Patients' perspectives on bronchiectasis: findings from a social media listening study.

Although it is of great importance for healthcare professionals to ensure that patients' needs and concerns are valued and that they feel confident in the quality of the care they receive, there have been few studies specifically addressing the opinions, experiences and needs of patients with bronchiectasis, and more importantly the emotional impact of the disease, diagnosis and treatment. Using enterprise grade social listening tools, a comprehensive search around bronchiectasis was performed in five languages, on different social media platforms between January 2018 and December 2019 to obtain the perspectives of patients and caregivers from nine countries on symptoms, treatments and burden of the disease. Over 27 000 mentions of bronchiectasis were identified on social media channels, 38.8% of which were posted by patients and caregivers. Approximately 1600 posts were found on bronchiectasis symptoms, out of which persistent cough, shortness of breath and mucus production (22%, 20% and 18%, respectively) were the most commonly discussed. The research revealed that existing diagnostic tests often delay diagnosis or provide inaccurate results, leading to multiple rounds of consults and substantial delays in treatment initiation and management of the disease. Misdiagnosis was common across different age groups, especially among patients without severe symptoms, and this was associated with an emotional burden of anger, confusion, frustration and anxiety. Analysis of social media presents a new approach to derive insights on patients' experiences and emotions with bronchiectasis and has the potential to complement more traditional approaches to drive more patient-focused drug development.

Medical education in Laos.

Medical education in Laos has undergone significant developments over the last century. A transition from a foreign to locally trained medical workforce has taken place, with international partners having an ongoing presence. Undergraduate and postgraduate medical education in Laos is now delivered by a single, government administered university. The transition to locally based training has had many flow-on benefits, including the retention of Lao doctors in the country and having graduates who are familiar with the local health system. A number of challenges do however exist. Medical resources in the Lao language are limited, teacher numbers and capacity are lacking and complex factors have led to a lack of uniformity in graduate competencies. Despite these challenges, the situation for medical education in Laos is a story of great optimism. Local staff has recognized the need for simple yet innovative solutions and processes are in place for the establishment of a licensing system for medical doctors and reforming existing curricula. Sustained, long-term relationships with partner organizations along with constructive use of technology are likely to be important factors affecting the future direction of medical education in Laos.

Patient participation in ERS guidelines and research projects: the EMBARC experience.

The European Multicentre Bronchiectasis Audit and Research Collaboration (EMBARC) is a European Respiratory Society (ERS) Clinical Research Collaboration dedicated to improving research and clinical care for people with bronchiectasis. EMBARC has created a European Bronchiectasis Registry, funded by the ERS and by the European Union (EU) Innovative Medicines Initiative Programme. From the outset, EMBARC had the ambition to be a patient-focussed project. In contrast to many respiratory diseases, however, there are no specific patient charities or European patient organisations for patients with bronchiectasis and no existing infrastructure for patient engagement. This article describes the experience of EMBARC and the European Lung Foundation in establishing a patient advisory group and then engaging this group in European guidelines, an international registry and a series of research studies. Patient involvement in research, clinical guidelines and educational activities is increasingly advocated and increasingly important. Genuine patient engagement can achieve a number of goals that are critical to the success of an EU project, including focussing activities on patient priorities, allowing patients to direct the clinical and research agenda, and dissemination of guidelines and research findings to patients and the general public. Here, we review lessons learned and provide guidance for future ERS task forces, EU-funded projects or clinical research collaborations that are considering patient involvement. EDUCATIONAL AIMS: To understand the different ways in which patients can contribute to clinical guidelines, research projects and educational activities.To understand the barriers and potential solutions to these barriers from a physician's perspective, in order to ensure meaningful patient involvement in clinical projects.To understand the barriers and potential solutions from a patient's perspective, in order to meaningfully involve patients in clinical projects.

European Respiratory Society guidelines for the management of adult bronchiectasis.

Bronchiectasis in adults is a chronic disorder associated with poor quality of life and frequent exacerbations in many patients. There have been no previous international guidelines.The European Respiratory Society guidelines for the management of adult bronchiectasis describe the appropriate investigation and treatment strategies determined by a systematic review of the literature.A multidisciplinary group representing respiratory medicine, microbiology, physiotherapy, thoracic surgery, primary care, methodology and patients considered the most relevant clinical questions (for both clinicians and patients) related to management of bronchiectasis. Nine key clinical questions were generated and a systematic review was conducted to identify published systematic reviews, randomised clinical trials and observational studies that answered these questions. We used the GRADE approach to define the quality of the evidence and the level of recommendations. The resulting guideline addresses the investigation of underlying causes of bronchiectasis, treatment of exacerbations, pathogen eradication, long term antibiotic treatment, anti-inflammatories, mucoactive drugs, bronchodilators, surgical treatment and respiratory physiotherapy.These recommendations can be used to benchmark quality of care for people with bronchiectasis across Europe and to improve outcomes.

