The fungal diversity in the lungs of children with cystic fibrosis captured by sputum-induction and bronchoalveolar lavage.

BACKGROUND: The prevalence of fungi in cystic fibrosis (CF) lung infections is poorly understood and studies have focused on adult patients. We investigated the fungal diversity in children with CF using bronchoalveolar lavage (BAL) and induced sputum (IS) samples to capture multiple lung niches. METHODS: Sequencing of the fungal ITS2 region and molecular mycobiota diversity analysis was performed on 25 matched sets of BAL-IS samples from 23 children collected as part of the CF-SpIT study (UKCRN14615; ISRCTNR12473810). RESULTS: Aspergillus and Candida were detected in all samples and were the most abundant and prevalent genera, followed by Dipodascus, Lecanicillium and Simplicillium. The presumptive CF pathogens Exophiala, Lomentospora and Scedosporium were identified at variable abundances in 100 %, 64 %, and 24 % of sample sets, respectively. Fungal pathogens observed at high relative abundance (≥40 %) were not accurately diagnosed by routine culture microbiology in over 50 % of the cohort. The fungal communities captured by BAL and IS samples were similar in diversity and composition, with exception to C. albicans being significantly increased in IS samples. The respiratory mycobiota varied greatly between individuals, with only 13 of 25 sample sets containing a dominant fungal taxon. In 11/25 BAL sample sets, airway compartmentalisation was observed with diverse mycobiota detected from different lobes of the lung. CONCLUSIONS: The paediatric mycobiota is diverse, complex and inadequately diagnosed by conventional microbiology. Overlapping fungal communities were identified in BAL and IS samples, showing that IS can capture fungal genera associated with the lower airway. Compartmentalisation of the lower airway presents difficulties for consistent mycobiota sampling.

Nonlinear charge and energy transport in anharmonic quasi-two-dimensional systems.

We study the localized states of an extra electron in an anisotropic quasi-two-dimensional system in which the electron-lattice interaction and the anharmonicity of the lattice vibrations are dominant in one direction. This model describes layers of polydiacetylene or other polymer chains, beta sheets of polypeptides, multilevel microstructures of conjugated polymers, and other low-dimensional systems. It is shown that for appropriate parameter values of the system an extra electron can excite a soliton-like mobile wave of the lattice deformation, within which it can get self-trapped. Such a bound state of an electron and the lattice deformation form a nonlinear two-component polaron-like entity, which can propagate with minimum of the energy dissipation. Our findings are based on the variational approach and the full numerical solution of the coupled system of nonlinear equations. These results suggest that the experimentally measured charge and energy transport over macroscopic distances in the above-mentioned systems can be provided by the soliton mechanism and thus have a potential impact on the theoretical background of the numerous applications of low-dimensional materials in nanoelectronics.

Patient and provider perspectives on barriers to myocardial infarction care among persons with human immunodeficiency virus in Tanzania: A qualitative study.

INTRODUCTION: People with HIV (PLWH) have an increased risk myocardial infarction (MI), and evidence suggests that MI is under-diagnosed in Tanzania. However, little is known about barriers to MI care among PLWH in the region. METHODS: In this qualitative study grounded in phenomenology, semi-structured interviews were conducted in northern Tanzania. Purposive sampling was used to recruit a diverse group of providers who care for PLWH and patients with HIV and electrocardiographic evidence of prior MI. Emergent themes were identified via inductive thematic analysis. RESULTS: 24 physician and patient participants were interviewed. Most participants explained MI as caused by emotional shock and were unaware of the association between HIV and increased MI risk. Providers described poor provider training regarding MI, high out-of-pocket costs, and lack of diagnostic equipment and medications. Patients reported little engagement with and limited knowledge of cardiovascular care, despite high engagement with HIV care. Most provider and patient participants indicated that they would prefer to integrate cardiovascular care with routine HIV care. CONCLUSIONS: PLWH face many barriers to MI care in Tanzania. There is a need for multifaceted interventions to educate providers and patients, improve access to MI diagnosis, and increase engagement with cardiovascular care among this population.

Future therapies for cystic fibrosis.

