Calibration is a measure of the agreement between the predicted probabilities and the observed frequencies and was assessed by visual inspection of calibration curves. We selected the model with the most promising performance for clinical implementation (that is, good model performance and a low number of predictors) for further evaluation in the test dataset., Results: For pain, the random forest model showed the most promising results based on discrimination, calibration, and number of predictors in the validation dataset. In the test dataset, this pain model had a poor AUC (0.59) and poor calibration. For function, the gradient boosting machine showed the most promising results in the validation dataset. This model had a good AUC (0.74) and good calibration in the test dataset. The baseline Michigan Hand outcomes Questionnaire hand function score was the only predictor in the model. For the hand function model, we made a web application that can be accessed via https://analyse.equipezorgbedrijven.nl/shiny/cmc1-prediction-model-Eng/., Conclusion: We developed a promising model that may allow clinicians to predict the chance of functional improvement in an individual patient undergoing surgery for thumb carpometacarpal osteoarthritis, which would thereby help in the decision-making process. However, caution is warranted because our model has not been externally validated. Unfortunately, the performance of the prediction model for pain is insufficient for application in clinical practice., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2022 by the Association of Bone and Joint Surgeons.)

Background: In the Saline Hypertonic in Preschoolers (SHIP) study, inhaled 7% hypertonic saline improved the lung clearance index in children aged 3-6 years with cystic fibrosis, but it remained unclear whether improvement is also seen in structural lung disease. We aimed to assess the effect of inhaled hypertonic saline on chest CT imaging in children aged 3-6 years with cystic fibrosis., Methods: Children with cystic fibrosis were enrolled in this multicentre, randomised, double-blind, controlled study at 23 cystic fibrosis centres in Spain, Denmark, the Netherlands, Italy, France, Belgium, the USA, Canada, and Australia. Eligible participants were children aged 3-6 years who were able to cooperate with chest CT imaging and comply with daily nebuliser treatment. Participants were randomly assigned 1:1 to receive inhaled 2 puffs of 100 μg salbutamol followed by 4mL of either 7% hypertonic saline or 0·9% isotonic saline twice per day for 48 weeks. Randomisation was stratified by age in North America and Australia, and by age and country in Europe. Chest CTs were obtained at baseline and 48 weeks and scored using the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis (PRAGMA-CF) method. The primary outcome was the difference between groups in the percentage of total lung volume occupied by abnormal airways (PRAGMA-CF %Disease) measured by chest CT at 48 weeks. Analysis was by intention-to-treat. This study is registered with Clinicaltrials.gov, NCT02950883., Findings: Between May 24, 2016, and Dec 18, 2019, 134 children were assessed for inclusion. 18 patients were excluded (nine had incomplete or unsuccessful chest CT at enrolment visit, two could not comply with CT training, two had acute respiratory infection, two withdrew consent, two for reasons unknown, and one was already on hypertonic saline). 116 participants were enrolled and randomly assigned to hypertonic saline (n=56) or isotonic saline (n=60). 12 patients dropped out of the study (seven in the hypertonic saline group and five in the isotonic saline group). Mean PRAGMA-CF %Disease at 48 weeks was 0·88% (95% CI 0·60-1·16) in the hypertonic saline group and 1·55% (1·25-1·84) in the isotonic saline group (mean difference 0·67%, 95% CI 0·26-1·08; p=0·0092) based on a linear regression model adjusted for baseline %Disease values and baseline age. Most adverse events in both groups were rated as mild, and the most common adverse event in both groups was cough., Interpretation: Inhaled hypertonic saline for 48 weeks had a positive effect on structural lung changes in children aged 3-6 years with cystic fibrosis relative to isotonic saline. This is the first demonstration of an intervention that alters structural lung disease in children aged 3-6 years with cystic fibrosis., Funding: Cystic Fibrosis Foundation., Competing Interests: Declaration of interests HAWMT reports grants from the Cystic Fibrosis Foundation and Health Holland, is director of the Erasmus MC- LungAnalysis laboratory, which also acts as the ECFS-CTN CT expert centre, and serves as consultant for Thirona on image analysis. Erasmus MC is expected to receive future license royalties for PRAGMA-CF. SDD reports grants from Cystic Fibrosis Foundation. MR reports grants from Cystic Fibrosis Foundation. FR served as consultant for Vertex, Bayer, Roche, Genentech, and Proteostasis. RAK reports grants from Cystic Fibrosis Foundation. KDHS reports grants from Cystic Fibrosis Foundation. SMS reports grants from the Cystic Fibrosis Foundation and National Health and Medical Research Foundation, and Telethon Kids Institute is expected to receive future license royalties for PRAGMA-CF. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Percentage Gleason pattern 4, invasive cribriform and/or intraductal carcinoma (IC/IDC) and minor pattern 5 are recognized as independent parameters for prostate cancer outcome, but are not incorporated in current grade groups (GGs). Two proof-of-principle studies have proposed alternative grading schemes based on percentage Gleason pattern 4/5 (integrated quantitative Gleason score; IQ-Gleason) and IC/IDC presence (cribriform grade; cGrade). Our objective was to compare the performance of GG, IQ-Gleason and cGrade for predicting biochemical recurrence and metastasis after radical prostatectomy (RP). RP specimens of 1064 patients were pathologically reviewed and graded according to the three schemes. Discriminative power for prediction of biochemical recurrence-free (BCRFS) and metastasis-free (MFS) survival was compared using Harrell's c-index. The GG distribution at RP was 207 (19.4%) GG1, 472 (44.4%) GG2, 126 (11.8%) GG3, 140 (13.2%) GG4 and 119 (11.2%) GG5. Grading according to 5-tier IQ-Gleason and cGrade systems led to categorical shifts in 49.8% and 29.7% of cases, respectively. Continuous IQ-Gleason had the best performance for predicting BCRFS (c-index 0.743, 95% confidence interval (CI) 0.715-0.771), followed by cGrade (c-index 0.738, 95%CI 0.712-0.759), 5-tier categorical IQ-Gleason (c-index 0.723, 95%CI 0.695-0.750) and GG (c-index 0.718, 95%CI 0.691-0.744). Continuous IQ-Gleason (c-index 0.834, 95%CI 0.802-0.863) and cGrade (c-index 0.834, 95%CI 0.808-0.866) both had better predictive value for MFS than categorical IQ-Gleason (c-index 0.823, 95%CI 0.788-0.857) and GG (c-index 0.806, 95%CI 0.777-0.839). In conclusion, the performance of prostate cancer grading can be improved by alternative grading schemes incorporating percent Gleason pattern 4/5 and IC/IDC., (© 2022. The Author(s).)