CSF-1 receptor signalling is governed by pre-requisite EHD1 mediated receptor display on the macrophage cell surface.

Colony stimulating factor-1 receptor (CSF-1R), a receptor tyrosine kinase (RTK), is the master regulator of macrophage biology. CSF-1 can bind CSF-1R resulting in receptor activation and signalling essential for macrophage functions such as proliferation, differentiation, survival, polarization, phagocytosis, cytokine secretion, and motility. CSF-1R activation can only occur after the receptor is presented on the macrophage cell surface. This process is reliant upon the underlying macrophage receptor trafficking machinery. However, the mechanistic details governing this process are incompletely understood. C-terminal Eps15 Homology Domain-containing (EHD) proteins have recently emerged as key regulators of receptor trafficking but have not yet been studied in the context of macrophage CSF-1R signalling. In this manuscript, we utilize primary bone-marrow derived macrophages (BMDMs) to reveal a novel function of EHD1 as a regulator of CSF-1R abundance on the cell surface. We report that EHD1-knockout (EHD1-KO) macrophages cell surface and total CSF-1R levels are significantly decreased. The decline in CSF-1R levels corresponds with reduced downstream macrophage functions such as cell proliferation, migration, and spreading. In EHD1-KO macrophages, transport of newly synthesized CSF-1R to the macrophage cell surface was reduced and was associated with the shunting of the receptor to the lysosome, which resulted in receptor degradation. These findings reveal a novel and functionally important role for EHD1 in governing CSF-1R signalling via regulation of anterograde transport of CSF-1R to the macrophage cell surface.

Nexus of signaling and endocytosis in oncogenesis driven by non-small cell lung cancer-associated epidermal growth factor receptor mutants.

Epidermal growth factor receptor (EGFR) controls a wide range of cellular processes, and aberrant EGFR signaling as a result of receptor overexpression and/or mutation occurs in many types of cancer. Tumor cells in non-small cell lung cancer (NSCLC) patients that harbor EGFR kinase domain mutations exhibit oncogene addiction to mutant EGFR, which confers high sensitivity to tyrosine kinase inhibitors (TKIs). As patients invariably develop resistance to TKIs, it is important to delineate the cell biological basis of mutant EGFR-induced cellular transformation since components of these pathways can serve as alternate therapeutic targets to preempt or overcome resistance. NSCLC-associated EGFR mutants are constitutively-active and induce ligand-independent transformation in nonmalignant cell lines. Emerging data suggest that a number of factors are critical for the mutant EGFR-dependent tumorigenicity, and bypassing the effects of TKIs on these pathways promotes drug resistance. For example, activation of downstream pathways such as Akt, Erk, STAT3 and Src is critical for mutant EGFR-mediated biological processes. It is now well-established that the potency and spatiotemporal features of cellular signaling by receptor tyrosine kinases such as EGFR, as well as the specific pathways activated, is determined by the nature of endocytic traffic pathways through which the active receptors traverse. Recent evidence indicates that NSCLC-associated mutant EGFRs exhibit altered endocytic trafficking and they exhibit reduced Cbl ubiquitin ligase-mediated lysosomal downregulation. More recent work has shown that mutant EGFRs undergo ligand-independent traffic into the endocytic recycling compartment, a behavior that plays a key role in Src pathway activation and oncogenesis. These studies are beginning to delineate the close nexus between signaling and endocytic traffic of EGFR mutants as a key driver of oncogenic processes. Therefore, in this review, we will discuss the links between mutant EGFR signaling and endocytic properties, and introduce potential mechanisms by which altered endocytic properties of mutant EGFRs may alter signaling and vice versa as well as their implications for NSCLC therapy.

A kinase inhibitor screen reveals protein kinase C-dependent endocytic recycling of ErbB2 in breast cancer cells.

