Phenotyping of COPD with MRI in comparison to same-day CT in a multi-centre trial.

OBJECTIVES: A prospective, multi-centre study to evaluate concordance of morphologic lung MRI and CT in chronic obstructive pulmonary disease (COPD) phenotyping for airway disease and emphysema. METHODS: A total of 601 participants with COPD from 15 sites underwent same-day morpho-functional chest MRI and paired inspiratory-expiratory CT. Two readers systematically scored bronchial wall thickening, bronchiectasis, centrilobular nodules, air trapping and lung parenchyma defects in each lung lobe and determined COPD phenotype. A third reader acted as adjudicator to establish consensus. Inter-modality and inter-reader agreement were assessed using Cohen's kappa (im-κ and ir-κ). RESULTS: The mean combined MRI score for bronchiectasis/bronchial wall thickening was 4.5/12 (CT scores, 2.2/12 for bronchiectasis and 6/12 for bronchial wall thickening; im-κ, 0.04-0.3). Expiratory right/left bronchial collapse was observed in 51 and 47/583 on MRI (62 and 57/599 on CT; im-κ, 0.49-0.52). Markers of small airways disease on MRI were 0.15/12 for centrilobular nodules (CT, 0.34/12), 0.94/12 for air trapping (CT, 0.9/12) and 7.6/12 for perfusion deficits (CT, 0.37/12 for mosaic attenuation; im-κ, 0.1-0.41). The mean lung defect score on MRI was 1.3/12 (CT emphysema score, 5.8/24; im-κ, 0.18-0.26). Airway-/emphysema/mixed COPD phenotypes were assigned in 370, 218 and 10 of 583 cases on MRI (347, 218 and 34 of 599 cases on CT; im-κ, 0.63). For all examined features, inter-reader agreement on MRI was lower than on CT. CONCLUSION: Concordance of MRI and CT for phenotyping of COPD in a multi-centre setting was substantial with variable inter-modality and inter-reader concordance for single diagnostic key features. CLINICAL RELEVANCE STATEMENT: MRI of lung morphology may well serve as a radiation-free imaging modality for COPD in scientific and clinical settings, given that its potential and limitations as shown here are carefully considered. KEY POINTS: • In a multi-centre setting, MRI and CT showed substantial concordance for phenotyping of COPD (airway-/emphysema-/mixed-type). • Individual features of COPD demonstrated variable inter-modality concordance with features of pulmonary hypertension showing the highest and bronchiectasis showing the lowest concordance. • For all single features of COPD, inter-reader agreement was lower on MRI than on CT.

Protocol of the IntenSify-Trial: An open-label phase I trial of the CYP3A inhibitor cobicistat and the cytostatics gemcitabine and nab-paclitaxel in patients with advanced stage or metastatic pancreatic ductal adenocarcinoma to evaluate the combination's pharmacokinetics, safety, and efficacy.

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab-paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab-paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab-paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m2 ) and cobicistat (150 mg) are fixed, three dose levels of nab-paclitaxel (75, 100, and 125 mg/m2 ) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT-Nr. 2019-001439-29, drks.de: DRKS00029409, and ct.gov: NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab-paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large-scale clinical study.

"Will I change nodule management recommendations if I change my CAD system?"-impact of volumetric deviation between different CAD systems on lesion management.