We are currently witnessing transformative change for people with cystic fibrosis with the introduction of small molecule, mutation-specific drugs capable of restoring function of the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). However, despite being a single gene disorder, there are multiple cystic fibrosis-causing genetic variants; mutation-specific drugs are not suitable for all genetic variants and also do not correct all the multisystem clinical manifestations of the disease. For many, there will remain a need for improved treatments. Those patients with gene variants responsive to CFTR modulators may have found these therapies to be transformational; research is now focusing on safely reducing the burden of symptom-directed treatment. However, modulators are not available in all parts of the globe, an issue which is further widening existing health inequalities. For patients who are not suitable for- or do not have access to- modulator drugs, alternative approaches are progressing through the trials pipeline. There will be challenges encountered in design and implementation of these trials, for which the established global CF infrastructure is a major advantage. Here, the Cystic Fibrosis National Research Strategy Group of the UK NIHR Respiratory Translational Research Collaboration looks to the future of cystic fibrosis therapies and consider priorities for future research and development.

Editorial Commentary: Double-Sling Transfer of Both the Conjoined Tendons and Long Head Biceps Tendon for Glenoid Bone Loss in Patients With Shoulder Instability Shows Biomechanical Benefit in Shoulder Abduction and External Rotation But May Be Insufficient in Mid-Range Arm Positions.

Recurrence of shoulder glenohumeral instability is exacerbated in cases of glenoid bone loss. Surgical bone transfer techniques well address the issue. Innovative soft-tissue tendon transfers may fill the defect plus provide a sling effect. Double-sling transfer of both the conjoined tendons and long head biceps tendon for glenoid bone loss in patients with shoulder instability shows biomechanical benefit in shoulder abduction and external rotation. However, as the sling effect is less pronounced in mid-range arm position, the benefit of double-sling transfer may be insufficient. Moreover, the biomechanical models are limited relative to the complexity of clinical glenohumeral function, and obviously limited to time-zero analysis. We should be careful before we abandon bony augmentation procedures.

Electron Diffraction Enables the Mapping of Coke in ZSM-5 Micropores Formed during Methanol-to-Hydrocarbons Conversion.

Unveiling the coke formation in zeolites is an essential prerequisite for tackling the deactivation of these catalysts in the transformations of hydrocarbons. Herein, we present the direct mapping of coke in the micropores of ZSM-5 catalysts used in methanol-to-hydrocarbons conversion by single-crystal electron diffraction analysis. The latter technique revealed a polycyclic aromatic structure along the straight channel, wherein the high-quality data permit refinement of its occupancy to about 40 %. These findings were exploited to analyze the evolution of micropore coke during the reaction. Herein, coke-associated signals, which correlate with the activity loss, indicate that the nucleation of coke commences in the intersections of sinusoidal and straight channels, while the formation of coke in the straight pores occurs in the late stages of deactivation. The findings uncover an attractive method for analyzing coke deposition in the micropore domain.

The lung microbiota in children with cystic fibrosis captured by induced sputum sampling.

BACKGROUND: Spatial topography of the cystic fibrosis (CF) lung microbiota is poorly understood in childhood. How best to sample the respiratory tract in children for microbiota analysis, and the utility of microbiota profiling in clinical management of early infection remains unclear. By comparison with bronchoalveolar lavage (BAL), we assessed the ability of induced sputum (IS) sampling to characterise the lower airway microbiota. METHODS: Sample sets from IS and two or three matched BAL compartments were obtained for microbiota analysis as part of the CF-Sputum Induction Trial (UKCRN_14615, ISRCTNR_12473810). Microbiota profiles and pathogen detection were compared between matched samples. RESULTS: Twenty-eight patients, aged 1.1-17.7 years, provided 30 sample sets. Within-patient BAL comparisons revealed spatial heterogeneity in 8/30 (27%) sample sets indicating that the lower airway microbiota from BAL is frequently compartmentalised in children with CF. IS samples closely resembled one or more matched BAL compartments in 15/30 (50%) sets, and were related in composition in a further 9/30 (30%). IS detected 86.2% of the Top 5 genera found across matched BAL samples. The sensitivity of IS to detect specific CF-pathogens identified in matched BAL samples at relative abundance ≥5% varied between 43 and 100%, with negative predictive values between 73 and 100%. CONCLUSIONS: Spatial heterogeneity of the lower airway microbiota was observed in BAL samples and presents difficulties for consistent lung sampling. IS captured a microbiota signature representative of the lower airway in 80% of cases, and is a straightforward, non-invasive intervention that can be performed frequently to aid pathogen diagnosis and understand microbiota evolution in children with CF.

