Complex roles of TGF-ß signaling pathways in lung development and bronchopulmonary dysplasia.

As survival of extremely preterm infants continues to improve, there is also an associated increase in bronchopulmonary dysplasia (BPD), one of the most significant complications of preterm birth. BPD development is multifactorial resulting from exposure to multiple antenatal and postnatal stressors. BPD has both short-term health implications and long-term sequelae including increased respiratory, cardiovascular, and neurological morbidity. Transforming growth factor ß (TGF-ß) is an important signaling pathway in lung development, organ injury, and fibrosis and is implicated in the development of BPD. This review provides a detailed account on the role of TGF-ß in antenatal and postnatal lung development, the effect of known risk factors for BPD on the TGF-ß signaling pathway, and how medications currently in use or under development, for the prevention or treatment of BPD, affect TGF-ß signaling.

Extracorporeal Life Support for Respiratory Failure in Patients With Electronic Cigarette or Vaping Product Use-Associated Lung Injury.

OBJECTIVES: Electronic cigarette or vaping product use-associated lung injury is a clinical entity that can lead to respiratory failure and death. Despite the severity of electronic cigarette or vaping product use-associated lung injury, the role of extracorporeal life support in its management remains unclear. Our objective was to describe the clinical characteristics and outcomes of patients with electronic cigarette or vaping product use-associated lung injury who received extracorporeal life support. DESIGN: We performed a retrospective review of records of electronic cigarette or vaping product use-associated lung injury patients who received extracorporeal life support. Standardized data were collected via direct contact with extracorporeal life support centers. Data regarding presentation, ventilatory management, extracorporeal life support details, and outcome were analyzed. SETTING: This was a multi-institutional, international case series with patients from 10 different institutions in three different countries. PATIENTS: Patients who met criteria for confirmed electronic cigarette or vaping product use-associated lung injury (based on previously reported diagnostic criteria) and were placed on extracorporeal life support were included. Patients were identified via literature review and by direct contact with extracorporeal life support centers. MEASUREMENTS AND MAIN RESULTS: Data were collected for 14 patients ranging from 16 to 45 years old. All had confirmed vape use within 3 months of presentation. Nicotine was the most commonly used vaping product. All patients had respiratory symptoms and radiographic evidence of bilateral pulmonary opacities. IV antibiotics and corticosteroids were universally initiated. Patients were intubated for 1.9 days (range, 0-6) prior to extracorporeal life support initiation. Poor oxygenation and ventilation were the most common indications for extracorporeal life support. Five patients showed evidence of ventricular dysfunction on echocardiography. Thirteen patients (93%) were placed on venovenous extracorporeal life support, and one patient required multiple rounds of extracorporeal life support. Total extracorporeal life support duration ranged from 2 to 37 days. Thirteen patients survived to hospital discharge; one patient died of septic shock. CONCLUSIONS: Electronic cigarette or vaping product use-associated lung injury can cause refractory respiratory failure and hypoxemia. These data suggest that venovenous extracorporeal life support can be an effective treatment option for profound, refractory respiratory failure secondary to electronic cigarette or vaping product use-associated lung injury.

Desidustat in Anemia due to Dialysis-Dependent Chronic Kidney Disease: A Phase 3 Study (DREAM-D).

