Defining the role of neutrophils in the lung during infection: Implications for tuberculosis disease.

Neutrophils are implicated in the pathogenesis of many diseases involving inflammation. Neutrophils are also critical to host defence and have a key role in the innate immune response to infection. Despite their efficiencies against a wide range of pathogens however, their ability to contain and combat Mycobacterium tuberculosis (Mtb) in the lung remains uncertain and contentious. The host response to Mtb infection is very complex, involving the secretion of various cytokines and chemokines from a wide variety of immune cells, including neutrophils, macrophages, monocytes, T cells, B cells, NK cells and dendritic cells. Considering the contributing role neutrophils play in the advancement of many diseases, understanding how an inflammatory microenvironment affects neutrophils, and how neutrophils interact with other immune cells, particularly in the context of the infected lung, may aid the design of immunomodulatory therapies. In the current review, we provide a brief overview of the mechanisms that underpin pathogen clearance by neutrophils and discuss their role in the context of Mtb and non-Mtb infection. Next, we examine the current evidence demonstrating how neutrophils interact with a range of human and non-human immune cells and how these interactions can differentially prime, activate and alter a repertoire of neutrophil effector functions. Furthermore, we discuss the metabolic pathways employed by neutrophils in modulating their response to activation, pathogen stimulation and infection. To conclude, we highlight knowledge gaps in the field and discuss plausible novel drug treatments that target host neutrophil metabolism and function which could hold therapeutic potential for people suffering from respiratory infections.

Clinical trial management: a profession in crisis?

Clinical trial managers play a vital role in the design and conduct of clinical trials in the UK. There is a current recruitment and retention crisis for this specialist role due to a complex set of factors, most likely to have come to a head due to the COVID-19 pandemic. Academic clinical trial units and departments are struggling to recruit trial managers to vacant positions, and multiple influences are affecting the retention of this highly skilled workforce. Without tackling this issue, we face major challenges in the delivery on the Department of Health and Social Care's Future of UK Clinical Research Delivery implementation plan. This article, led by a leading network of and for UK Trial Managers, presents some of the issues and ways in which national stakeholders may be able to address this.

Graves' disease associated with HIV disease and late immune reconstitution inflammatory syndrome following the initiation of antiretroviral therapy.

SUMMARY: Both human immunodeficiency virus (HIV) and antiretroviral therapy (ART) are associated with endocrine dysfunction (1). The term 'immune reconstitution inflammatory syndrome' (IRIS) describes an array of inflammatory conditions that occur during the return of cell-mediated immunity following ART. Graves' disease (GD) occurs rarely as an IRIS following ART. In this study, we describe the case of a 40-year-old Brazilian female who was diagnosed with HIV following admission with cryptococcal meningitis and salmonellosis. At this time, she was also diagnosed with adrenal insufficiency. Her CD4 count at diagnosis was 17 cells/µL which rose to 256 cells/µL over the first 3 months of ART. Her HIV viral load, however, consistently remained detectable. When viral suppression was finally achieved 21 months post diagnosis, an incremental CD4 count of 407 cells/µL over the following 6 months ensued. Subsequently, she was diagnosed with a late IRIS to cryptococcus 32 months following initial ART treatment, which manifested as non-resolving lymphadenitis and resolved with high-dose steroids. Following the initiation of ART for 45 months, she developed symptomatic Graves' hyperthyroidism. At this time, her CD4 count had risen to 941 cells/µL. She has been rendered euthyroid on carbimazole. This case serves to remind us that GD can occur as an IRIS post ART and typically has a delayed presentation. LEARNING POINTS: Endocrinologists should be aware of the endocrine manifestations of HIV disease, in particular, thyroid pathology. Endocrinologists should be aware that IRIS can occur following the initiation of ART. Thyroid dysfunction can occur post ART of which Graves' disease (GD) is the most common thyroid manifestation. GD as a manifestation of ART-induced IRIS can have a delayed presentation. Infectious disease physicians should be aware of endocrine manifestations associated with HIV and ART.

Up to 5-year retention of abatacept in Belgian patients with moderate-to-severe rheumatoid arthritis: a sub-analysis of the international, observational ACTION study.