Surgical palliative care disparities.

Surgical palliative care is an interdisciplinary treatment modality that aims to decrease suffering and improve the quality of life of seriously ill surgical patients. Although surgical palliative care is increasingly being found to positively impact patient quality of life, disparities in surgical palliative care remain poorly defined. While the field of medical palliative care has demonstrated certain racial/ethnic, socioeconomic, and geographic groups are at higher risks for receiving worse palliative care, there is no analogous consensus in the field of surgical palliative care. This is largely secondary to a paucity of research focus in this field. Given that the aforementioned disparities experienced by minoritized patient populations has led to significant morbidity, it is important to understand and call attention to disparities existing within the field of surgical palliative care as well. To advance the knowledge of current healthcare shortcomings and progress towards equitable surgical palliative care, this paper reviews the current state of surgical palliative care disparities evidence, details gaps in knowledge, and highlights priorities for future surgical palliative care research. The articles identified in this review noted disparate surgical palliative care access and outcomes across various racial/ethnic groups, age ranges, socioeconomic classes, hospital populations, and regions. However, evidence scarcity necessitates more robust research be performed to adequately identify at risk groups and understand the factors supporting disparity development.

The use of minimally invasive interspinous process devices for the treatment of lumbar canal stenosis: a narrative literature review.

Minimally invasive interspinous process devices (IPD), including interspinous distraction devices (IDD) and interspinous stabilizers (ISS), are increasingly utilized for treating symptomatic lumbar canal stenosis (LCS). There is ongoing debate around their efficacy and safety over traditional decompression techniques with and without interbody fusion (IF). This study presents a comprehensive review of IPD and investigates if: (I) minimally invasive IDD can effectively substitute direct neural decompression and (II) ISS are appropriate substitutes for fusion after decompression. Articles published up to 22nd January 2020 were obtained from PubMed search. Relevant articles published in the English language were selected and critically reviewed. Observational studies across different IPD brands consistently show significant improvements in clinical outcomes and patient satisfaction at short-term follow-up. Compared to non-operative treatment, mini-open IDD was had significantly greater quality of life and clinical outcome improvements at 2-year follow-up. Compared to open decompression, mini-open IDD had similar clinical outcomes, but associated with higher complications, reoperation risks and costs. Compared to open decompression with concurrent IF, ISS had comparable clinical outcomes with reduced operative time, blood loss, length of stay and adjacent segment mobility. Mini-open IDD had better outcomes over non-operative treatment in mild-moderate LCS at 2-year follow-up, but had similar outcomes with higher risk of re-operations than open decompression. ISS with open decompression may be a suitable alternative to decompression and IF for stable grade 1 spondylolisthesis and central stenosis. To further characterize this procedure, future studies should focus on examining enhanced new generation IPD devices, longer-term follow-up and careful patient selection.

Role of vertebroplasty and balloon kyphoplasty in pathological fracture in myeloma: a narrative review.

BACKGROUND: Up to 70% of multiple myeloma (MM) patients develop vertebral metastasis and subsequent pathological vertebral fractures (PVF). With contemporary systemic therapies, life expectancy of MM patients has improved drastically, and the need to manage pain and associated disability from PVF is increasingly a high priority. The aim of this review is to provide an updated comprehensive synthesis of evidence in the use of vertebral augmentation, including percutaneous vertebroplasty (PV) and balloon kyphoplasty (BKP), to treat MM-related PVF. METHODS: A comprehensive multi-database search in accordance with PRISMA guidelines was performed up to 10 February 2021. Relevant English language articles were selected and critically reviewed. FINDINGS: A total of 23 clinical studies have been included in the review. PV and BKP showed significant pain and functional improvements in terms of analgesia requirements, Cervical Spine Function Score, Eastern Cooperative Oncology Group scale, EQ-5D score, Karnofsky score, Neck Pain Disability Index, Oswestry Disability Index, Short form-36 (SF-36) questionnaire and VAS pain scale. Both procedures also reported promising radiographic outcomes in terms of vertebral height improvement, maintenance and restoration, as well as kyphotic deformity correction. Asymptomatic cement leakage was commonly reported. There was no significant difference between the two procedures. CONCLUSION: PV and BKP are safe and effective procedure that offers pain relief, reduction in pain associated disability and reduction of fracture incidence. Its minimally invasive approach is associated with minimal morbidity risk, making it a viable option in frail patients. LEVEL OF EVIDENCE IV: Narrative review.