Transcranial direct current stimulation (tDCS) over the contralateral primary motor cortex of the target muscle (conventional tDCS) has been described to enhance corticospinal excitability, as measured with transcranial magnetic stimulation. Recently, tDCS targeting the brain regions functionally connected to the contralateral primary motor cortex (motor network tDCS) was reported to enhance corticospinal excitability more than conventional tDCS. We compared the effects of motor network tDCS, 2 mA conventional tDCS, and sham tDCS on corticospinal excitability in 21 healthy participants in a randomized, single-blind within-subject study design. We applied tDCS for 12 min and measured corticospinal excitability with TMS before tDCS and at 0, 15, 30, 45, and 60 min after tDCS. Statistical analysis showed that neither motor network tDCS nor conventional tDCS significantly increased corticospinal excitability relative to sham stimulation. Furthermore, the results did not provide evidence for superiority of motor network tDCS over conventional tDCS. Motor network tDCS seems equally susceptible to the sources of intersubject and intrasubject variability previously observed in response to conventional tDCS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Van der Cruijsen, Jonker, Andrinopoulou, Wijngaarden, Tangkau, Tulen, Frens, Ribbers and Selles.)

Multiple studies have reported the effectiveness of treatment on contracture reduction in Dupuytren's disease. However, very few studies have attempted to quantify to which extent patient and disease characteristics influence the chance of achieving a straight finger after surgery. Therefore, the aim of this study is to explore to which extent pre-operative patient and disease characteristics can reliably predict a straight finger after surgery for Dupuytren's disease. In total, 812 and 281 patients, who underwent a limited fasciectomy or needle fasciotomy, respectively, were included in the final analyses. Analysis was performed using a logistic modeling framework. For both treatments, the combination of the extension deficit at baseline; which finger is most affected, which joint is most affected, and the number of affected fingers provided reliable predictions. Classical patient characteristics, such as age and sex, had no additional predictive value. The models presented in this study provide reliable predictions and could be helpful in informing patients and managing their expectations., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

This study proposes a Bayesian joint model with extended random effects structure that incorporates nested repeated measures and provides simultaneous inference on treatment effects over time and drop-out patterns. The proposed model includes flexible splines to characterize the circadian variation inherent in blood pressure sequences, and we assess the effectiveness of an intervention to resolve pediatric obstructive sleep apnea. We demonstrate that the proposed model and its conventional two-stage counterpart provide similar estimates of nighttime blood pressure but estimates on the mean evolution of daytime blood pressure are discrepant. Our simulation studies tailored to the motivating data suggest reasonable estimation and coverage probabilities for both fixed and random effects. Computational challenges of model implementation are discussed., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2022 Enas M. Ghulam et al.)

Background: Symptom improvement is an important goal when considering surgery for carpal tunnel syndrome. There is currently no prediction model available to predict symptom improvement for patients considering a carpal tunnel release (CTR)., Objective: To predict using a model the probability of clinically relevant symptom improvement at 6 mo after CTR., Methods: We split a cohort of 2119 patients who underwent a mini-open CTR and completed the Boston Carpal Tunnel Questionnaire preoperatively and 6 mo postoperatively into training (75%) and validation (25%) data sets. Patients who improved more than the minimal clinically important difference of 0.8 at the Boston Carpal Tunnel Questionnaire-symptom severity scale were classified as "improved." Logistic regression, random forests, and gradient boosting machines were considered to train prediction models. The best model was selected based on discriminative ability (area under the curve) and calibration in the validation data set. This model was further assessed in a holdout data set (N = 397)., Results: A gradient boosting machine with 5 predictors was chosen as optimal trade-off between discriminative ability and the number of predictors. In the holdout data set, this model had an area under the curve of 0.723, good calibration, sensitivity of 0.77, and specificity of 0.55. The positive predictive value was 0.50, and the negative predictive value was 0.81., Conclusion: We developed a prediction model for clinically relevant symptom improvement 6 mo after a CTR, which required 5 patient-reported predictors (18 questions) and has reasonable discriminative ability and good calibration. The model is available online and might help shared decision making when patients are considering a CTR., (Copyright © Congress of Neurological Surgeons 2021. All rights reserved.)