ErbB2 overexpression drives oncogenesis in 20-30% cases of breast cancer. Oncogenic potential of ErbB2 is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation of ErbB2 recycling is incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 breast cancer cells to identify kinases whose inhibition alters the clearance of cell surface ErbB2 induced by Hsp90 inhibitor 17-AAG. Less ErbB2 clearance was observed with broad-spectrum PKC inhibitor Ro 31-8220. A similar effect was observed with Go 6976, a selective inhibitor of classical Ca(2+)-dependent PKCs (α, ß1, ßII, and γ). PKC activation by PMA promoted surface ErbB2 clearance but without degradation, and ErbB2 was observed to move into a juxtanuclear compartment where it colocalized with PKC-α and PKC-δ together with the endocytic recycling regulator Arf6. PKC-α knockdown impaired the juxtanuclear localization of ErbB2. ErbB2 transit to the recycling compartment was also impaired upon PKC-δ knockdown. PMA-induced Erk phosphorylation was reduced by ErbB2 inhibitor lapatinib, as well as by knockdown of PKC-δ but not that of PKC-α. Our results suggest that activation of PKC-α and -δ mediates a novel positive feedback loop by promoting ErbB2 entry into the endocytic recycling compartment, consistent with reported positive roles for these PKCs in ErbB2-mediated tumorigenesis. As the endocytic recycling compartment/pericentrion has emerged as a PKC-dependent signaling hub for G-protein-coupled receptors, our findings raise the possibility that oncogenesis by ErbB2 involves previously unexplored PKC-dependent endosomal signaling.

Is it intelligent to intercalate? A two centre cross-sectional study exploring the value of intercalated degrees, and the possible effects of the recent tuition fee rise in England.

AIMS AND OBJECTIVES: To explore the value of intercalated degrees, including student perceptions and academic sequelae. To gauge the likely effect of the recent tuition fee rise and to identify any differences in intercalated degrees between Bristol and Sheffield universities. DESIGN: Cross-sectional study using questionnaires. SETTING: Bristol and Sheffield Medical Schools, UK. PARTICIPANTS: 1484 medical students in their clinical years were e-mailed the questionnaire. 578 students responded: 291 from Bristol and 287 from Sheffield (n=578; mean age=22.41; SD 1.944; 38.9% male; 61.1% female). The response rate from previous intercalators was 52.5% from Bristol and 58.7% from Sheffield, while for non-intercalators it was 27.7% and 34.6%, respectively. MAIN OUTCOME MEASURES: (1) Student preconceptions, opinions, results and academic sequelae from intercalated degrees at both centres. (2) Students' attitudes concerning the effect of the increase in tuition fees. RESULTS: Those with clinical academic supervisors gained significantly more posters (p=0.0002) and publications (p<0.0001), and also showed a trend to gain more first class honours (p=0.055). Students at Sheffield had a significantly greater proportion of clinical academic supervisors than students at Bristol (p<0.0001). 89.2% said that an intercalated degree was the right decision for them; however, only 27.4% stated they would have intercalated if fees had been £9000 per annum. CONCLUSIONS: Students clearly value intercalated degrees, feel they gained a substantial advantage over their peers as well as skills helpful for their future careers. The rise in tuition fees is likely to reduce the number of medical students opting to undertake an intercalated degree, and could result in a further reduction in numbers following an academic path. Sheffield University have more intercalating students supervised by clinical academics. Clinical academics appear more effective as supervisors for medical students undertaking an intercalated degree in terms of results and additional academic sequelae.

Functional studies in living animals using multiphoton microscopy.

In vivo microscopy is a powerful method for studying fundamental issues of physiology and pathophysiology. The recent development of multiphoton fluorescence microscopy has extended the reach of in vivo microscopy, supporting high-resolution imaging deep into the tissues and organs of living animals. As compared with other in vivo imaging techniques, multiphoton microscopy is uniquely capable of providing a window into cellular and subcellular processes in the context of the intact, functioning animal. In addition, the ability to collect multiple colors of fluorescence from the same sample makes in vivo microscopy uniquely capable of characterizing up to three parameters from the same volume, supporting powerful correlative analyses. Since its invention in 1990, multiphoton microscopy has been increasingly applied to numerous areas of medical investigation, providing invaluable insights into cell physiology and pathology. However, researchers have only begun to realize the true potential of this powerful technology as it has proliferated beyond the laboratories of a relatively few pioneers. In this article we present an overview of the advantages and limitations of multiphoton microscopy as applied to in vivo imaging. We also review specific examples of the application of in vivo multiphoton microscopy to studies of physiology and pathology in a variety of organs including the brain, skin, skeletal muscle, tumors, immune cells, and visceral organs.