Cystic fibrosis newborn screening: the importance of bloodspot sample quality.

OBJECTIVE: Wales has an immunoreactive trypsin (IRT)-DNA cystic fibrosis (CF) newborn screening (NBS) programme. Most CF NBS false negative cases are due to an IRT concentration below the screening threshold. The accuracy of IRT results is dependent on the quality of the dried bloodspot (DBS) sample. The aim of this study was to determine the cause of false negative cases in CF NBS and their relationship to DBS quality. DESIGN: Longitudinal birth cohort. SETTING: Wales 1996-2016. PATIENTS: Children with CF. INTERVENTIONS: Identification of all CF patients with triangulation of multiple data sources to detect false negative cases. MAIN OUTCOME MEASURES: False negative cases. RESULTS: Over 20 years, 673 952 infants were screened and 239 were diagnosed with CF (incidence 1:2819). The sensitivity of the programme was 0.958, and positive predictive value was 0.476. Eighteen potential false negatives were identified, of whom eight were excluded: four screened outside Wales, two had complex comorbidities, no identified cystic fibrosis transmembrane conductance regulator (CFTR) variants on extended analysis and thus not considered to have CF and two were diagnosed after their 16th birthday. Of the 10 false negatives, 9 had a low DBS IRT and at least one common CFTR variant and thus should have received a sweat test under the programme. DBS cards were available for inspection for five of the nine false negative cases-all were classified as small/insufficient or poor quality. CONCLUSIONS: The majority of false negatives had a low bloodspot IRT, and this was associated with poor quality DBS. The optimal means to improve the sensitivity of our CF NBS programme would be to improve DBS sample quality.

Effect of Slope and Varus Correction High Tibial Osteotomy in the ACL-Deficient and ACL-Reconstructed Knee on Kinematics and ACL Graft Force: A Biomechanical Analysis.

BACKGROUND: Correction of high posterior tibial slope is an important treatment option for revision of anterior cruciate ligament (ACL) failure as seen in clinical and biomechanical studies. In cases with moderate to severe medial compartment arthritis, an additional varus correction osteotomy may be added to improve alignment. PURPOSE: To investigate the influence of coronal and sagittal correction high tibial osteotomy in ACL-deficient and ACL-reconstructed knees on knee kinematics and ACL graft load. STUDY DESIGN: Controlled laboratory study. METHODS: Ten cadaveric knees were selected according to previous computed tomography measurements with increased native slope and slight varus tibial alignment (mean ± SD): slope, 9.9°± 1.4°; medial proximal tibia angle, 86.5°± 2.1°; age, 47.7 ± 5.8 years. A 10° anterior closing-wedge osteotomy, as well as an additional 5° of simulated varus correction osteotomy, were created and fixed using an external fixator. Four alignment conditions-native, varus correction, slope correction, and combined varus and slope correction-were randomly tested in 2 states: ACL-deficient and ACL-reconstructed. Compressive axial loads were applied to the tibia while mounted on a free-moving X-Y table and free-rotating tibia in a knee testing fixture. Three-dimensional motion tracking captured anterior tibial translation (ATT) and internal tibial rotation. Change of tensile forces on the reconstructed ACL graft were recorded. RESULTS: In the ACL-deficient knee, an isolated varus correction led to a significant increase of ATT by 4.3 ± 4.0 mm (P = .04). Isolated slope reduction resulted in the greatest decrease of ATT by 6.2 ± 4.3 mm (P < .001). In the ACL-reconstructed knee, ATT showed comparable changes, while combined varus and slope correction led to lower ATT by 3.7 ± 2.6 mm (P = .01) than ATT in the native alignment. Internal tibial rotation was not significantly altered by varus correction but significantly increased after isolated slope correction by 4.0°± 4.1° (P < .01). Each isolated or combined osteotomy showed decreased forces on the graft as compared with the native state. The combined varus and slope osteotomy led to a mean decrease of ACL graft force by 33% at 200 N and by 58% at 400 N as compared with the native condition (P < .001). CONCLUSION: A combined varus and slope correction led to a relevant decrease of ATT in the ACL-deficient and ACL-reconstructed cadaveric knee. ACL graft forces were significantly decreased after combined varus and slope correction. Thus, our biomechanical findings support the treatment goal of a perpendicular-aligned tibial plateau for ACL insufficiencies, especially in cases of revision surgery. CLINICAL RELEVANCE: This study shows the beneficial knee kinematics and reduced forces on the ACL graft after combined varus and slope correction.