BACKGROUND: A phase 3 study to assess the efficacy and safety of the desidustat, an oral hypoxia-inducible factor prolyl hydroxylase inhibitor, against the epoetin alfa for the treatment of anemia in patients with chronic kidney disease (CKD) with dialysis dependency. METHODS: DREAM-D was a phase 3, multicenter, open-label, randomized, active-controlled clinical study conducted across 38 centers in India. A total of 392 patients with clinical diagnosis of anemia due to CKD with dialysis need (Erythrocyte Stimulating Agent [ESA] naïve or prior ESA users) and with baseline hemoglobin levels of 8.0-11.0 g/dL (inclusive) were randomized in a 1:1 ratio to receive either desidustat oral tablets (thrice a week) or epoetin alfa subcutaneous injection for 24 weeks to maintain a hemoglobin level of 10-12 g/dL. The primary endpoint was to assess the change in the hemoglobin level between the desidustat and the epoetin alfa groups from the baseline to evaluation period week 16-24. The key secondary efficacy endpoint was the number of patients with hemoglobin response. RESULTS: The least square mean (standard error) change in hemoglobin from the baseline to week 16-24 was 0.95 (0.09) g/dL in the desidustat group and 0.80 (0.09) g/dL in the epoetin alfa group (difference: 0.14 [0.14] g/dL; 95% confidence interval: -0.1304, 0.4202), which met the prespecified noninferiority margin. The number of hemoglobin responders was significantly higher in the desidustat group (106 [59.22%]) when compared to the epoetin alfa group (89 [48.37%]) (p = 0.0382). The safety profile of the desidustat oral tablet was comparable with the epoetin alfa injection. There were no new risks or no increased risks seen with the use of desidustat compared to epoetin alfa. CONCLUSION: In this study, desidustat was found to be noninferior to epoetin in the treatment of anemia in CKD patients on dialysis and it was well-tolerated. Clinical Trial Registry Identifier: CTRI/2019/12/022312 (India).

The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy.

The human complement Factor H-related 5 protein (FHR5) antagonizes the main circulating complement regulator Factor H, resulting in the deregulation of complement activation. FHR5 normally contains nine short complement regulator (SCR) domains, but a FHR5 mutant has been identified with a duplicated N-terminal SCR-1/2 domain pair that causes CFHR5 nephropathy. To understand how this duplication causes disease, we characterized the solution structure of native FHR5 by analytical ultracentrifugation and small-angle X-ray scattering. Sedimentation velocity and X-ray scattering indicated that FHR5 was dimeric, with a radius of gyration (Rg ) of 5.5 ± 0.2 nm and a maximum protein length of 20 nm for its 18 domains. This result indicated that FHR5 was even more compact than the main regulator Factor H, which showed an overall length of 26-29 nm for its 20 SCR domains. Atomistic modeling for FHR5 generated a library of 250,000 physically realistic trial arrangements of SCR domains for scattering curve fits. Only compact domain structures in this library fit well to the scattering data, and these structures readily accommodated the extra SCR-1/2 domain pair present in CFHR5 nephropathy. This model indicated that mutant FHR5 can form oligomers that possess additional binding sites for C3b in FHR5. We conclude that the deregulation of complement regulation by the FHR5 mutant can be rationalized by the enhanced binding of FHR5 oligomers to C3b deposited on host cell surfaces. Our FHR5 structures thus explained key features of the mechanism and pathology of CFHR5 nephropathy.

Weaning oxygen in infants with bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease commonly seen in preterm infants as the sequelae following respiratory distress syndrome. The management of evolving BPD aims to minimise lung injury and prevent the impact of hypoxia and hyperoxia. Proposed morbidities include respiratory instability, pulmonary hypertension, suboptimal growth, altered cerebral oxygenation and long-term neurodevelopmental impairment. The ongoing management and associated morbidity present a significant burden for carers and healthcare systems. Long-term oxygen therapy may be required for variable duration, though there is a lack of consensus and wide variation in practise when weaning supplemental oxygen. Furthermore, a shift in care towards earlier discharge and community care underlines the importance of a structured discharge and weaning process that eliminates the potential risks associated with hypoxia and hyperoxia. This review article describes recent evidence outlining oxygen saturation reference ranges in young infants, on which structured guidance can be based.

An update on controversies in e-cigarettes.