Favorable efficacy and safety profiles have been demonstrated for abatacept in patients with rheumatoid arthritis (RA) in randomized controlled trials, but these data require validation during long-term follow-ups in routine clinical practice. This study explored long-term safety and retention rates in RA patients treated with intravenous abatacept in the Belgian cohort of the international AbataCepT In rOutiNe clinical practice (ACTION) study (NCT02109666). This non-interventional, observational, longitudinal study included Belgian patients aged ≥ 18 years with moderate-to-severe RA who started intravenous abatacept treatment as first- or second/further-line biologic therapy in routine clinical practice. Between October 2010 and December 2012, 141 patients were enrolled in this cohort, of whom 135 evaluable patients (6 biologic-naïve; 129 previously exposed to ≥ 1 prior biologic disease modifying anti-rheumatic drugs) were eligible for the descriptive analysis; 131/135 were included in the effectiveness analysis. Mean disease duration was 10.5 years (standard deviation 9.7) before abatacept initiation. RA patients presented with high disease activity and comorbidity rate, having failed multiple previous treatment options. In this cohort, the 5-year abatacept retention rate was 34% (95% confidence interval, 23-45%) per protocol, and 51% (95% confidence interval, 40-61%) when temporary discontinuations of abatacept > 84 days (n = 24) were not considered as treatment discontinuations. After 5 years of abatacept treatment, clinical outcomes were favorable [good/moderate European League Against Rheumatism (EULAR) responses in 91.7% patients]. No new safety signals were detected for abatacept in routine clinical practice. In this difficult-to-treat Belgian RA population, high retention rates, good clinical outcomes and favorable safety profile were observed with abatacept.

The mechanical responses of advecting cells in confined flow.

Fluid dynamics have long influenced cells in suspension. Red blood cells and white blood cells are advected through biological microchannels in both the cardiovascular and lymphatic systems and, as a result, are subject to a wide variety of complex fluidic forces as they pass through. In vivo, microfluidic forces influence different biological processes such as the spreading of infection, cancer metastasis, and cell viability, highlighting the importance of fluid dynamics in the blood and lymphatic vessels. This suggests that in vitro devices carrying cell suspensions may influence the viability and functionality of cells. Lab-on-a-chip, flow cytometry, and cell therapies involve cell suspensions flowing through microchannels of approximately 100-800 µ m. This review begins by examining the current fundamental theories and techniques behind the fluidic forces and inertial focusing acting on cells in suspension, before exploring studies that have investigated how these fluidic forces affect the reactions of suspended cells. In light of these studies' findings, both in vivo and in vitro fluidic cell microenvironments shall also be discussed before concluding with recommendations for the field.

Performance comparison of 159 Thoroughbred racehorses and matched cohorts before and after desmotomy of the interspinous ligament.

Racehorses may perform poorly because of impinging dorsal spinous processes (DSPs) of the thoracolumbar vertebrae. No study has looked objectively at the long-term outcome of racehorses undergoing desmotomy of the interspinous ligament as a treatment for horses with poor performance caused by impinging DSPs. The aim of this study was to examine objectively, by using pre-operative and post-operative racing records, the effectiveness of desmotomy of the interspinous ligament (DISL) in improving the performance of racehorses with impinging DSPs. Medical records of all horses undergoing desmotomy of one or more interspinous ligaments at a referral equine hospital, between February 2015 and September 2016, were reviewed. The study was confined to Thoroughbred racehorses with sufficient historical information and racetrack data to allow their racing performances be compared to that of matched controls. Matched controls were of the same age, sex, and racing type and were trained at the same time by the same trainer as those undergoing desmotomy. The time to follow-up was at least 12 months. Of the 6545 horses presented for poor performance or lameness during the study period, 236 horses (3.6%) underwent desmotomy of one or more interspinous ligaments, and of these, 159 met the inclusion criteria. Horses undergoing desmotomy had significantly better improvement in racing performance than did matched controls. Eight horses developed unilateral neurogenic atrophy of epaxial musculature. DISL between impinging DSPs can improve the performance of racehorses experiencing from poor performance caused by pain resulting from the impinging processes.

Uptake of cancer screening services among middle and older ages in Ireland: the role of healthcare eligibility.

OBJECTIVES: The aim of this analysis was to examine the association between public healthcare eligibility combined with private health insurance (PHI) status and the uptake of breast and prostate cancer screening services among middle and older age groups in Ireland. STUDY DESIGN: This is a cross-sectional analysis using The Irish Longitudinal Study on Ageing (TILDA). METHODS: The analysis included 6902 people aged 50 years and older who completed an in-house interview as part of TILDA. The interview collects information on a range of demographic, socio-economic, health and health service usage variables including the uptake of cancer screening services. An eligibility variable was created using information on public healthcare entitlement and PHI status. The association between eligibility and the uptake of two cancer screening services-mammogram and prostate-specific antigen (PSA) test-was examined using weighted multivariate logistic regression analysis. RESULTS: The uptake of a mammogram and PSA testing was significantly higher in those with PHI. This relationship held after controlling for a range of confounders including health and socio-economic status. CONCLUSIONS: More research is required to identify the reasons for the higher uptake of cancer screening services among those with PHI, given that insurance does not confer any advantages in accessing these services. It is possible that the higher uptake is explained by differential access to secondary care services between those with and without PHI. Consideration of the integrated nature of healthcare systems is essential when seeking to maximise the uptake of services (such as cancer screening) that potentially involve multiple parts of the healthcare system.

