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Cystic fibrosis (CF) is one of the most common autosomal recessive diseases in the world population. Allergic bronchopulmonary aspergillosis (ABPA) is a severe complication of CF, the diagnosis of which is based on symptoms and blood IgE levels. However, many techniques of specific IgG levels' measures are used, whose clinical significance is still unclear. We evaluated the clinical evolution of CF in children who presented a first IgG seroconversion. Monocentric pediatric case-control study led in Rouen, France. Every patient with a first IgG seroconversion was paired with a seronegative patient. Clinical data, functional respiratory investigations, CT scan, and biologic data were collected a year before ( ), at the time of IgG seroconversion ( ), and one year after ( ). Thirty-six cases were paired with 36 controls. Median age was 8. Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) were significantly lower at ( = 0.025) and ( = 0.027), respectively, and more pulmonary exacerbations were observed in the case population ( = 0.047). Higher levels of specific IgE against were observed at ( = 0.001), ( = 0.014), and ( = 0.04) in the case population. On the CT scan, bronchiectasis and pulmonary infiltrates were more frequent in the case population ( = 0.01 and = 0.003, respectively). We found that the first IgG seroconversion was associated with changes in clinical, respiratory functional, biologic, and radiologic parameters in CF pediatric population. IgG seroconversion is an important step in the evolution of CF. A systematic search for seroconversion is therefore essential to assess the measures to be taken.

Background Pulmonary hemosiderosis is a rare and complex disease in children. A previous study from the French RespiRare® network led to two important findings: 20% of the children presented with both pulmonary hemosiderosis and Down syndrome (DS), and at least one tested autoantibody was found positive in 50%. This study investigates the relationships between pulmonary hemosiderosis and DS. Methods Patients younger than 20 years old and followed for pulmonary hemosiderosis were retrieved from the RespiRare® database. Clinical, biological, functional, and radiological findings were collected, and DS and non-DS patients’ data were compared. Results A total of 34 patients (22 girls and 12 boys) were included, among whom nine (26%) presented with DS. The mean age at diagnosis was 4.1 ± 3.27 years old for non-DS and 2.9 ± 3.45 years old for DS patients. DS patients tended to present a more severe form of the disease with an earlier onset, more dyspnoea at diagnosis, more frequent secondary pulmonary hypertension, and an increased risk of fatal evolution. Conclusions DS patients have a higher risk of developing pulmonary hemosiderosis, and the disease seems to be more severe in this population. This could be due to the combination of an abnormal lung capillary bed with fragile vessels, a higher susceptibility to autoimmune lesions, and a higher risk of evolution toward pulmonary hypertension. A better screening for pulmonary hemosiderosis and a better prevention of hypoxia in DS paediatric patients may prevent a severe evolution of the disease.

RT amplification reaction has revealed that various single viruses or viral co-infections caused acute bronchiolitis in infants, and RV appeared to have a growing involvement in early respiratory diseases. Because remaining controversial, the objective was to determine prospectively the respective role of RSV, RV, hMPV and co-infections on the severity of acute bronchiolitis in very young infants. 209 infants (median age: 2.4 months) were enrolled in a prospective study of infants <1 year old, hospitalized for a first episode of bronchiolitis during the winter epidemic season and with no high risk for severe disease. The severity was assessed by recording SaO(2)% at admission, a daily clinical score (scale 0-18), the duration of oxygen supplementation and the length of hospitalization. Viruses were identified in 94.7% by RT amplification reaction: RSV only (45.8%), RV only (7.2%), hMPV only (3.8%), dual RSV/RV (14.3%), and other virus only (2%) or coinfections (9%). RV compared respectively with RSV and dual RSV/RV infection caused a significant less severe disease with a lower clinical score (5[3.2-6] vs. 6[4-8], p = 0.01 and 5.5[5-7], p = 0.04), a shorter time in oxygen supplementation (0[0-1] days vs. 2[0-3] days, p = 0.02 and 2[0-3] days, p = 0.03) and a shorter hospital stay (3[3-4.7] days vs.6 [5-8] days, p = 0.001 and 5[4-6] days, p = 0.04). Conversely, RSV infants had also longer duration of hospitalization in comparison with RSV/RV (p = 0.01) and hMPV (p = 0.04). The multivariate analyses showed that the type of virus carried was independently associated with the duration of hospitalization. This study underlined the role of RV in early respiratory diseases, as frequently carried by young infants with a first acute bronchiolitis. RSV caused the more severe disease and conversely RV the lesser severity. No additional effect of dual RSV/RV infection was observed on the severity.