E-cigarettes are electronic nicotine delivery systems (ENDS) which mimic tobacco smoking without the combustion of tobacco. These devices have been misleadingly marketed as "less harmful" alternatives to conventional smoking tobacco products. The e-liquid in e-cigarettes include nicotine, a humectant and other additives including flavourings, colourants, or adulterants such as bacterial and fungal products. In this review, we discuss the contrasting views of the tobacco lobby and most professional societies. We describe the epidemiology of the use of these devices, with a widespread and significant rise in youth e-cigarette use seen in both the USA and Europe. We also describe what is known about the toxicity and mechanisms of EVALI (e-cigarette or vaping associated lung injury). This characterised by respiratory failure with an intense inflammatory response. The presentations are diverse and clinicians should consider vaping as a possible cause of any unusual respiratory illness in patients who have a history of vaping or other use of e-cigarette-related products. Second hand exposure to e-cigarettes is also harmful through respiration and transdermal absorption. E-cigarettes have a worse acute toxicity than tobacco and their long-term toxicity is unknown, and we advocate for the immediate, most vigorous anti-vaping legislation possible.

Two distinct conformations of factor H regulate discrete complement-binding functions in the fluid phase and at cell surfaces.

Factor H (FH) is the major regulator of C3b in the alternative pathway of the complement system in immunity. FH comprises 20 short complement regulator (SCR) domains, including eight glycans, and its Y402H polymorphism predisposes those who carry it to age-related macular degeneration. To better understand FH complement binding and self-association, we have studied the solution structures of both the His-402 and Tyr-402 FH allotypes. Analytical ultracentrifugation revealed that up to 12% of both FH allotypes self-associate, and this was confirmed by small-angle X-ray scattering (SAXS), MS, and surface plasmon resonance analyses. SAXS showed that monomeric FH has a radius of gyration (Rg ) of 7.2-7.8 nm and a length of 25 nm. Starting from known structures for the SCR domains and glycans, the SAXS data were fitted using Monte Carlo methods to determine atomistic structures of monomeric FH. The analysis of 29,715 physically realistic but randomized FH conformations resulted in 100 similar best-fit FH structures for each allotype. Two distinct molecular structures resulted that showed either an extended N-terminal domain arrangement with a folded-back C terminus or an extended C terminus and a folded-back N terminus. These two structures are the most accurate to date for glycosylated full-length FH. To clarify FH functional roles in host protection, crystal structures for the FH complexes with C3b and C3dg revealed that the extended N-terminal conformation accounted for C3b fluid-phase regulation, the extended C-terminal conformation accounted for C3d binding, and both conformations accounted for bivalent FH binding to glycosaminoglycans on the target cell surface.

ERS statement on tracheomalacia and bronchomalacia in children.

Tracheomalacia and tracheobronchomalacia may be primary abnormalities of the large airways or associated with a wide variety of congenital and acquired conditions. The evidence on diagnosis, classification and management is scant. There is no universally accepted classification of severity. Clinical presentation includes early-onset stridor or fixed wheeze, recurrent infections, brassy cough and even near-death attacks, depending on the site and severity of the lesion. Diagnosis is usually made by flexible bronchoscopy in a free-breathing child but may also be shown by other dynamic imaging techniques such as low-contrast volume bronchography, computed tomography or magnetic resonance imaging. Lung function testing can provide supportive evidence but is not diagnostic. Management may be medical or surgical, depending on the nature and severity of the lesions, but the evidence base for any therapy is limited. While medical options that include bronchodilators, anti-muscarinic agents, mucolytics and antibiotics (as well as treatment of comorbidities and associated conditions) are used, there is currently little evidence for benefit. Chest physiotherapy is commonly prescribed, but the evidence base is poor. When symptoms are severe, surgical options include aortopexy or posterior tracheopexy, tracheal resection of short affected segments, internal stents and external airway splinting. If respiratory support is needed, continuous positive airway pressure is the most commonly used modality either via a face mask or tracheostomy. Parents of children with tracheobronchomalacia report diagnostic delays and anxieties about how to manage their child's condition, and want more information. There is a need for more research to establish an evidence base for malacia. This European Respiratory Society statement provides a review of the current literature to inform future study.