A Life-Saving Palsy: Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) Presenting As Hand Weakness during Cardiopulmonary Resuscitation (CPR) Training

Aim To describe a case of acute and transient hand weakness that developed during cardiopulmonary resuscitation (CPR) training. Hereditary neuropathy with liability to pressure palsies (HNPP) should be considered in patients with recurrent, painless motor or sensory neuropathies at sites of peripheral nerve compression. Methods Nerve conduction studies confirmed neuropraxia of the distal ulnar nerve with a mild background demyelinating peripheral neuropathy. Results A positive family history emerged and HNPP was confirmed by genetic testing. HNPP is most reliably diagnosed by molecular testing for peripheral myelin protein 22 (PMP22) gene deletion or point mutation on chromosome 17p11.2. Conclusion CPR, a procedure carried out by medical professionals on a daily basis, is a high-energy manual task and provides multiple opportunities for nerve compression. This case demonstrates the importance of having a high index of clinical suspicion of this disorder in patients. Recognising a diagnosis of HNPP may prevent unnecessary surgical decompression.

Iatrogenic Bowel Injury at Exchange of Supra-Pubic Catheter

Suprapubic catheter insertion and exchange is a common urological procedure, but it is not without risks and complications. While bowel perforation is a recognised complication at suprapubic catheter insertion, it is not commonly reported at suprapubic catheter exchange. We report our experience of recognition, diagnosis and subsequent successful management of the most important complication related to suprapubic catheters.

Calcific myonecrosis: diagnostic dilemma.

Calcific myonecrosis is a rare benign condition affecting mainly the muscles of a single leg compartment. It is thought to follow a history of trauma with a latent period of years. Patients present with a slowly growing mass. Differential diagnosis from a malignant tumour can be made from the history and the distinctive radiographical features of a fusiform lesion with predominantly peripheral calcifications. Magnetic resonance imaging may be necessary to confirm the diagnosis; treatment is largely symptomatic.

The Anatomical Society's core anatomy syllabus for undergraduate nursing.

The Anatomical Society has developed a series of learning outcomes in consultation with nursing educators delivering anatomical content to undergraduate (preregistration) nursing students. A Delphi panel methodology was adopted to select experts within the field that would recommend core anatomical content in undergraduate nursing programmes throughout the UK. Using the Anatomical Society's Core Gross Anatomy Syllabus for Medical Students as a foundation, a modified Delphi technique was used to develop discipline-specific outcomes to nursing graduates. The Delphi panel consisted of 48 individuals (n = 48) with a minimum of 3 years' experience teaching anatomy to nursing students, representing a broad spectrum of UK Higher Education Institutions. The output from this study was 64 nursing specific learning outcomes in anatomy that are applicable to all undergraduate (preregistration) programmes in the UK. The new core anatomy syllabus for Undergraduate Nursing offers a basic anatomical framework upon which nurse educators, clinical mentors and nursing students can underpin their clinical practice and knowledge. The learning outcomes presented may be used to develop anatomy teaching within an integrated nursing curriculum.

Measuring healthcare expenditure: different methods, different results.

BACKGROUND: Accurate information on healthcare expenditure is essential; however, a number of issues arise when healthcare expenditure is being measured. Traditionally healthcare expenditure data in Ireland have been limited, especially data that facilitate comparable analysis through time and across particular programmes or services. Recently however, a major development in Irish healthcare expenditure estimates was the publication of Irish healthcare current expenditure estimates for 2013 according to the international standard of the OECD System of Health Accounts (SHA). AIMS: The aim of the analysis presented in this paper is to examine how alternative methodologies for measuring healthcare can influence the estimate(s) of healthcare expenditure. METHODS: The methods and results (in terms of healthcare expenditure) of the Central Statistics Office (CSO) application of SHA methodology will be compared and contrasted with an alternative methodology for measuring healthcare expenditure developed by Wren et al. [1]. RESULTS: The two approaches to measuring healthcare expenditure in Ireland reached a very similar figure for total current healthcare expenditure in 2013. However, there were considerable disparities in the components of expenditure. CONCLUSIONS: There is no one absolute definition or estimate of healthcare expenditure, and different methodological approaches to estimating expenditure will likely yield different results. Therefore, care is required when assessing healthcare expenditure to ensure that there is a clear understanding about what is and is not included in the estimate.

Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE-LY trial.

