The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN

Primary ciliary dyskinesia; Rare genetic disorder; Lung diseasesDiscinesia ciliar primaria; Trastorno genético raro; Enfermedades pulmonaresDiscinesia ciliar primària; Trastorn genètic rar; Malalties pulmonarsPrimary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients

Airspace Diameter Map-A Quantitative Measurement of All Pulmonary Airspaces to Characterize Structural Lung Diseases.

(1) Background: Stereological estimations significantly contributed to our understanding of lung anatomy and physiology. Taking stereology fully 3-dimensional facilitates the estimation of novel parameters. (2) Methods: We developed a protocol for the analysis of all airspaces of an entire lung. It includes (i) high-resolution synchrotron radiation-based X-ray tomographic microscopy, (ii) image segmentation using the free machine-learning tool Ilastik and ImageJ, and (iii) calculation of the airspace diameter distribution using a diameter map function. To evaluate the new pipeline, lungs from adult mice with cystic fibrosis (CF)-like lung disease (βENaC-transgenic mice) or mice with elastase-induced emphysema were compared to healthy controls. (3) Results: We were able to show the distribution of airspace diameters throughout the entire lung, as well as separately for the conducting airways and the gas exchange area. In the pathobiological context, we observed an irregular widening of parenchymal airspaces in mice with CF-like lung disease and elastase-induced emphysema. Comparable results were obtained when analyzing lungs imaged with μCT, sugges-ting that our pipeline is applicable to different kinds of imaging modalities. (4) Conclusions: We conclude that the airspace diameter map is well suited for a detailed analysis of unevenly distri-buted structural alterations in chronic muco-obstructive lung diseases such as cystic fibrosis and COPD

Dynamics of respiratory symptoms during infancy and associations with wheezing at school age

Children with frequent respiratory symptoms in infancy have an increased risk for later wheezing, but the association with symptom dynamics is unknown. We developed an observer-independent method to characterise symptom dynamics and tested their association with subsequent respiratory morbidity. In this birth-cohort of healthy neonates, we prospectively assessed weekly respiratory symptoms during infancy, resulting in a time series of 52 symptom scores. For each infant, we calculated the transition probability between two consecutive symptom scores. We used these transition probabilities to construct a Markov matrix, which characterised symptom dynamics quantitatively using an entropy parameter. Using this parameter, we determined phenotypes by hierarchical clustering. We then studied the association between phenotypes and wheezing at 6 years. In 322 children with complete data for symptom scores during infancy (16 864 observations), we identified three dynamic phenotypes. Compared to the low-risk phenotype, the high-risk phenotype, defined by the highest entropy parameter, was associated with an increased risk of wheezing (odds ratio (OR) 3.01, 95% CI 1.15-7.88) at 6 years. In this phenotype, infants were more often male (64%) and had been exposed to environmental tobacco smoke (31%). In addition, more infants had siblings (67%) and attended childcare (38%). We describe a novel method to objectively characterise dynamics of respiratory symptoms in infancy, which helps identify abnormal clinical susceptibility and recovery patterns of infant airways associated with persistent wheezing

A BEAT-PCD consensus statement:a core outcome set for pulmonary disease interventions in primary ciliary dyskinesia

BACKGROUND: Consistent use of reliable and clinically appropriate outcome measures is a priority for clinical trials, with clear definitions to allow comparability. We aimed to develop a core outcome set (COS) for pulmonary disease interventions in primary ciliary dyskinesia (PCD).METHODS: A multidisciplinary international PCD expert panel was set up. A list of outcomes was created based on published literature. Using a modified three-round e-Delphi technique, the panel was asked to decide on relevant end-points related to pulmonary disease interventions and how they should be reported. First, inclusion of an outcome in the COS was determined. Second, the minimum information that should be reported per outcome. The third round finalised statements. Consensus was defined as ≥80% agreement among experts.RESULTS: During the first round, experts reached consensus on four out of 24 outcomes to be included in the COS. Five additional outcomes were discussed in subsequent rounds for their use in different subsettings. Consensus on standardised methods of reporting for the COS was reached. Spirometry, health-related quality-of-life scores, microbiology and exacerbations were included in the final COS.CONCLUSION: This expert consensus resulted in a COS for clinical trials on pulmonary health among people with PCD.</p

The disease-specific clinical trial network for primary ciliary dyskinesia: PCD-CTN

Primary ciliary dyskinesia (PCD) is a rare genetic disorder characterised by impaired mucociliary clearance leading to irreversible lung damage. In contrast to other rare lung diseases like cystic fibrosis (CF), there are only few clinical trials and limited evidence-based treatments. Management is mainly based on expert opinions and treatment is challenging due to a wide range of clinical manifestations and disease severity. To improve clinical and translational research and facilitate development of new treatments, the clinical trial network for PCD (PCD-CTN) was founded in 2020 under the framework of the European Reference Network (ERN)-LUNG PCD Core. Applications from European PCD sites interested in participating in the PCD-CTN were requested. Inclusion criteria consisted of patient numbers, membership of ERN-LUNG PCD Core, use of associated standards of care, experience in PCD and/or CF clinical research, resources to run clinical trials, good clinical practice (GCP) certifications and institutional support. So far, applications from 22 trial sites in 18 European countries have been approved, including >1400 adult and >1600 paediatric individuals with PCD. The PCD-CTN is headed by a coordinating centre and consists of a steering and executive committee, a data safety monitoring board and committees for protocol review, training and standardisation. A strong association with patient organisations and industrial companies are further cornerstones. All participating trial sites agreed on a code of conduct. As CTNs from other diseases have demonstrated successfully, this newly formed PCD-CTN operates to establish evidence-based treatments for this orphan disease and to bring new personalised treatment approaches to patients

A modified CO2/O2 Guedel airway improves capnographic accuracy compared with a CO2/O2 nasal cannula: An infant manikin study.