Eradication therapy for Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Chronic infection with Burkholderia cepacia complex species remains a significant problem for clinicians treating people with cystic fibrosis. Colonisation with Burkholderia cepacia complex species is linked to a more rapid decline in lung function and increases morbidity and mortality. There remain no objective guidelines for strategies to eradicate Burkholderia cepacia complex in cystic fibrosis lung disease, as these are inherently resistant to the majority of antibiotics and there has been very little research in this area. This review aims to examine the current treatment options for people with cystic fibrosis with acute infection with Burkholderia cepacia complex and to identify an evidence-based strategy that is both safe and effective. This is an updated version of the review. OBJECTIVES: To identify whether treatment of Burkholderia cepacia complex infections can achieve eradication, or if treatment can prevent or delay the onset of chronic infection. To establish whether following eradication, clinical outcomes are improved and if there are any adverse effects. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Last search: 12 March 2019.We also searched electronic clinical trials registers for the USA and Europe.Date of last search: 12 March 2019. SELECTION CRITERIA: Randomised or quasi-randomised studies in people with cystic fibrosis of antibiotics or alternative therapeutic agents used alone or in combination, using any method of delivery and any treatment duration, to eradicate Burkholderia cepacia complex infections compared to another antibiotic, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed for inclusion in the review the eligibility of 52 studies (79 references) identified by the search of the Group's Trial Register and the other electronic searches. MAIN RESULTS: No studies looking at the eradication of Burkholderia cepacia complex species were identified. AUTHORS' CONCLUSIONS: The authors have concluded that there was an extreme lack of evidence in this area of treatment management for people with cystic fibrosis. Without further comprehensive studies, it is difficult to draw conclusions about a safe and effective management strategy for Burkholderia cepacia complex eradication in cystic fibrosis. Thus, while the review could not offer clinicians evidence of an effective eradication protocol for Burkholderia cepacia complex, it has highlighted an urgent need for exploration and research in this area, specifically the need for well-designed multi-centre randomised controlled studies of a variety of (novel) antibiotic agents.

Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

BACKGROUND: People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: 31 January 2019.We also searched online trial registries. Date of latest search: 25 February 2019. SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study; authors also assessed the quality of the evidence using the GRADE criteria. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. MAIN RESULTS: We identified 15 studies for possible inclusion in the review. Five studies reporting results from a total of 354 participants (aged 5 to 50 years) were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One cross-over trial had 26 participants who received the first-arm treatment but only 15 received the second arm. One study had a low risk of bias for all criteria assessed; the remaining included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias.There was little or no difference between treatment groups in: forced expiratory volume in one second, mean difference (MD) 0.33 (95% confidence interval (CI) -2.81 to 3.48, moderate-quality evidence); forced vital capacity, MD 0.29 (95% CI -6.58 to 7.16, low-quality evidence); % weight for height, MD -0.82 (95% CI -3.77 to 2.13, low-quality evidence); body mass index, MD 0.00 (95% CI -0.42 to 0.42, low-quality evidence); or in the incidence of ototoxicity, relative risk 0.56 (95% CI 0.04 to 7.96, moderate-quality evidence). Once-daily treatment in children probably improved the percentage change in creatinine, MD -8.20 (95% CI -15.32 to -1.08, moderate-quality evidence), but showed no difference in adults, MD 3.25 (95% CI -1.82 to 8.33, moderate-quality evidence). The included trials did not report antibiotic resistance patterns or quality of life. AUTHORS' CONCLUSIONS: Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Fifteen-minute consultation: An evidence-based approach to the child with preschool wheeze.

Preschool wheeze is very common and its prevalence is increasing. It consumes considerable healthcare resources and has a major impact on children and their families due to significant morbidity associated with acute episodes.History taking is the main diagnostic instrument in the assessment of preschool wheeze. Diagnosis and management is complicated by a broad differential and associations with many other diseases and conditions that give rise to noisy breathing, which could be misinterpreted as wheeze. Several clinical phenotypes have been described but they have limitations and do not clearly inform therapeutic decisions. New insights in aetiopathogenesis modify treatment options and lay foundation for further research. An understanding of the approach and available evidence to assess and manage wheeze informs best patient care and use of resources.Our objective is to demonstrate a focused history, examination and management options in a preschool child with wheeze.

Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

BACKGROUND: People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. This is an update of a previously published review. OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: 24 June 2016. SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study; authors also assessed the quality of the evidence using the GRADE criteria. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. MAIN RESULTS: Fifteen studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants (aged 5 to 50 years) were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One study had a low risk of bias for all criteria assessed; the remaining three included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias.There was no significant difference between treatment groups in: forced expiratory volume in one second, mean difference 0.33 (95% confidence interval -2.81 to 3.48, moderate quality evidence); forced vital capacity, mean difference 0.29 (95% confidence interval -6.58 to 7.16, low quality evidence); % weight for height, mean difference -0.82 (95% confidence interval -3.77 to 2.13, low quality evidence); body mass index, mean difference 0.00 (95% confidence interval -0.42 to 0.42, low quality evidence); or in the incidence of ototoxicity, relative risk 0.56 (95% confidence interval 0.04 to 7.96, moderate quality evidence). The percentage change in creatinine significantly favoured once-daily treatment in children, mean difference -8.20 (95% confidence interval -15.32 to -1.08, moderate quality evidence), but showed no difference in adults, mean difference 3.25 (95% confidence interval -1.82 to 8.33, moderate quality evidence). The included trials did not report antibiotic resistance patterns or quality of life. AUTHORS' CONCLUSIONS: Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Eradication therapy for Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Chronic infection with Burkholderia cepacia complex species remains a significant problem for clinicians treating people with cystic fibrosis. Colonisation with Burkholderia cepacia complex species is linked to a more rapid decline in lung function and increases morbidity and mortality. There remain no objective guidelines for strategies to eradicate Burkholderia cepacia complex in cystic fibrosis lung disease, as these are inherently resistant to the majority of antibiotics and there has been very little research in this area. This review aims to examine the current treatment options for people with cystic fibrosis with acute of Burkholderia cepacia complex and to identify an evidence-based strategy that is both safe and effective. This is an updated version of the review. OBJECTIVES: To identify whether treatment of Burkholderia cepacia complex infections can achieve eradication, or if treatment can prevent or delay the onset of chronic infection. To establish whether following eradication, clinical outcomes are improved and if there are any adverse effects. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Last search: 14 July 2016.We also searched electronic clinical trials registers for the USA and Europe.Date of last search: 14 July 2016. SELECTION CRITERIA: Randomised or quasi-randomised studies in people with cystic fibrosis of antibiotics or alternative therapeutic agents used alone or in combination, using any method of delivery and any treatment duration, to eradicate Burkholderia cepacia complex infections compared to another antibiotic, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed for inclusion in the review the eligibility of 50 studies (70 references) identified by the search of the Group's Trial Register and the other electronic searches. MAIN RESULTS: No studies looking at the eradication of Burkholderia cepacia complex species were identified. AUTHORS' CONCLUSIONS: The authors have concluded that there was an extreme lack of evidence in this area of treatment management for people with cystic fibrosis. Without further comprehensive studies, it is difficult to draw conclusions about a safe and effective management strategy for Burkholderia cepacia complex eradication in cystic fibrosis. Thus, while the review could not offer clinicians evidence of an effective eradication protocol for Burkholderia cepacia complex, it has highlighted an urgent need for exploration and research in this area, specifically the need for well-designed multi-centre randomised controlled studies of a variety of (novel) antibiotic agents.

Bronchopulmonary Dysplasia Within and Beyond the Neonatal Unit.

BACKGROUND: Bronchopulmonary dysplasia (BPD), also known as chronic lung disease of prematurity or chronic neonatal lung disease, is a major cause of respiratory illness in premature babies. Newborn babies survive at gestational ages of 23 to 26 weeks, earlier than when BPD was first described. New mechanisms of lung injury have therefore emerged and the clinical and pathological characteristics of pulmonary involvement have changed. PURPOSE: Improved neonatal intensive care unit modalities have increased survival rates; the overall prevalence of the condition, however, has not changed. Management of evolving BPD aims at minimizing lung injury. Management of established, especially severe BPD, still poses significant clinical challenge as these babies need long-term oxygen therapy (LTOT) for variable length of time. We aim to give an overview of management of established BPD with particular focus on weaning home oxygen therapy at our local center in the United Kingdom. SEARCH AND RESULTS: On the basis of most recent evidence, we concluded that an integrated pathway for managing babies on LTOT is very important after discharge from neonatal unit. IMPLICATIONS FOR PRACTICE: A structured weaning pathway for premature babies on home oxygen improves outcome. IMPLICATIONS FOR RESEARCH: The management of severe BPD and related complications, particularly during the first 2 years of life, remains a continuing challenge for parents and healthcare providers. The most beneficial respiratory support strategy to minimize lung injury and/or promote lung healing remains unclear and requires further investigation.

