Issues in Medicine.

Rasmussen aneurysms are abnormalities of the pulmonary arterial system caused by tuberculosis (TB). They are associated with a highmortality rate when they cause life-threatening haemoptysis. High TB-prevalence regions have a large burden of TB-related haemoptysisbut often limited resources. This series of 25 patients who presented with life-threatening haemoptysis from current and/or previous TBwere found to have abnormal pulmonary arteries on computed tomography pulmonary angiogram (CTPA), which were judged to belikely contributors to their bleeding, either in isolation or with concomitant abnormal bronchial or systemic vasculature. These patientsunderwent transcatheter placement of Amplatzer vascular plugs in the feeder pulmonary artery. Bronchial and systemic lesions wereaddressed separately as needed. Immediate technical success was achieved in all patients, but four of them experienced intraoperativehaemoptysis related to dislodgement of the occluding platelet plug by the high-pressure automatic injector and wire. At 48 hours after theprocedure, 18 (72%) remained haemoptysis-free. Six of these experienced recurrence within 1 year of their procedure. Pulmonary arteryplacement of an Amplatzer vascular plug is a feasible option for treating bleeding Rasmussen aneurysms, but should be part of a combinedapproach to addressing suspected culprit vascular lesions in all intrathoracic vascular systems.

Cell-free DNA analysis in current cancer clinical trials: a review.

Cell-free DNA (cfDNA) analysis represents a promising method for the diagnosis, treatment selection and clinical follow-up of cancer patients. Although its general methodological feasibility and usefulness has been demonstrated, several issues related to standardisation and technical validation must be addressed for its routine clinical application in cancer. In this regard, most cfDNA clinical applications are still limited to clinical trials, proving its value in several settings. In this paper, we review the current clinical trials involving cfDNA/ctDNA analysis and highlight those where it has been useful for patient stratification, treatment follow-up or development of novel approaches for early diagnosis. Our query included clinical trials, including the terms 'cfDNA', 'ctDNA', 'liquid biopsy' AND 'cancer OR neoplasm' in the FDA and EMA public databases. We identified 1370 clinical trials (FDA = 1129, EMA = 241) involving liquid-biopsy analysis in cancer. These clinical trials show promising results for the early detection of cancer and confirm cfDNA as a tool for real-time monitoring of acquired therapy resistance, accurate disease-progression surveillance and improvement of treatment, situations that result in a better quality of life and extended overall survival for cancer patients.

New insights into spontaneous pneumothorax: A review.

A spontaneous pneumothorax is a pneumothorax that does not arise from trauma or an iatrogenic cause. Although the traditional classification of either primary or secondary spontaneous pneumothorax based on the absence or presence of overt underlying lung disease is still widely used, it is now well recognised that primary spontaneous pneumothorax is associated with underlying pleuropulmonary disease. Current evidence indicates that computed tomography screening for underlying disease should be considered in patients who present with spontaneous pneumothorax. Recent evidence suggests that conservative management has similar recurrence rates, less complications and shorter hospital stay compared with invasive interventions, even in large primary spontaneous pneumothoraces of >50%. A more conservative approach which is based on clinical assessment rather than pneumothorax size can thus be followed during the acute management in selected stable patients. The purpose of this review is to revisit the aetiology of spontaneous pneumothorax, identify which patients should be investigated for secondary causes and to give an overview of the management strategies at initial presentation as well as secondary prevention.

ß-Cell and renal transplantation options for diabetes.

Despite major advances in structured education, insulin delivery and glucose monitoring, diabetes self-management remains an unremitting challenge. Insulin therapy is inextricably linked to risk of dangerous hypoglycaemia and sustained hyperglycaemia remains a leading cause of renal failure. This review sets out to demystify transplantation for diabetes multidisciplinary teams, facilitating consideration and incorporation within holistic overall person-centred management. Deceased and living donor kidney, whole pancreas and isolated islet transplant procedures, indications and potential benefits are described, in addition to outcomes within the integrated UK transplant programme.

Utility of routine chest radiography in ocular tuberculosis and sarcoidosis.