Single Level Percutaneous Vertebroplasty for Vertebral Hemangiomata - A Review of Outcomes.

BACKGROUND: Percutaneous vertebroplasty is a minimally invasive technique to treat patients with symptomatic vertebral hermangiomata. OBJECTIVES: We present a single-operator series of cases to demonstrate the clinical outcomes and complication profiles for this technique. STUDY DESIGN: This is a retrospective multi-center cohort study. SETTING: Procedures were performed across multiple hospitals in Italy by a single proceduralist. METHODS: All patients with symptomatic vertebral hermangiomata that had percutaneous vertebroplasty over a 14-year period (March 1999 to April 2013) by a single proceduralist were included in this study. Information collected included demographic data, vertebral level of intervention, cement volume used, and the Visual Analogue Score for pain that was assessed pre- and post-intervention. Patients were followed up for a minimum of one year. RESULTS: Percutaneous vertebroplasty was performed for 50 patients. All patients had an improvement in pain, with 39 patients (78%) reporting complete pain relief. A unipedicular approach was undertaken in 41 cases (82%), and bipedicular approach in 8 patients (16%), while a transoral approach was used in one patient. The mean cement volume per vertebral level was 6.8 mL (1 - 18 mL). Recurrent symptoms occurred in 2 patients (4%) requiring repeat vertebroplasty. There were no cases of symptomatic cement leak, and no cases of procedural morbidity or mortality. LIMITATIONS: As a multicenter study conducted over a 14-year time period, there may be heterogeneity in procedural technique and rehabilitation protocols. There were no cases of cement leakage in our study, which could be an underreporting of cases. This is could be due to none of our patients receiving a post procedural computerized tomography scan, which is more sensitive in detecting cement leakage when compared to procedural fluoroscopy. CONCLUSION: Percutaneous vertebroplasty is associated with good post-procedural outcomes in patients with vertebral hermangiomata. Complications such as neurological injury and cement leakages are rare.

Efficiency and stability evaluation of Cu2O/MWCNTs filters for virus removal from water.

Both multi-walled carbon nanotubes (MWCNTs) and metal or metal oxides have demonstrated virus removal efficacy in drinking water applications. In this study, MWCNTs were coated with copper(I) oxide (Cu2O) using three distinct synthesis procedures (copper ion attachment, copper hydroxide precipitation, and [Cu(NH3)4]2+ complex attachment) and virus removal efficacy (using MS2 bacteriophages) was evaluated. All synthesis procedures resulted in the presence of adsorbed, nanosized Cu2O particles on the MWCNTs, shown using X-ray diffraction. Further, transmission electron microscopy confirmed uniform copper(I) oxide distribution along the MWCNTs for all three materials. Virus removal efficacy was assessed for all three synthesised composites both before and after material conditioning (filtering for at least 24 h/280 mL/h), and accounting for additional MS2 inactivation in the permeate due to continued copper inactivation from dissolved/desorbed copper in permeate (time-control). Material conditioning influenced virus removal, with the first litres of water containing higher concentrations of copper than the sixth litres of water, suggesting excess or non-bonded copper species dissolve from filters. Higher copper dissolution was observed for water at pH 5 than at pH 7, which decreased with time. Copper dissolution most likely caused an associated decrease in copper adsorbed to MWCNTs in the filters, which may explain the observed lower MS2 removal efficacy after conditioning. Additionally, the time-control study (immediately after filtration as compared to 2 h after filtration) highlighted continued MS2 inactivation in the permeate over time. The obtained results indicate that the synthesis procedure influences virus removal efficacy for MWCNTs coated with copper oxides and that virus removal is likely due to not only virus electrostatic adsorption to the coated MWCNTs, but also through antiviral properties of copper which continues to act in the permeate. In conclusion, it is highly important to revise the methods of testing filter materials for virus removal, as well as procedure for virus concentration evaluation.