OBJECTIVES: To evaluate and compare the measurement accuracy of two different computer-aided diagnosis (CAD) systems regarding artificial pulmonary nodules and assess the clinical impact of volumetric inaccuracies in a phantom study. METHODS: In this phantom study, 59 different phantom arrangements with 326 artificial nodules (178 solid, 148 ground-glass) were scanned at 80 kV, 100 kV, and 120 kV. Four different nodule diameters were used: 5 mm, 8 mm, 10 mm, and 12 mm. Scans were analyzed by a deep-learning (DL)-based CAD and a standard CAD system. Relative volumetric errors (RVE) of each system vs. ground truth and the relative volume difference (RVD) DL-based vs. standard CAD were calculated. The Bland-Altman method was used to define the limits of agreement (LOA). The hypothetical impact on LungRADS classification was assessed for both systems. RESULTS: There was no difference between the three voltage groups regarding nodule volumetry. Regarding the solid nodules, the RVE of the 5-mm-, 8-mm-, 10-mm-, and 12-mm-size groups for the DL CAD/standard CAD were 12.2/2.8%, 1.3/ - 2.8%, - 3.6/1.5%, and - 12.2/ - 0.3%, respectively. The corresponding values for the ground-glass nodules (GGN) were 25.6%/81.0%, 9.0%/28.0%, 7.6/20.6%, and 6.8/21.2%. The mean RVD for solid nodules/GGN was 1.3/ - 15.2%. Regarding the LungRADS classification, 88.5% and 79.8% of all solid nodules were correctly assigned by the DL CAD and the standard CAD, respectively. 14.9% of the nodules were assigned differently between the systems. CONCLUSIONS: Patient management may be affected by the volumetric inaccuracy of the CAD systems and hence demands supervision and/or manual correction by a radiologist. KEY POINTS: • The DL-based CAD system was more accurate in the volumetry of GGN and less accurate regarding solid nodules than the standard CAD system. • Nodule size and attenuation have an effect on the measurement accuracy of both systems; tube voltage has no effect on measurement accuracy. • Measurement inaccuracies of CAD systems can have an impact on patient management, which demands supervision by radiologists.

Quantitative CT analysis of lung parenchyma to improve malignancy risk estimation in incidental pulmonary nodules.

OBJECTIVES: To assess the value of quantitative computed tomography (QCT) of the whole lung and nodule-bearing lobe regarding pulmonary nodule malignancy risk estimation. METHODS: A total of 251 subjects (median [IQR] age, 65 (57-73) years; 37% females) with pulmonary nodules on non-enhanced thin-section CT were retrospectively included. Twenty percent of the nodules were malignant, the remainder benign either histologically or at least 1-year follow-up. CT scans were subjected to in-house software, computing parameters such as mean lung density (MLD) or peripheral emphysema index (pEI). QCT variable selection was performed using logistic regression; selected variables were integrated into the Mayo Clinic and the parsimonious Brock Model. RESULTS: Whole-lung analysis revealed differences between benign vs. malignant nodule groups in several parameters, e.g. the MLD (-766 vs. -790 HU) or the pEI (40.1 vs. 44.7 %). The proposed QCT model had an area-under-the-curve (AUC) of 0.69 (95%-CI, 0.62-0.76) based on all available data. After integrating MLD and pEI into the Mayo Clinic and Brock Model, the AUC of both clinical models improved (AUC, 0.91 to 0.93 and 0.88 to 0.91, respectively). The lobe-specific analysis revealed that the nodule-bearing lobes had less emphysema than the rest of the lung regarding benign (EI, 0.5 vs. 0.7 %; p < 0.001) and malignant nodules (EI, 1.2 vs. 1.7 %; p = 0.001). CONCLUSIONS: Nodules in subjects with higher whole-lung metrics of emphysema and less fibrosis are more likely to be malignant; hereby the nodule-bearing lobes have less emphysema. QCT variables could improve the risk assessment of incidental pulmonary nodules. KEY POINTS: • Nodules in subjects with higher whole-lung metrics of emphysema and less fibrosis are more likely to be malignant. • The nodule-bearing lobes have less emphysema compared to the rest of the lung. • QCT variables could improve the risk assessment of incidental pulmonary nodules.

Influence of Lung Reconstruction Algorithms on Interstitial Lung Pattern Recognition on CT.