Eradication therapy for Burkholderia cepacia complex in people with cystic fibrosis.

BACKGROUND: Chronic infection with Burkholderia cepacia complex species remains a significant problem for clinicians treating people with cystic fibrosis. Colonisation with Burkholderia cepacia complex species is linked to a more rapid decline in lung function and increases morbidity and mortality. There remain no objective guidelines for strategies to eradicate Burkholderia cepacia complex in cystic fibrosis lung disease, as these are inherently resistant to the majority of antibiotics and there has been very little research in this area. This review aims to examine the current treatment options for people with cystic fibrosis with acute of Burkholderia cepacia complex and to identify an evidence-based strategy that is both safe and effective. OBJECTIVES: To identify whether treatment of Burkholderia cepacia complex infections can achieve eradication, or if treatment can prevent or delay the onset of chronic infection. To establish whether following eradication, clinical outcomes are improved and if there are any adverse effects. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews.Last search: 13 January 2014.We also searched electronic clinical trials registers for the USA and Europe.Date of last search: 28 November 2013. SELECTION CRITERIA: Randomised or quasi-randomised studies in people with cystic fibrosis of antibiotics used alone or in combination, using any method of delivery and any treatment duration, to eradicate Burkholderia cepacia complex infections compared to another antibiotic, placebo or no treatment. DATA COLLECTION AND ANALYSIS: Two authors independently assessed for inclusion in the review the eligibility of 43 studies (61 references) identified by the search of the Group's Trial Register and the other electronic searches. MAIN RESULTS: No studies looking at the eradication of Burkholderia cepacia complex species were identified. AUTHORS' CONCLUSIONS: The authors have concluded that there was an extreme lack of evidence in this area of treatment management for people with cystic fibrosis. Without further comprehensive studies, it is difficult to draw conclusions about a safe and effective management strategy for Burkholderia cepacia complex eradication in cystic fibrosis. Thus, while the review could not offer clinicians evidence of an effective eradication protocol for Burkholderia cepacia complex, it has highlighted an urgent need for exploration and research in this area, specifically the need for well-designed multi-centre randomised controlled studies of a variety of (novel) antibiotic agents.

Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis.

BACKGROUND: People with cystic fibrosis, who are chronically colonised with the organism Pseudomonas aeruginosa, often require multiple courses of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations. The properties of aminoglycosides suggest that they could be given in higher doses less often. OBJECTIVES: To assess the effectiveness and safety of once-daily versus multiple-daily dosing of intravenous aminoglycoside antibiotics for the management of pulmonary exacerbations in cystic fibrosis. SEARCH METHODS: We searched the Cystic Fibrosis Specialist Register held at the Cochrane Cystic Fibrosis and Genetic Disorders Group's editorial base, comprising references identified from comprehensive electronic database searches, handsearching relevant journals and handsearching abstract books of conference proceedings.Date of the most recent search: 25 November 2013. SELECTION CRITERIA: All randomised controlled trials, whether published or unpublished, in which once-daily dosing of aminoglycosides has been compared with multiple-daily dosing in terms of efficacy or toxicity or both, in people with cystic fibrosis. DATA COLLECTION AND ANALYSIS: The two authors independently selected the studies to be included in the review and assessed the risk of bias of each study. Data were independently extracted by each author. Authors of the included studies were contacted for further information. As yet unpublished data were obtained for one of the included studies. MAIN RESULTS: Fifteen studies were identified for possible inclusion in the review. Four studies reporting results from a total of 328 participants were included in this review. All studies compared once-daily dosing with thrice-daily dosing. One study had a low risk of bias for all criteria assessed; the remaining three included studies had a high risk of bias from blinding, but for other criteria were judged to have either an unclear or a low risk of bias.There was no significant difference between treatment groups in: forced expiratory volume at one second, mean difference 0.33 (95% confidence interval -2.81 to 3.48); forced vital capacity, mean difference 0.29 (95% confidence interval -6.58 to 7.16); % weight for height, mean difference -0.82 (95% confidence interval -3.77 to 2.13); body mass index, mean difference 0.00 (95% confidence interval -0.42 to 0.42); or in the incidence of ototoxicity, relative risk 0.56 (95% confidence interval 0.04 to 7.96). The percentage change in creatinine significantly favoured once-daily treatment in children, mean difference -8.20 (95% confidence interval -15.32 to -1.08), but showed no difference in adults, mean difference 3.25 (95% confidence interval -1.82 to 8.33). AUTHORS' CONCLUSIONS: Once- and three-times daily aminoglycoside antibiotics appear to be equally effective in the treatment of pulmonary exacerbations of cystic fibrosis. There is evidence of less nephrotoxicity in children.