BACKGROUND: Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF. OBJECTIVES: To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE-LY trial. METHODS: HAS-BLED, ORBIT, ATRIA and HEMORR2 HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated. RESULTS: There were 1182 (6.5%) major bleeding events during a median follow-up of 2.0 years. For all the four schemes, high-risk subgroups had higher risk of major bleeding (all P < 0.001). The ORBIT score showed the best discrimination with c-indices of 0.66, 0.66 and 0.62, respectively, for major, life-threatening and intracranial bleeding, which were significantly better than for the HAS-BLED score (difference in c-indices: 0.050, 0.053 and 0.048, respectively, all P < 0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P = 0.0019), ATRIA (P < 0.001) and HEMORR2 HAGES (P < 0.001) scores. HAS-BLED score showed a nonsignificant trend for interaction (P = 0.0607). CONCLUSIONS: Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.

A two-step method for variable selection in the analysis of a case-cohort study.

Background: Accurate detection and estimation of true exposure-outcome associations is important in aetiological analysis; when there are multiple potential exposure variables of interest, methods for detecting the subset of variables most likely to have true associations with the outcome of interest are required. Case-cohort studies often collect data on a large number of variables which have not been measured in the entire cohort (e.g. panels of biomarkers). There is a lack of guidance on methods for variable selection in case-cohort studies. Methods: We describe and explore the application of three variable selection methods to data from a case-cohort study. These are: (i) selecting variables based on their level of significance in univariable (i.e. one-at-a-time) Prentice-weighted Cox regression models; (ii) stepwise selection applied to Prentice-weighted Cox regression; and (iii) a two-step method which applies a Bayesian variable selection algorithm to obtain posterior probabilities of selection for each variable using multivariable logistic regression followed by effect estimation using Prentice-weighted Cox regression. Results: Across nine different simulation scenarios, the two-step method demonstrated higher sensitivity and lower false discovery rate than the one-at-a-time and stepwise methods. In an application of the methods to data from the EPIC-InterAct case-cohort study, the two-step method identified an additional two fatty acids as being associated with incident type 2 diabetes, compared with the one-at-a-time and stepwise methods. Conclusions: The two-step method enables more powerful and accurate detection of exposure-outcome associations in case-cohort studies. An R package is available to enable researchers to apply this method.

The Hidden Burden of Outpatient Repeat PSA Testing in a Prospective Cohort.

PSA testing is widespread throughout Europe for diagnostic purposes and follow up. We performed a prospective outpatient cohort study of 250 men (2013-2015) in two hospital sites. Included were those men being followed up by urology with PSA blood testing. First appointments and those men in whom non-PSA tests were ordered by urology were excluded. The median age was 67.2yrs (46-88). Eighty-one point two percent of samples had a combination of 21 different serology tests at an added cost of >€18,000. Abnormal serology resulted in 53 referrals. Twenty-six-six percent of correspondence referenced abnormal serology other than PSA. Follow up of non-PSA test results poses a challenge in an outpatient setting with failure to appropriately follow-up on abnormal results, increased costs, and medico-legal implications. There is currently no Irish legislature in place to safeguard hospital physicians. This study quantifies the levels of expenditure, resources and risk associated with ambulant PSA testing.

Outcomes of an integrated community-based nurse-led cardiovascular disease prevention programme.

BACKGROUND: National guidance for England recommends that cardiovascular disease (CVD) should be managed as a family of diseases in the community. Here, we describe the results of such an approach. METHODS: Patients with established CVD or who were at high multifactorial risk (HRI) underwent a 12-week community-based nurse-led prevention programme (MyAction) that included lifestyle and risk factor management, prescription of medication and weekly exercise and education sessions. RESULTS: Over a 6-year period, 3232 patients attended an initial assessment; 63% were male, and 48% belonged to black and minority ethnic groups. 56% attended an end-of-programme assessment, and 33% attended a one year assessment. By the end of the programme, there was a significant reduction in smoking prevalence but only in HRI (-3.7%, p<0.001). Mediterranean diet score increased in both CVD (+1.2, p<0.001) and HRI (+1.5; p<0.001), as did fitness levels (CVD +0.8 estimated Mets maximum, p<0.001, HRI +0.9 estimated Mets maximum, p<0.001) and the proportions achieving their physical activity targets (CVD +40%, p<0.001, HRI +37%, p<0.001). There were significant increases in proportions achieving their blood pressure (CVD +15.4%, p<0.001, HRI +25%, p<0.001 and low-density lipoprotein cholesterol targets (CVD +6%, p=0.004, HRI +23%, p<0.001). Statins and antihypertensive medications significantly increased in HRI. Significant improvements in depression scores and quality-of-life measures were also seen. The majority of improvements were maintained at 1 year. CONCLUSION: These results demonstrate that an integrated vascular prevention programme is feasible in practice and reduces cardiovascular risk in patients with established CVD and in those at high multifactorial risk.

Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit. REPORT: Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. DISCUSSION: Homozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from 'Classical' OI. CONCLUSIONS: Here we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.