Despite current recommendations, there is no recent scientific study comparing the influence of CT reconstruction kernels on lung pattern recognition in interstitial lung disease (ILD).To evaluate the sensitivity of lung (i70) and soft (i30) CT kernel algorithms for the diagnosis of ILD patterns.We retrospectively extracted between 15-25 pattern annotations per case (1 annotation = 15 slices of 1 mm) from 23 subjects resulting in 408 annotation stacks per lung kernel and soft kernel reconstructions. Two subspecialized chest radiologists defined the ground truth in consensus. 4 residents, 2 fellows, and 2 general consultants in radiology with 3 to 13 years of experience in chest imaging performed a blinded readout. In order to account for data clustering, a generalized linear mixed model (GLMM) with random intercept for reader and nested for patient and image and a kernel/experience interaction term was used to analyze the results.The results of the GLMM indicated, that the odds of correct pattern recognition is 12 % lower with lung kernel compared to soft kernel; however, this was not statistically significant (OR 0.88; 95%-CI, 0.73-1.06; p = 0.187). Furthermore, the consultants' odds of correct pattern recognition was 78 % higher than the residents' odds, although this finding did not reach statistical significance either (OR 1.78; 95%-CI, 0.62-5.06; p = 0.283). There was no significant interaction between the two fixed terms kernel and experience. Intra-rater agreement between lung and soft kernel was substantial (κ = 0.63 ±â€Š0.19). The mean inter-rater agreement for lung/soft kernel was κ = 0.37 ±â€Š0.17/κ = 0.38 ±â€Š0.17.There is no significant difference between lung and soft kernel reconstructed CT images for the correct pattern recognition in ILD. There are non-significant trends indicating that the use of soft kernels and a higher level of experience lead to a higher probability of correct pattern identification. · There is no significant difference between lung and soft kernel reconstructed CT images for the correct pattern recognition in interstitial lung disease.. · There are even non-significant tendencies that the use of soft kernels lead to a higher probability of correct pattern identification.. · These results challenge the current recommendations and the routinely performed separate lung kernel reconstructions for lung parenchyma analysis.. CITATION FORMAT: · Klaus JB, Christodoulidis S, Peters AA et al. Influence of Lung Reconstruction Algorithms on Interstitial Lung Pattern Recognition on CT. Fortschr Röntgenstr 2023; 195: 47 - 54.

Up to 10 years clinical performance of zirconia ceramic and metal-ceramic fixed partial dentures: A retrospective study.

STATEMENT OF PROBLEM: Completely veneered zirconia ceramic (ZC) fixed partial dentures (FPDs) have been reported to have a higher incidence of ceramic chipping than the standard metal-ceramic FPDs. However, data from comparative long-term studies are sparse. PURPOSE: The purpose of this retrospective study was to compare the long-term survival, chipping-free survival, and success of ceramic-veneered high noble metal alloy (HN), base metal alloy (cobalt-chromium alloy) (CC), and ZC FPDs and to isolate risk factors for the incidence of failure, veneer chipping, and overall complications. MATERIAL AND METHODS: Data from 289 study participants (58.7% women; mean age, 57.97 ±11.51 years) provided with a total of 400 FPDs comprising 197 (49.3%) HN FPDs, 121 (30.3%) CC FPDs, and 82 (20.5%) ZC FPDs fabricated from presintered 3 mol% yttria-stabilized zirconia (mean time of service, 6.85 ±3.25 years) were evaluated. Of these, 278 (69.5%) FPDs were provided by dentists and 122 (30.5%) by dental students. Five- and 10-year survival, chipping-free survival, and success rates were calculated using the Kaplan-Meier method and compared with the log-rank test. Risk factors were assessed using Cox regression analysis. The study was exploratory, so all P values were considered exploratory and descriptive. RESULTS: The 5- and 10-year survival rates were 94.7% and 77.8% for HN, 93.7% and 81.2% for CC, and 92.9% and 53.3% for ZC FPDs, respectively, indicating no clear difference in survival among the framework materials. The 5- and 10-year chipping-free rates were 94.1% and 82.8% for HN, 96.1% and 78.9% for CC, and 82.6% and 62.2% for ZC FPDs, respectively, indicating a difference between HN and ZC, and CC and ZC restorations. The 5- and 10-year success rates were 83.7% and 55.3% for HN, 86.5% and 51.4% for CC, and 68.9% and 30.2% for ZC FPDs, respectively, indicating a difference between HN and ZC, and CC and ZC restorations. The Cox regression model indicated framework material as an influencing risk factor for success, and this influence persisted when chipping was investigated. Compared with zirconia, the use of a metal alloy reduced the risk of chipping or the occurrence of complications by up to one-third. CONCLUSIONS: All FPDs showed high 5-year survival rates and acceptable 10-year survival rates with no strong differences among the materials. Higher success and chipping-free rates were observed for both HN and CC restorations compared with ZC restorations. Metal frameworks had a lower risk for complications or veneer chipping than zirconia frameworks.

Magnetic resonance guided adaptive stereotactic body radiotherapy for lung tumors in ultracentral location: the MAGELLAN trial (ARO 2021-3).

BACKGROUND: Stereotactic Body Radiotherapy (SBRT) is a standard treatment for inoperable primary and secondary lung tumors. In case of ultracentral tumor location, defined as tumor contact with vulnerable mediastinal structures such as the proximal bronchial tree (PBT) or esophagus, SBRT is associated with an increased risk for severe complications. Magnetic resonance (MR)-guided SBRT can mitigate this risk based on gated dose delivery and daily plan adaptation. The MAGELLAN trial aims to find the maximum tolerated dose (MTD) of MR-guided SBRT of ultracentral lung tumors (ULT). PATIENTS AND METHODS: MAGELLAN is a prospective phase I dose escalation trial. A maximum of 38 patients with primary and secondary ULT with a tumor size ≤ 5 cm will be enrolled. Ultracentral location is defined as an overlap of the planning target volume (PTV) with the PBT or esophagus. Patients are treated at a 0.35 Tesla MR-linac (MRIdian® Linac, ViewRay Inc. ) employing a gating strategy and daily plan adaptation. Dose escalation starts at 10 × 5.5 Gy (biologically effective dose BED3/10: 155.83 Gy/85.25 Gy), may proceed up to 10 × 6.5 Gy (BED3/10: 205.83 Gy/107.25 Gy) and is guided by a customized time-to-event continual reassessment method (TITE CRM) with backup element, which alternately assigns patients to dose escalation and backup cohorts. DISCUSSION: The results of the MAGELLAN trial will guide further research and clinical implementation of MR-guided SBRT as ablative treatment of ULT. Moreover, the combination of MR-guided radiotherapy with TITE-CRM including a backup element may serve as blueprint for future radiation dose escalation studies in critical locations. TRIAL REGISTRATION: Registered at ClinicalTrials.gov: NCT04925583 on 14th June 2021.

Estimands-A Basic Element for Clinical Trials.

BACKGROUND: Clinical trials are of central importance for the evaluation and comparison of treatments. The transparency and intelligibility of the treatment effect under investigation is an essential matter for physicians, patients, and health-care authorities. The estimand framework has been introduced because many trials are deficient in this respect. METHODS: Introduction, definition, and application of the estimand framework on the basis of an example and a selective review of the literature. RESULTS: The estimand framework provides a systematic approach to the definition of the treatment effect under investigation in a clinical trial. An estimand consists of five attributes: treatment, population, variable, population-level summary, and handling of intercurrent events. Each of these attributes is defined in an interdisciplinary discussion during the trial planning phase, based on the clinical question being asked. Special attention is given to the handling of intercurrent events (ICEs): these are events-e.g., discontinuation or modification of treatment or the use of emergency medication-that can occur once the treatment has begun and might affect the possibility of observing the endpoints or their interpretability. There are various strategies for the handling of ICEs; these can, for example, also reflect the existing intention-to-treat (ITT) principle. Per-protocol analyses, in contrast, are prone to bias and cannot be represented in a sensible manner by an estimand, although they may be performed as a supplementary analysis. The discussion of potential intercurrent events and how they should appropriately be handled in view of the aim of the trial must already take place in the planning phase. CONCLUSION: Use of the estimand framework should make it easier for both physicians and patients to understand what trials reveal about the efficacy of treatment, and to compare the results of different trials.

Categories, components, and techniques in a modular construction of basket trials for application and further research.

Basket trials have become a virulent topic in medical and statistical research during the last decade. The core idea of them is to treat patients, who express the same genetic predisposition-either personally or their disease-with the same treatment irrespective of the location of the disease. The location of the disease defines each basket and the pathway of the treatment uses the common genetic predisposition among the baskets. This opens the opportunity to share information among baskets, which can consequently increase the information of the basket-wise response with respect to the investigated treatment. This further allows dynamic decisions regarding futility and efficacy of individual baskets during the ongoing trial. Several statistical designs have been proposed on how a basket trial can be conducted and this has left an unclear situation with many options. The different designs propose different mathematical and statistical techniques, different decision rules, and also different trial purposes. This paper presents a broad overview of existing designs, categorizes them, and elaborates their similarities and differences. A uniform and consistent notation facilitates the first contact, introduction, and understanding of the statistical methodologies and techniques used in basket trials. Finally, this paper presents a modular approach for the construction of basket trials in applied medical science and forms a base for further research of basket trial designs and their techniques.

Adaptive MR-Guided Stereotactic Radiotherapy is Beneficial for Ablative Treatment of Lung Tumors in High-Risk Locations.