Individualized prediction is a hallmark of clinical medicine and decision making. However, most existing prediction models rely on biomarkers and clinical outcomes available at a single time. This is in contrast to how health states progress and how physicians deliver care, which relies on progressively updating a prognosis based on available information. With the use of joint models of longitudinal and survival data, it is possible to dynamically adjust individual predictions regarding patient prognosis. This article aims to introduce the reader to the development of dynamic risk predictions and to provide the necessary resources to support their implementation and assessment, such as adaptable R code, and the theory behind the methodology. Furthermore, measures to assess the predictive performance of the derived predictions and extensions that could improve the predictions are presented. We illustrate personalized predictions using an online dataset consisting of patients with chronic liver disease (primary biliary cirrhosis)., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

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., Competing Interests: Declaration of Competing Interest None., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Disclosure:The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors received no financial support for research, authorship, and/or publication of this article., (Copyright © 2021 by the American Society of Plastic Surgeons.)

Background: Dupilumab was equally effective among all racial subgroups in clinical trials, but a direct comparison in daily practice is lacking., Objectives: To investigate the effectiveness of dupilumab in patients with atopic dermatitis (AD) in the Netherlands and Japan over 80 weeks of treatment., Methods: A longitudinal comparative cohort study was conducted in patients with AD who were treated with dupilumab in daily practice. We used linear mixed-effects models to determine changes over time., Results: We found statistically significant differences in sex, disease onset, body mass index and therapeutic history between Dutch (n = 208) and Japanese (n = 153) patients. The baseline Eczema Area and Severity Index (EASI) score was higher in Japanese patients (23·8 vs. 14·8), while baseline Patient-Reported Outcome Measures (PROMs) were higher in Dutch patients. EASI scores decreased quickly to a level indicating 'mild disease' (EASI < 7), and remained low in both countries. However, PROMs showed different trajectories with better scores in Japan., Conclusions: Dupilumab showed significant, comparable and sustained improvement of EASI scores in Japanese and Dutch patients. However, we found striking differences in the effect on PROMs between the countries, with a better outcome in Japanese patients., (© 2021 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

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., (Copyright © 2021 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Characterizing seasonal trend in lung function in individuals with chronic lung disease may lead to timelier treatment of acute respiratory symptoms and more precise distinction between seasonal exposures and variability. Limited research has been conducted to assess localized seasonal fluctuation in lung function decline in individuals with cystic fibrosis (CF) in context with routinely collected demographic and clinical data. We conducted a longitudinal cohort study of 253 individuals aged 6-22 years with CF receiving care at a pediatric Midwestern US CF center with median (range) of follow-up time of 4.7 (0-9.95) years, implementing two distinct models to estimate seasonality effects. The outcome, lung function, was measured as percent-predicted of forced expiratory volume in 1 second (FEV 1 ). Both models showed that older age, being male, using Medicaid insurance and having Pseudomonas aeruginosa infection corresponded to accelerated FEV 1 decline. A sine wave model for seasonality had better fit to the data, compared to a linear model with categories for seasonality. Compared to international cohorts, seasonal fluctuations occurred earlier and with greater volatility, even after adjustment for ambient temperature. Average lung function peaked in February and dipped in August, and FEV1 fluctuation was 0.81 % predicted (95% CI: 0.52 to 1.1). Adjusting for temperature shifted the peak and dip to March and September, respectively, and decreased FEV 1 fluctuation to 0.45 % predicted (95% CI: 0.08 to 0.82). Understanding localized seasonal variation and its impact on lung function may allow researchers to perform precision public health for lung diseases and disorders at the point-of-care level.

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., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This study develops a comprehensive method to assess seasonal influences on a longitudinal marker and compare estimates between cohorts. The method extends existing approaches by (i) combining a sine-cosine model of seasonality with a specialized covariance function for modeling longitudinal correlation; (ii) performing mediation analysis on a seasonality model. An example dataset and R code are provided. The bundle of methods is referred to as seasonality, mediation and comparison (SMAC). The case study described utilizes lung function as the marker observed on a cystic fibrosis cohort but SMAC can be used to evaluate other markers and in other disease contexts. Key aspects of customization are as follows.•This study introduces a novel seasonality model to fit trajectories of lung function decline and demonstrates how to compare this model to a conventional model in this context.•Steps required for mediation analyses in the seasonality model are shown.•The necessary calculations to compare seasonality models between cohorts, based on estimation coefficients, are derived in the study., Competing Interests: The authors have no competing interests to declare., (© 2021 The Authors. Published by Elsevier B.V.)