BACKGROUND: Tuberculosis (TB) and sarcoidosis commonly present with pulmonary and ocular involvement. Routine chest radiography (CXR) is recommended in the workup for suspected intraocular TB (IOTB) or intraocular sarcoidosis (IOS); however, data on the utility of CXR in this setting are lacking. METHODS: A post-hoc analysis was performed of a prospectively collected data set comprising 104 patients with uveitis of unknown cause. A pulmonologist and thoracic radiologist, blinded to the final diagnosis, independently reported these CXRs as being in keeping with TB or sarcoidosis. RESULTS: CXRs were reported as normal/indeterminate (n = 88), probable/previous TB (n = 9) or possible/probable sarcoidosis (n = 8), with a 96% inter-observer concordance. CXRs were more often abnormal in IOS than in IOTB (5/8 vs. 5/34, P = 0.01). CXR had a sensitivity of 14.7%, specificity of 94.3%, positive predictive value (PPV) of 55.6% and negative predictive value (NPV) of 69.5% for IOTB, compared with a sensitivity of 62.5%, specificity of 96.9%, PPV of 62.5% and NPV of 96.9% for IOS. Overall diagnostic accuracy was 54.5% (58.1% in human immunodeficiency virus [HIV] positive participants) in the case of IOTB and 79.9% for IOS. CONCLUSION: CXR had high specificity and NPV for IOS, and poor overall diagnostic accuracy for IOTB, including in the HIV-positive population.

Factors that influence quality and yield of circulating-free DNA: A systematic review of the methodology literature.

BACKGROUND: Circulating-free DNA (cfDNA) is under investigation as a liquid biopsy of cancer for early detection, monitoring disease progression and therapeutic response. This systematic review of the primary cfDNA literature aims to identify and evaluate factors that influence recovery of cfDNA, and to outline evidence-based recommendations for standardization of methods. METHODS: A search of the Ovid and Cochrane databases was undertaken in May 2018 to obtain relevant literature on cfDNA isolation and quantification. Retrieved titles and abstracts were reviewed by two authors. The factors evaluated include choice of specimen type (plasma or serum); time-to-processing of whole blood; blood specimen tube; centrifugation protocol (speed, time, temperature and number of spins); and methods of cfDNA isolation and quantification. FINDINGS: Of 4,172 articles identified through the database search, 52 proceeded to full-text review and 37 met the criteria for inclusion. A quantitative analysis was not possible, due to significant heterogeneity in methodological approaches between studies. Therefore, included data was tabulated and a textual qualitative synthesis approach was taken. INTERPRETATION: This is the first systematic review of methodological factors that influence recovery and quantification of cfDNA, enabling recommendations to be made that will support standardization of methodological approaches towards development of blood-based cancer tests.

The current aetiology of malignant pleural effusion in the Western Cape Province, South Africa.

BACKGROUND: Malignant pleural effusion (MPE) represents a very common cause of pleural exudates, and is one of the most challenging pleural disorders to manage. This could be attributed to the paucity of high-quality experimental evidence, and inconsistent practice worldwide. South Africa (SA) currently has no data regarding the aetiology of MPE. OBJECTIVES: To identify the most common malignancies causing MPE in a population served by a large tertiary hospital in SA, and specifically the relative contribution of mesothelioma. A secondary objective was to evaluate the efficacy of chemical pleurodesis in a subset of patients. METHODS: We retrospectively included all known cases of MPE evaluated at our institution over a 3-year period with a tissue diagnosis of MPE. RESULTS: The most common causes of MPE in a total of 274 patients were lung cancer (n=174, 63.5%), breast cancer (n=32, 11.7%), unknown primary (n=22, 11.7%) and mesothelioma (n=27, 9.9%). Talc pleurodesis was performed in 81 of 194 patients (41.8%) referred to our division, and was radiologically successful in 22 of 25 (88.0%) followed up to 3 months. CONCLUSIONS: The main cause of MPE in our setting was lung cancer, followed by breast cancer, unknown primary and mesothelioma. Chemical pleurodesis was a viable palliative measure for MPE in this population.

Loss of end-differentiated ß-cell phenotype following pancreatic islet transplantation.

Replacement of pancreatic ß-cells through deceased donor islet transplantation is a proven therapy for preventing recurrent life-threatening hypoglycemia in type 1 diabetes. Although near-normal glucose levels and insulin independence can be maintained for many years following successful islet transplantation, restoration of normal functional ß-cell mass has remained elusive. It has recently been proposed that dedifferentiation/plasticity towards other endocrine phenotypes may play an important role in stress-induced ß-cell dysfunction in type 2 diabetes. Here we report loss of end-differentiated ß-cell phenotype in 2 intraportal islet allotransplant recipients. Despite excellent graft function and sustained insulin independence, all examined insulin-positive cells had lost expression of the end-differentiation marker, urocortin-3, or appeared to co-express the α-cell marker, glucagon. In contrast, no insulin+ /urocortin-3- cells were seen in nondiabetic deceased donor control pancreatic islets. Loss of end-differentiated phenotype may facilitate ß-cell survival during the stresses associated with islet isolation and culture, in addition to sustained hypoxia following engraftment. As further refinements in islet isolation and culture are made in parallel with exploration of alternative ß-cell sources, graft sites, and ultimately fully vascularized bioengineered insulin-secreting microtissues, differentiation status immunostaining provides a novel tool to assess whether fully mature ß-cell phenotype has been maintained.