PURPOSE: To explore the benefit of adaptive magnetic resonance-guided stereotactic body radiotherapy (MRgSBRT) for treatment of lung tumors in different locations with a focus on ultracentral lung tumors (ULT). PATIENTS & METHODS: A prospective cohort of 21 patients with 23 primary and secondary lung tumors was analyzed. Tumors were located peripherally (N = 10), centrally (N = 2) and ultracentrally (N = 11, planning target volume (PTV) overlap with proximal bronchi, esophagus and/or pulmonary artery). All patients received MRgSBRT with gated dose delivery and risk-adapted fractionation. Before each fraction, the baseline plan was recalculated on the anatomy of the day (predicted plan). Plan adaptation was performed in 154/165 fractions (93.3%). Comparison of dose characteristics between predicted and adapted plans employed descriptive statistics and Bayesian linear multilevel models. The posterior distributions resulting from the Bayesian models are presented by the mean together with the corresponding 95% compatibility interval (CI). RESULTS: Plan adaptation decreased the proportion of fractions with violated planning objectives from 94% (predicted plans) to 17% (adapted plans). In most cases, inadequate PTV coverage was remedied (predicted: 86%, adapted: 13%), corresponding to a moderate increase of PTV coverage (mean +6.3%, 95% CI: [5.3-7.4%]) and biologically effective PTV doses (BED10) (BEDmin: +9.0 Gy [6.7-11.3 Gy], BEDmean: +1.4 Gy [0.8-2.1 Gy]). This benefit was smaller in larger tumors (-0.1%/10 cm³ PTV [-0.2 to -0.02%/10 cm³ PTV]) and ULT (-2.0% [-3.1 to -0.9%]). Occurrence of exceeded maximum doses inside the PTV (predicted: 21%, adapted: 4%) and violations of OAR constraints (predicted: 12%, adapted: 1%, OR: 0.14 [0.04-0.44]) was effectively reduced. OAR constraint violations almost exclusively occurred if the PTV had touched the corresponding OAR in the baseline plan (18/19, 95%). CONCLUSION: Adaptive MRgSBRT is highly recommendable for ablative treatment of lung tumors whose PTV initially contacts a sensitive OAR, such as ULT. Here, plan adaptation protects the OAR while maintaining best-possible PTV coverage.

Zika virus infection in pregnancy: a protocol for the joint analysis of the prospective cohort studies of the ZIKAlliance, ZikaPLAN and ZIKAction consortia.

INTRODUCTION: Zika virus (ZIKV) infection in pregnancy has been associated with microcephaly and severe neurological damage to the fetus. Our aim is to document the risks of adverse pregnancy and birth outcomes and the prevalence of laboratory markers of congenital infection in deliveries to women experiencing ZIKV infection during pregnancy, using data from European Commission-funded prospective cohort studies in 20 centres in 11 countries across Latin America and the Caribbean. METHODS AND ANALYSIS: We will carry out a centre-by-centre analysis of the risks of adverse pregnancy and birth outcomes, comparing women with confirmed and suspected ZIKV infection in pregnancy to those with no evidence of infection in pregnancy. We will document the proportion of deliveries in which laboratory markers of congenital infection were present. Finally, we will investigate the associations of trimester of maternal infection in pregnancy, presence or absence of maternal symptoms of acute ZIKV infection and previous flavivirus infections with adverse outcomes and with markers of congenital infection. Centre-specific estimates will be pooled using a two-stage approach. ETHICS AND DISSEMINATION: Ethical approval was obtained at each centre. Findings will be presented at international conferences and published in peer-reviewed open access journals and discussed with local public health officials and representatives of the national Ministries of Health, Pan American Health Organization and WHO involved with ZIKV prevention and control activities.

Carbon ion radiotherapy as definitive treatment in non-metastasized pancreatic cancer: study protocol of the prospective phase II PACK-study.