Using atomistic solution scattering modelling to elucidate the role of the Fc glycans in human IgG4.

Human immunoglobulin G (IgG) exists as four subclasses IgG1-4, each of which has two Fab subunits joined by two hinges to a Fc subunit. IgG4 has the shortest hinge with 12 residues. The Fc subunit has two glycan chains, but the importance of glycosylation is not fully understood in IgG4. Here, to evaluate the stability and structure of non-glycosylated IgG4, we performed a multidisciplinary structural study of glycosylated and deglycosylated human IgG4 A33 for comparison with our similar study of human IgG1 A33. After deglycosylation, IgG4 was found to be monomeric by analytical ultracentrifugation; its sedimentation coefficient of 6.52 S was reduced by 0.27 S in reflection of its lower mass. X-ray and neutron solution scattering showed that the overall Guinier radius of gyration RG and its cross-sectional values after deglycosylation were almost unchanged. In the P(r) distance distribution curves, the two M1 and M2 peaks that monitor the two most common distances within IgG4 were unchanged following deglycosylation. Further insight from Monte Carlo simulations for glycosylated and deglycosylated IgG4 came from 111,382 and 117,135 possible structures respectively. Their comparison to the X-ray and neutron scattering curves identified several hundred best-fit models for both forms of IgG4. Principal component analyses showed that glycosylated and deglycosylated IgG4 exhibited different conformations from each other. Within the constraint of unchanged RG and M1-M2 values, the glycosylated IgG4 models showed more restricted Fc conformations compared to deglycosylated IgG4, but no other changes. Kratky plots supported this interpretation of greater disorder upon deglycosylation, also observed in IgG1. Overall, these more variable Fc conformations may demonstrate a generalisable impact of deglycosylation on Fc structures, but with no large conformational changes in IgG4 unlike those seen in IgG1.

Why and how should children be protected from the deluge of vaping related media and marketing overexposure?

E-cigarettes are products delivering nicotine via inhalation and are devised to mimic tobacco smoking. While they were initially introduced as a device putatively to aid with smoking cessation, their use is now far broader than that. Use by children is significantly increasing. There is growing evidence of the potential harms of vaping. E-liquids used for e-cigarettes contain a wide range of harmful substances, and the clinical consequences of this are now being increasingly demonstrated, such as the rise in cases of e-cigarette- or vaping-associated lung injury. In addition, early use may result in long-term nicotine addiction. Vaping companies utilise marketing methods that distinctly target young people, and weak legislation in the UK allows them free rein to expose children to vaping. In this review we demonstrate why children must be protected from vaping. We must have stringent legislation to prevent easy access to e-cigarettes, including banning the convenience and affordability disposable vapes provide, and prevent marketing that does not warn about the potential health effects. The Australia approach of prescription or pharmacy only access for smoking cessation should be considered to limit exposure of children and minimise use by nonsmokers.