Inhaled corticosteroids in COPD: Personalising the therapeutic choice.

There has been a recent surge in interest in the role of inhaled corticosteroids (ICS) in the treatment of COPD, especially regarding patients with high eosinophil counts. Evidence has shown that despite the increase in localised adverse effects and a small increase in non-fatal pneumonia events with ICS use, ICS still have an important role to play in reducing exacerbation rates and addressing the inflammation that is at the heart of the pathogenesis of COPD. Current international guidelines recommend the use of ICS only in patients with severe disease. This review examines the potential role of ICS in all COPD patients.

A patient with weakness and an abnormal chest radiograph: A case report.

A 40-year-old black male presented to ICU after intubation for airway protection due to rapid onset of neck weakness and swallowing difficulty. His chest radiograph showed an unusual mediastinal opacity for which a computer tomography (CT) scan was done, confirming a mediastinal mass.

Gut microbiota of Type 1 diabetes patients with good glycaemic control and high physical fitness is similar to people without diabetes: an observational study.

AIM: Type 1 diabetes is the product of a complex interplay between genetic susceptibility and exposure to environmental factors. Existing bacterial profiling studies focus on people who are most at risk at the time of diagnosis; there are limited data on the gut microbiota of people with long-standing Type 1 diabetes. This study compared the gut microbiota of patients with Type 1 diabetes and good glycaemic control and high levels of physical-fitness with that of matched controls without diabetes. METHODS: Ten males with Type 1 diabetes and ten matched controls without diabetes were recruited; groups were matched for gender, age, BMI, peak oxygen uptake (VO2max ), and exercise habits. Stool samples were analysed using next-generation sequencing of the 16S rRNA gene to obtain bacterial profiles from each individual. Phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) was implemented to predict the functional content of the bacterial operational taxonomic units. RESULTS: Faecalibacterium sp., Roseburia sp. and Bacteroides sp. were typically the most abundant members of the community in both patients with Type 1 diabetes and controls, and were present in every sample in the cohort. Each bacterial profile was relatively individual and no significant difference was reported between the bacterial profiles or the Shannon diversity indices of Type 1 diabetes compared with controls. The functional profiles were more conserved and the Type 1 diabetes group were comparable with the control group. CONCLUSIONS: We show that both gut microbiota and resulting functional bacterial profiles from patients with long-standing Type 1 diabetes in good glycaemic control and high physical fitness levels are comparable with those of matched people without diabetes.

Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI.

Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk. SUMMARY: Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions.

Enabling dual cellular destinations of polymeric nanoparticles for treatment following partial injury to the central nervous system.

Following neurotrauma, oxidative stress is spread via the astrocytic syncytium and is associated with increased aquaporin 4 (AQP4), inflammatory cell infiltration, loss of neurons and glia and functional deficits. Herein we evaluate multimodal polymeric nanoparticles functionalized with an antibody to an extracellular epitope of AQP4, for targeted delivery of an anti-oxidant as a therapeutic strategy following partial optic nerve transection. Using fluorescence microscopy, spectrophotometry, correlative nanoscale secondary ion mass spectrometry (NanoSIMS) and transmission electron microscopy, in vitro and in vivo, we demonstrate that functionalized nanoparticles are coated with serum proteins such as albumin and enter both macrophages and astrocytes when administered to the site of a partial optic nerve transection in rat. Antibody functionalized nanoparticles synthesized to deliver the antioxidant resveratrol are effective in reducing oxidative damage to DNA, AQP4 immunoreactivity and preserving visual function. Non-functionalized nanoparticles evade macrophages more effectively and are found more diffusely, including in astrocytes, however they do not preserve the optic nerve from oxidative damage or functional loss following injury. Our study highlights the need to comprehensively investigate nanoparticle location, interactions and effects, both in vitro and in vivo, in order to fully understand functional outcomes.