BACKGROUND: Radiotherapy is known to improve local tumor control in locally advanced pancreatic cancer (LAPC), although there is a lack of convincing data on a potential overall survival benefit of chemoradiotherapy over chemotherapy alone. To improve efficacy of radiotherapy, new approaches need to be evolved. Carbon ion radiotherapy is supposed to be more effective than photon radiotherapy due to a higher relative biological effectiveness (RBE) and due to a steep dose-gradient making dose delivery highly conformal. METHODS: The present Phase II PACK-study investigates carbon ion radiotherapy as definitive treatment in LAPC as well as in locally recurrent pancreatic cancer. A total irradiation dose of 48 Gy (RBE) will be delivered in twelve fractions. Concurrent chemotherapy is accepted, if indicated. The primary endpoint is the overall survival rate after 12 months. Secondary endpoints are progression free survival, safety, quality of life and impact on tumor markers CA 19-9 and CEA. A total of twenty-five patients are planned for recruitment over 2 years. DISCUSSION: Recently, Japanese researches could show promising results in a Phase I/II-study evaluating chemoradiotherapy of carbon ion radiotherapy and gemcitabine in LAPC. The present prospective PACK-study investigates the efficacy of carbon ion radiotherapy in pancreatic cancer at Heidelberg Ion Beam Therapy Center (HIT) in Germany. TRIAL REGISTRATION: The trial is registered at ClinicalTrials.gov: NCT04194268 (Retrospectively registered on December, 11th 2019).

Balloon Eustachian Tuboplasty (BET) in Children: A Retrospective Multicenter Analysis.

OBJECTIVE: Generation of pilot data for planning of prospective BET-studies for treatment of dilatory Eustachian tube (ET) dysfunction in children. STUDY DESIGN: Retrospective multicenter analysis. SETTING: Nine ENT departments at tertiary care teaching hospitals. PATIENTS: 4-12-year-old children with chronic otitis media with effusion (COME) for more than 3 months or more than 3 episodes of acute otitis media during the last year, having failed standard surgical therapy at least once. INTERVENTION: BET with or without paracentesis, ventilation tube insertion, or tympanoplasty. MAIN OUTCOME MEASURES: Tympanic membrane appearance, tympanometry, and hearing threshold. RESULTS: Two hundred ninety-nine ETs of 167 children were treated. Mean age was 9.1 years (95% confidence interval [95% CI]: 8.7-9.4 yr). In 249 ears (83.3%), COME and/or retraction of the tympanic membrane were the indication for BET. Median hearing threshold was 20 dB HL (95% CI: 0-46 dB). One hundred fifty-five ears (51.8%, 95% CI: 46.1-57.4%) showed a tympanogram type B. Treatment consisted of BET without other interventions ("BET-only") in 70 children, 128 ears. Median length of follow-up for 158 (94.6%) children was 2.6 months (95% CI: 0.3-16.1 mo). After treatment, the tympanic membrane appeared normal in 196 ears (65.6%, 95% CI: 60.0-70.8%, p < 0.001). Median hearing threshold improved to 10 dB HL (95% CI: 0-45 dB, p < 0.001). Tympanograms shifted toward type A and C (type A: 39.1%, 95% CI: 33.7-44.7, p < 0.001). These improvements were also observed in subgroup analyses of "BET-only" treatment and the indication of "COME" respectively. CONCLUSION: BET is improving a variety of dilatory ET dysfunction-related ear diseases in children. This study provides detailed data for design and planning of prospective studies on BET in children.

Study protocol for the multicentre cohorts of Zika virus infection in pregnant women, infants, and acute clinical cases in Latin America and the Caribbean: the ZIKAlliance consortium.

BACKGROUND: The European Commission (EC) Horizon 2020 (H2020)-funded ZIKAlliance Consortium designed a multicentre study including pregnant women (PW), children (CH) and natural history (NH) cohorts. Clinical sites were selected over a wide geographic range within Latin America and the Caribbean, taking into account the dynamic course of the ZIKV epidemic. METHODS: Recruitment to the PW cohort will take place in antenatal care clinics. PW will be enrolled regardless of symptoms and followed over the course of pregnancy, approximately every 4 weeks. PW will be revisited at delivery (or after miscarriage/abortion) to assess birth outcomes, including microcephaly and other congenital abnormalities according to the evolving definition of congenital Zika syndrome (CZS). After birth, children will be followed for 2 years in the CH cohort. Follow-up visits are scheduled at ages 1-3, 4-6, 12, and 24 months to assess neurocognitive and developmental milestones. In addition, a NH cohort for the characterization of symptomatic rash/fever illness was designed, including follow-up to capture persisting health problems. Blood, urine, and other biological materials will be collected, and tested for ZIKV and other relevant arboviral diseases (dengue, chikungunya, yellow fever) using RT-PCR or serological methods. A virtual, decentralized biobank will be created. Reciprocal clinical monitoring has been established between partner sites. Substudies of ZIKV seroprevalence, transmission clustering, disabilities and health economics, viral kinetics, the potential role of antibody enhancement, and co-infections will be linked to the cohort studies. DISCUSSION: Results of these large cohort studies will provide better risk estimates for birth defects and other developmental abnormalities associated with ZIKV infection including possible co-factors for the variability of risk estimates between other countries and regions. Additional outcomes include incidence and transmission estimates of ZIKV during and after pregnancy, characterization of short and long-term clinical course following infection and viral kinetics of ZIKV. STUDY REGISTRATIONS: clinicaltrials.gov NCT03188731 (PW cohort), June 15, 2017; clinicaltrials.gov NCT03393286 (CH cohort), January 8, 2018; clinicaltrials.gov NCT03204409 (NH cohort), July 2, 2017.