Detecting respiratory infection in children with cystic fibrosis: Cough swab, sputum induction or bronchoalveolar lavage.

Young children with cystic fibrosis (CF) are generally very well, cough free and non-productive, and are often incapable of spontaneously expectorating sputum even if actively coughing during an exacerbation. Obtaining a meaningful airway sample for microbiological analysis is therefore problematic, yet essential if lower airway infection is to be detected and adequately treated. Recently there has been increasing interest in the use of sputum-induction in young children with CF, as a simple, cost effective, well tolerated and frequently repeatable approach to sampling the lower airway, and the relative merits of this approach to bacterial sampling are discussed. Culture-independent microbiology has increased our understanding of the respiratory microbiota and has challenged the current paradigm of "single pathogen causes disease". Understanding how to diagnose infection using these new, highly sensitive technologies will be important. How we should best intervene to optimise, manipulate and prevent disruption of the respiratory microbiota is likely to greatly influence how we manage infection in the future.

Mediators of Corneal Haze Following Implantation of Presbyopic Corneal Inlays.

Purpose: To identify protein mediators of corneal haze following presbyopic corneal inlay surgery. Methods: Tears were collected from eyes with corneal haze following surgery with a shape-changing corneal inlay. Samples were subjected to quantitative proteomic analysis using iTRAQ and proteins significantly increased or decreased (1.3-fold or more) in haze eyes relative to fellow eyes were identified. Expression ratios were compared to postoperative eyes without corneal haze to identify proteins selectively increased or decreased in corneal haze eyes. Results: Inlay-associated haze occurred in 35% of eyes (6 of 17). Of 1443 unique tear proteins identified, eight proteins were selectively reduced in tears from postoperative haze eyes and one protein selectively increased. Proteins reduced in haze eyes included complement 4a (level relative to nonhaze eyes 0.464, P = 0.037), complement factor H (0.589, P = 0.048), immunoglobulin kappa variable 2-29 (0.128, P = 0.006), immunoglobulin kappa variable 2D-28 (0.612, P = 0.025), immunoglobulin lambda variable 7-46 (0.482, P = 0.007), S100 calcium binding protein A4 (0.614, P = 0.048), Shootin-1 (0.614, P = 0.048), and tissue inhibitor of metalloproteinase-1 (0.736, P = 0.023). The Xaa-Pro aminopeptidase 1 was increased in haze eyes relative to nonhaze eyes (1.517, P = 0.023). Conclusions: Corneal haze following corneal inlay surgery is associated with reduction in levels of known inflammatory and immune mediators. These findings represent a starting point for elucidation of pathways involved in corneal haze following synthetic inlay implantation and may enable development of targeted therapies that modulate the haze response.

The CF-Sputum Induction Trial (CF-SpIT) to assess lower airway bacterial sampling in young children with cystic fibrosis: a prospective internally controlled interventional trial.