BACKGROUND Capnography via a CO2/O2 nasal cannula is commonly used for respiratory monitoring during sedation. However, signal disturbances are frequently encountered, especially in young children. OBJECTIVE Sampling ports placed closer to the trachea have been shown to result in improved signal quality. In a manikin model of a 6-month-old infant we compared capnography from a modified Guedel airway with a CO2 port located at the tip with that from a CO2/O2 nasal cannula. DESIGN A comparison study using an artificial model of a breathing 6-month-old infant. SETTING Department of Paediatrics, Inselspital Bern, Switzerland, from March 2016 to June 2016. MATERIAL Modified CO2/O2 Guedel airway. INTERVENTIONS Capnography using a modified CO2/O2 Guedel airway or a CO2/O2 nasal cannula was performed for tidal volumes of 20 to 80 ml (in steps of 20 ml), respiratory rates of 20 to 60 min (in steps of 10 min) and with different O2 flows (0 to 2 l min, in steps of 0.5 l). MAIN OUTCOME MEASURES Comparison of differences between tracheal and device CO2. Secondary outcomes included the effect of various respiratory settings and O2 flows on the CO2 difference. RESULTS The tracheal to device CO2 difference was significantly smaller when using a modified CO2/O2 Guedel airway vs. a CO2/O2 nasal cannula: Mean ± SD, 16.8 ± 4.9 vs. 24.1 ± 5.9 mmHg, P less than 0.0001. An O2 flow of 0.5 to 2 l min did not influence the tracheal to device CO2 difference with the modified CO2/O2 Guedel airway in contrast to the CO2/O2 nasal cannula where there were significant differences (P < 0.0001). The effect of various tidal volumes and respiratory rates proved to be similar in both devices. CONCLUSION Capnography traces derived from a sample port at the tip of a modified CO2/O2 Guedel airway were more accurate than those obtained from a CO2/O2 nasal cannula. TRIAL REGISTRATION Not applicable

Small neuroendocrine tumor of the duodenal bulb: Endoscopic submucosal dissection, laparoscopic and endoscopic cooperative surgery or surgery?

Neuroendocrine neoplasms of the gastric tube are less common than adenocarcinomas. Topography includes stomach, small intestine, Vater ampulla, and gross intestine. They are graded as neuroendocrine tumors grade I and II (NETs GI and GII) and neuroendocrine carcinomas GIII based on Ki-67 index and mitotic count.[1] Endoscopic treatment for GI NETs ≤1 cm that does not extend beyond the submucosal layer and does not demonstrate lymph node metastasis is recommended. Tumors ≥2 cm, with lymph node metastasis, are indicated for surgical treatment. The treatment strategy for tumors between 10 and 20 mm in size remains controversial.[2] We present a rare case of a 60-year-old male patient with end-stage renal failure who underwent a screening pretransplantation endoscopic control. Colonoscopy had no pathological findings. Gastroscopy reveals an abnormal mucosa in the anterior upper part of the duodenal bulb that was described as a micronodular mucosa and a central nodule of 6 mm with erythematous mucosa. Histology of the micronodular mucosa reveals a heterotopic gastric mucosa and a small hyperplastic polyp. Biopsies from the nodule reveal a carcinoid tumor (NET GI). Immunohistochemistry: Positive chromogranin levels, low mitotic index (1/10 HPF), and Ki-67 index 2 cm) and those of the duodenal bulb with histological extensions and the lack of assessing depth invasion

A multi-scale model of gas transport in the lung to study heterogeneous lung ventilation during the multiple-breath washout test.

The multiple-breath washout (MBW) is a lung function test that measures the degree of ventilation inhomogeneity (VI). The test is used to identify small airway impairment in patients with lung diseases like cystic fibrosis. However, the physical and physiological factors that influence the test outcomes and differentiate health from disease are not well understood. Computational models have been used to better understand the interaction between anatomical structure and physiological properties of the lung, but none of them has dealt in depth with the tracer gas washout test in a whole. Thus, our aim was to create a lung model that simulates the entire MBW and investigate the role of lung morphology and tissue mechanics on the tracer gas washout procedure. To this end, we developed a multi-scale lung model to simulate the inert gas transport in airways of all size. We then applied systematically different modifications to geometrical and mechanical properties of the lung model (compliance, residual airway volume and flow resistance) which have been associated with VI. The modifications were applied to distinct parts of the model, and their effects on the gas distribution within the lung and on the gas concentration profile were assessed. We found that variability in compliance and residual volume of the airways, as well as the spatial distribution of this variability in the lung had a direct influence on gas distribution among airways and on the MBW pattern (washout duration, characteristic concentration profile during each expiration), while the effects of variable flow resistance were negligible. Based on these findings, it is possible to classify different types of inhomogeneities in the lung and relate them to specific features of the MBW pattern, which builds the basis for a more detailed association of lung function and structure