Four selenoprotein P genes exist in salmonids: Analysis of their origin and expression following Se supplementation and bacterial infection.

The following research was conducted to elucidate the evolution and expression of salmonid selenoprotein P (SelP), a selenoprotein that is unique in having multiple selenocysteine (Sec) residues, following supranutritional selenium supplementation and infection in rainbow trout. We show that in salmonids SelP is present as four paralogues and that the diversification of SelP genes during vertebrate evolution relates to whole genome duplication events. With 17 and 16 selenocysteine residues for rainbow trout (Oncorhynchus mykiss)/Atlantic salmon (Salmo salar) SelPa1 and SelPa2 proteins respectively and 1 or 2 (trout or salmon) and 4 or 3 (trout or salmon) selenocysteine residues for salmonid SelPb1 and SelPb2 proteins respectively, this is the highest number of (predicted) multiple selenocysteine containing SelP proteins reported for any vertebrate species to date. To investigate the effects of selenium form on SelP expression we added different concentrations (1 nM- 10 µM) of organic or inorganic selenium to a trout cell line (RTG-2 cells) and analysed changes in mRNA abundance. We next studied the impact of supplementation on the potential modulation of these transcripts by PAMPs and proinflammatory cytokines in RTG-2 and RTS-11 cells. These experiments revealed that selenium type influenced the responses, and that SelP gene subfunctionalisation was apparent. To get an insight into the expression patterns in vivo we conducted a feeding trial with 2 diets differing in selenium content and 5 weeks later challenged the trout with a bacterial pathogen (Aeromonas salmonicida). Four tissues were analysed for SelP paralogue expression. The results show a significant induction of SelPa1 in gills and intestine following infection in selenium supplemented fish and for SelPa2 in gills. SelPb1 was significantly reduced in head kidney of both diet groups following infection, whilst SelPb2 was significantly upregulated in skin of both diet groups post infection. Overall these findings reveal differential expression profiles for the SelPa/SelPb paralogues in trout, influenced by selenium supply, cell type/tissue and stimulant. The increase of multiple Sec containing SelP proteins in salmonids could indicate an enhanced requirement for selenium in this lineage.

High-throughput proteomic profiling of the fish liver following bacterial infection.

BACKGROUND: High-throughput proteomics was used to determine the role of the fish liver in defense responses to bacterial infection. This was done using a rainbow trout (Oncorhynchus mykiss) model following infection with Aeromonas salmonicida, the causative agent of furunculosis. The vertebrate liver has multifaceted functions in innate immunity, metabolism, and growth; we hypothesize this tissue serves a dual role in supporting host defense in parallel to metabolic adjustments that promote effective immune function. While past studies have reported mRNA responses to A. salmonicida in salmonids, the impact of bacterial infection on the liver proteome remains uncharacterized in fish. RESULTS: Rainbow trout were injected with A. salmonicida or PBS (control) and liver extracted 48 h later for analysis on a hybrid quadrupole-Orbitrap mass spectrometer. A label-free method was used for protein abundance profiling, which revealed a strong innate immune response along with evidence to support parallel rewiring of metabolic and growth systems. 3076 proteins were initially identified against all proteins (n = 71,293 RefSeq proteins) annotated in a single high-quality rainbow trout reference genome, of which 2433 were maintained for analysis post-quality filtering. Among the 2433 proteins, 109 showed significant differential abundance following A. salmonicida challenge, including many upregulated complement system and acute phase response proteins, in addition to molecules with putative functions that may support metabolic re-adjustments. We also identified novel expansions in the complement system due to gene and whole genome duplication events in salmonid evolutionary history, including eight C3 proteins showing differential changes in abundance. CONCLUSIONS: This study provides the first high-throughput proteomic examination of the fish liver in response to bacterial challenge, revealing novel markers for the host defense response, and evidence of metabolic remodeling in conjunction with activation of innate immunity.