Background Idiopathic pulmonary hemosiderosis (IPH) is a rare cause of alveolar hemorrhage in children and its pathophysiology remains obscure. Classically, diagnosis is based on a triad including hemoptysis, diffuse parenchymal infiltrates on chest X-rays, and iron-deficiency anemia. We present the French pediatric cohort of IPH collected through the French Reference Center for Rare Lung Diseases (RespiRare®, http://www.respirare.fr ). Methods Since 2008, a national network/web-linked RespiRare® database has been set up in 12 French pediatric respiratory centres. It is structured as a medical recording tool with extended disease-specific datasets containing clinical information relevant to all forms of rare lung diseases including IPH. Results We identified 25 reported cases of IPH in children from the database (20 females and 5 males). Among them, 5 presented with Down syndrome. Upon diagnosis, median age was 4.3 [0.8-14.0] yrs, and the main manifestations were: dyspnea (n = 17, 68%), anemia (n = 16, 64%), cough (n = 12, 48%), febrile pneumonia (n = 11, 44%) and hemoptysis (n = 11, 44%). Half of the patients demonstrated diffuse parenchymal infiltrates on chest imaging, and diagnosis was ascertained either by broncho-alveolar lavage indicating the presence of hemosiderin-laden macrophages (19/25 cases), or lung biopsy (6/25). In screened patients, initial auto-immune screening revealed positive antineutrophilic cytoplasmic antibodies (ANCA) (n = 6, 40%), antinuclear antibodies (ANA) (n = 5, 45%) and specific coeliac disease antibodies (n = 4, 28%). All the patients were initially treated by corticosteroids. In 13 cases, immunosuppressants were introduced due to corticoresistance and/or major side effects. Median length of follow-up was 5.5 yrs, with a satisfactory respiratory outcome in 23/25 patients. One patient developed severe pulmonary fibrosis, and another with Down syndrome died as a result of severe pulmonary hemorrhage. Conclusion The present cohort provides substantial information on clinical expression and outcomes of pediatric IPH. Analysis of potential contributors supports a role of auto-immunity in disease development and highlights the importance of genetic factors.

ObjectiveDyspnoea and sleep-disordered breathing (SDB) are common in children with life-limiting conditions but studies on treatment with non-invasive ventilation (NIV) or continuous positive airway pressure (CPAP) are scarce. The aim of the study was to describe children treated with long-term NIV/CPAP within a paediatric palliative care programme in France.MethodsCross-sectional survey on children and young adults with complex medical conditions treated within the French paediatric NIV network with long-term NIV/CPAP. Characteristics of the patients were analysed and patient-related outcome measures of NIV/CPAP benefit were reported.ResultsThe data of 50 patients (68% boys), median age 12 (0.4–21) years were analysed. Twenty-three (46%) patients had a disorder of the central nervous system and 5 (10%) a chromosomal anomaly. Thirty-two (64%) patients were treated with NIV and 18 (36%) with CPAP. NIV/CPAP was initiated on an abnormal Apnoea-Hypopnoea Index in 18 (36%) of the patients, an abnormal nocturnal gas exchange alone in 28 (56%), and after an acute respiratory failure in 11 (22%) of the patients. Mean objective NIV/CPAP adherence was 9.3±3.7 hours/night. NIV/CPAP was associated with a decrease in dyspnoea in 60% of patients, an increase in sleep duration in 60% and in sleep quality in 74%, and an improvement in parents’ sleep in 40%.ConclusionsIn children with life-limiting conditions, long-term NIV/CPAP may be associated with relief of dyspnoea, an improvement of SDB and an improvement in parents’ sleep.

Multidimensional fitness landscapes provide insights into the molecular basis of laboratory and natural evolution. To date, such efforts usually focus on limited protein families and a single enzyme trait, with little concern about the relationship between protein epistasis and conformational dynamics. Here, we report a multiparametric fitness landscape for a cytochrome P450 monooxygenase that was engineered for the regio- and stereoselective hydroxylation of a steroid. We develop a computational program to automatically quantify non-additive effects among all possible mutational pathways, finding pervasive cooperative signs and magnitude epistasis on multiple catalytic traits. By using quantum mechanics and molecular dynamics simulations, we show that these effects are modulated by long-range interactions in loops, helices and β-strands that gate the substrate access channel allowing for optimal catalysis. Our work highlights the importance of conformational dynamics on epistasis in an enzyme involved in secondary metabolism and offers insights for engineering P450s. Connecting conformational dynamics and epistasis has so far been limited to a few proteins and a single fitness trait. Here, the authors provide evidence of positive epistasis on multiple catalytic traits in the evolution and dynamics of engineered cytochrome P450 monooxygenase, offering insights for in silico protein design.

ObjectiveImaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers.MethodsAn online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery.ResultsA total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI.ConclusionA minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of ≤ 3 mm. No common standard could be obtained regarding advanced MRI protocols and PET.Importance of the studyWe believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed “minimal core of imaging” in clinical routine will facilitate future cooperative studies.

PurposeThis study was conducted in order to investigate the safety and accuracy of percutaneous transluminal forceps biopsy (PTFB) during percutaneous biliary drainage (PTBD) in patients with a suspicion of malignant biliary stricture.Material and methodsFifty consecutive patients with obstructive jaundice underwent PTFB during PTBD. Biopsy specimens were obtained using 5.2-F flexible biopsy forceps and these specimens were independently analysed by two pathologists. Consensus was obtained in case of discrepancy. Biopsy was considered as a true positive when tumour cells were retrieved. In the absence of tumour cells, comparison with available surgical findings and/or endoscopic ultrasound fine-needle aspiration (EUS-FNA) and/or percutaneous liver biopsy and/or imaging or clinical follow-up was made to distinguish true and false negatives. Specificity, sensitivity, positive predictive value, negative predictive value and accuracy were calculated. Influence of tumour location and pre-operative imaging findings was evaluated. Adverse events were reported.ResultsBiliary drainage and tissue sampling were achieved in 100% of patients. Sensitivity and specificity were 70 and 100%, respectively, while overall accuracy was 72%. After excluding the first 25 patients, accuracy and sensitivity for tissue sampling reached 80 and 78%, respectively. Sensitivity was better (87%) if stenosis was located at the upper part of the biliary tree, compared to the lower part (55%). In case of cholangiocarcinoma or intraductal invasion suspected on imaging, biopsy was contributive in 84 and 81% of patients, respectively. Four complications occurred consisting of one bile leak, two haemobilia and one pneumoperitoneum.ConclusionPTFB combined with PTBD is a safe and effective technique for both histopathological diagnosis and biliary decompression of biliary strictures.Key PointsImplications for patient care:• Percutaneous transbiliary forceps biopsy is technically feasible (100% of tissue sampling in our study) and is a safe technique.• Radiological management combining PTFB plus PTBD may allow diagnosis and treatment of the biliary stricture at the same time.• Sensitivity and accuracy for PTFB reached 78 and 80%, respectively, with a 100% specificity.

Vaccinia virus (VV) vaccination is used to immunize against smallpox and historically was considered to have been successful if a skin lesion formed at the vaccination site. While antibody responses have been widely proposed as a correlate of efficacy and protection in humans, the role of cellular and humoral immunity in VV-associated skin lesion formation was unknown. We therefore investigated whether long-term residual humoral and cellular immune memory to VV, persisting 30 years after vaccination, could control VV-induced skin lesion in revaccinated individuals. Here, we have shown that residual VV-specific IFN-gamma+TNF-alpha+ or IFN-gamma+IL-2+ CD4+ lymphocytes but not CD8+ effector/memory lymphocytes expressing a skin-homing marker are inversely associated with the size of the skin lesion formed in response to revaccination. Indeed, high numbers of residual effector T cells were associated with lower VV skin lesion size after revaccination. In contrast, long-term residual VV-specific neutralizing antibody (NAbs) titers did not affect skin lesion formation. However, the size of the skin lesion strongly correlated with high levels of NAbs boosted after revaccination. These findings demonstrate a potential role for VV-specific CD4+ responses at the site of VV-associated skin lesion, thereby providing new insight into immune responses at these sites and potentially contributing to the development of new approaches to measure the efficacy of VV vaccination.

[...]in diffuse low-grade gliomas, two randomised-like studies4,5 have provided indisputable conclusions about the relationship between improved survival and extent of resection. [...]this survival benefit still persists after adjusting for molecular markers.4 Last but not least, although it is stated that “quality of life is a high priority to patients and carers”, there is no mention of cognitive and quality of life assessments as a general recommendation. Supplementary Material 1 M Weller, M van den Bent,...