BACKGROUND: Pathogen surveillance is challenging but crucial in children with cystic fibrosis-who are often non-productive of sputum even if actively coughing-because infection and lung disease begin early in life. The role of sputum induction as a diagnostic tool for infection has not previously been systematically addressed in young children with cystic fibrosis. We aimed to assess the pathogen yield from sputum induction compared with that from cough swab and single-lobe, two-lobe, and six-lobe bronchoalveolar lavage. METHODS: This prospective internally controlled interventional trial was done at the Children's Hospital for Wales (Cardiff, UK) in children with cystic fibrosis aged between 6 months and 18 years. Samples from cough swab, sputum induction, and single-lobe, two-lobe, and six-lobe bronchoalveolar lavage were matched for within-patient comparisons. Primary outcomes were comparative pathogen yield between sputum induction and cough swab for stage 1, and between sputum induction, and single-lobe, two-lobe, and six-lobe bronchoalveolar lavage for stage 2. Data were analysed as per protocol. This study is registered with the UK Clinical Research Network (14615) and with the International Standard Randomised Controlled Trial Network Registry (12473810). FINDINGS: Between Jan 23, 2012, and July 4, 2017, 124 patients were prospectively recruited to the trial and had 200 sputum induction procedures for stage 1. 167 (84%) procedures were successful and the procedure was well tolerated. Of the 167 paired samples, 63 (38%) sputum-induction samples were pathogen positive compared with 24 (14%) cough swabs (p<0·0001; odds ratio [OR] 7·5; 95% CI 3·19-17·98). More pathogens were isolated from sputum induction than cough swab (79 [92%] of 86 vs 27 [31%] of 86; p<0·0001). For stage 2, 35 patients had a total of 41 paired sputum-induction and bronchoalveolar lavage procedures. Of the 41 paired samples, 28 (68%) were positive for at least one of the concurrent samples. 39 pathogens were isolated. Sputum induction identified 27 (69%) of the 39 pathogens, compared with 22 (56%; p=0·092; OR 3·3, 95% CI 0·91-12·11) on single-lobe, 28 (72%; p=1·0; OR 1·1, 95% CI 0·41-3·15) on two-lobe, and 33 (85%; p=0·21; OR 2·2, 95% CI 0·76-6·33) on six-lobe bronchoalveolar lavage. INTERPRETATION: Sputum induction is superior to cough swab for pathogen detection, is effective at sampling the lower airway, and is a credible surrogate for bronchoalveolar lavage in symptomatic children. A substantial number of bronchoscopies could be avoided if sputum induction is done first and pathogens are appropriately treated. Both sputum induction and six-lobe bronchoalveolar lavage provide independent, sizeable gains in pathogen detection compared with the current gold-standard two-lobe bronchoalveolar lavage. We propose that sputum induction and six-lobe bronchoalveolar lavage combined are used as standard of care for comprehensive lower airway pathogen detection in children with cystic fibrosis. FUNDING: Health and Care Research Wales-Academic Health Science Collaboration and Wellcome Trust Institutional Strategic Support Fund.

Weekly paclitaxel and concurrent pazopanib following doxorubicin and cyclophosphamide as neoadjuvant therapy for HER-negative locally advanced breast cancer: NSABP Foundation FB-6, a phase II study.

This multicenter single-arm phase II study evaluated the addition of pazopanib to concurrent weekly paclitaxel following doxorubicin and cyclophosphamide as neoadjuvant therapy in human epidermal growth factor receptor (HER2)-negative locally advanced breast cancer (LABC). Patients with HER2-negative stage III breast cancer were treated with doxorubicin 60 mg/m(2) and cyclophosphamide 600 mg/m(2) for four cycles every 3 weeks followed by weekly paclitaxel 80 mg/m(2) on days 1, 8, and 15 every 28 days for four cycles concurrently with pazopanib 800 mg orally daily prior to surgery. Post-operatively, pazopanib was given daily for 6 months. The primary endpoint was pathologic complete response (pCR) in the breast and lymph nodes. Between July 2009 and March 2011, 101 patients with stage IIIA-C HER2-negative breast cancer were enrolled. The pCR rate in evaluable patients who initiated paclitaxel and pazopanib was 17 % (16/93). The pCR rate was 9 % (6/67) in hormone receptor-positive tumors and 38 % (10/26) in triple-negative tumors. Pre-operative pazopanib was completed in only 39 % of patients. The most frequent grade 3 and 4 adverse events during paclitaxel and pazopanib were neutropenia (27 %), diarrhea (5 %), ALT and AST elevations (each 5 %), and hypertension (5 %). Although the pCR rate of paclitaxel and pazopanib following AC chemotherapy given as neoadjuvant therapy in women with LABC met the pre-specified criteria for activity, there was substantial toxicity, which led to a high discontinuation rate of pazopanib. The combination does not appear to warrant further evaluation in the neoadjuvant setting for breast cancer.