Skills in minimally invasive and open surgery show limited transferability to robotic surgery: results from a prospective study.

BACKGROUND: There is limited evidence on the transferability of conventional laparoscopic and open surgical skills to robotic-assisted surgery. The primary aim of this study was to evaluate the transferability of expertise in conventional laparoscopy and open surgery to robotic-assisted surgery using the da Vinci Skills Simulator (dVSS). Secondary aims included evaluating the influence of individual participants' characteristics. METHODS: Participants performed four tasks on the dVSS: Peg Board 1 (PB), Pick and Place (PP), Thread the Rings (TR), and Suture Sponge 1 (SS). Participants were classified into three groups (Novice, Intermediate, Experts) according to experience in laparoscopic and open surgery. All tasks were performed twice except for SS. Performance was assessed using the built-in scoring system. RESULTS: 37 medical students and 25 surgeons participated. Experts did not perform significantly better than less experienced participants on the dVSS. Specifically, with regard to laparoscopic experience, total simulator scores were: Novices 68.2 ± 28.8; Intermediates 65.1 ± 31.2; Experts 65.1 ± 30.0; p = 0.611. Regarding open surgical experience, scores were: Novices 68.6 ± 28.7; Intermediates 68.2 ± 30.8; Experts 63.2 ± 30.3; p = 0.305. Although there were some significant differences among groups for single parameters in specific tasks, there was no constant superiority of one group. Laparoscopic and open surgical Novices improved significantly in overall score and time for all three tasks (p < 0.05). Laparoscopic intermediates improved only in PP time (4.64 ± 3.42; p = 0.006), open Intermediates in PB score (11.98 ± 13.01; p = 0.025), and open Experts in PP score (6.69 ± 11.48; p = 0.048). Laparoscopic experts showed no improvement. Participants with gaming experience had better overall scores than non-gamers when comparing all second attempts (Gamer 83.62 ± 7.57; Non-Gamer 76.31 ± 12.78; p = 0.008) as well as first and second attempts together (Gamer 72.08 ± 8.86; Non-Gamer 65.45 ± 11.68; p = 0.039). Musical and sports experience showed no correlation with robotic performance. CONCLUSIONS: Robotic-assisted surgery requires skills distinct from conventional laparoscopy or open surgery. Basic robotic skills training prior to patient contact should be required.

Cerebral oxygenation and desaturations in preterm infants - a longitudinal data analysis.

OBJECTIVE: Hypoxemic episodes commonly occur in very preterm infants and may be associated with several adverse effects. Cerebral tissue oxygen saturation (StO2) as measured by near infrared spectroscopy (NIRS) may be a useful measure to assess brain oxygenation. However, knowledge on variability of StO2 is limited in preterm infants at this time, so StO2 dependency on arterial oxygenation (SpO2) and heart rate (HR) was assessed in preterm infants using statistical methods of time series analysis. STUDY DESIGN: StO2, SpO2, and HR were recorded from 15 preterm infants every 2 seconds for six hours. Statistical methods of time series and longitudinal data analysis were applied to the data. RESULT: The mean StO2 level was found as 72% (95% confidence interval (CI) 55.5% -85.5%) based on a moving average process with a 5 minute order. Accordingly, longitudinal SpO2 measurements showed a mean level of 91% (95% CI 69% -98%). Generally, compensation strategies to cope with both StO2 and SpO2 desaturations were observed in the studied patients. SpO2 had a significant effect on cerebral oxygenation (p < 0.001), but HR did not, which led to inconclusive results considering different time intervals. CONCLUSION: In infants with intermittent hypoxemia and bradycardia, we found a mean StO2 level of 72% and a strong correlation with SpO2. We observed large differences between individuals in the ability to maintain StO2 at a stable level.