Differential neutrophil activation in viral infections: Enhanced TLR-7/8-mediated CXCL8 release in asthma

© 2015 The Authors. Respirology published by Wiley Publishing Asia Pty Ltd on behalf of Asian Pacific Society of Respirology. Background and objective Respiratory viral infections are a major cause of asthma exacerbations. Neutrophils accumulate in the airways and the mechanisms that link neutrophilic inflammation, viral infections and exacerbations are unclear. This study aims to investigate anti-viral responses in neutrophils from patients with and without asthma and to investigate if neutrophils can be directly activated by respiratory viruses. Methods Neutrophils from peripheral blood from asthmatic and non-asthmatic individuals were isolated and stimulated with lipopolysaccharide (LPS) (1 μg/mL), f-met-leu-phe (fMLP) (100 nM), imiquimod (3 μg/mL), R848 (1.5 μg/mL), poly I:C (10 μg/mL), RV16 (multiplicity of infection (MOI)1), respiratory syncytial virus (RSV) (MOI1) or influenza virus (MOI1). Cell-free supernatants were collected after 1 h of neutrophil elastase (NE) and matrix metalloproteinase (MMP)-9 release, or after 24 h for CXCL8 release. Results LPS, fMLP, imiquimod and R848 stimulated the release of CXCL8, NE and MMP-9 whereas poly I:C selectively induced CXCL8 release only. R848-induced CXCL8 release was enhanced in neutrophils from asthmatics compared with non-asthmatic cells (P < 0.01). RSV triggered the release of CXCL8 and NE from neutrophils, whereas RV16 or influenza had no effect. Conclusion Neutrophils release CXCL8, NE and MMP-9 in response to viral surrogates with R848-induced CXCL8 release being specifically enhanced in asthmatic neutrophils. Toll-like receptor (TLR7/8) dysregulation may play a role in neutrophilic inflammation in viral-induced exacerbations. We aimed to investigate and compare neutrophil responses to bacterial compounds and viral mimetics as well as compare responses between people with and without asthma. We also investigated neutrophil responses to live respiratory viruses. Here we provide a novel comprehensive comparison showing differential and specific activation in innate immune cells. See Editorial, page 1

Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

Long-term outcome among men with conservatively treated localised prostate cancer

Optimal management of clinically localised prostate cancer presents unique challenges, because of its highly variable and often indolent natural history. There is an urgent need to predict more accurately its natural history, in order to avoid unnecessary treatment. Medical records of men diagnosed with clinically localised prostate cancer, in the UK, between 1990 and 1996 were reviewed to identify those who were conservatively treated, under age 76 years at the time of pathological diagnosis and had a baseline prostate-specific antigen (PSA) measurement. Diagnostic biopsy specimens were centrally reviewed to assign primary and secondary Gleason grades. The primary end point was death from prostate cancer and multivariate models were constructed to determine its best predictors. A total of 2333 eligible patients were identified. The most important prognostic factors were Gleason score and baseline PSA level. These factors were largely independent and together, contributed substantially more predictive power than either one alone. Clinical stage and extent of disease determined, either from needle biopsy or transurethral resection of the prostate (TURP) chips, provided some additional prognostic information. In conclusion, a model using Gleason score and PSA level identified three subgroups comprising 17, 50, and 33% of the cohort with a 10-year prostate cancer specific mortality of <10, 10–30, and >30%, respectively. This classification is a substantial improvement on previous ones using only Gleason score, but better markers are needed to predict survival more accurately in the intermediate group of patients

Association of treatment satisfaction and psychopathological sub-syndromes among involuntary patients with psychotic disorders

Publisher's version: http://www.springerlink.com/content/rx24036274667t10

General practitioners’ perspectives on campaigns to promote rapid help-seeking behaviour at the onset of rheumatoid arthritis

Objective. To explore general practitioners’ (GPs’ ) perspectives on public health campaigns to encourage people with the early symptoms of rheumatoid arthritis (RA) to seek medical help rapidly. Design. Nineteen GPs participated in four semistructured focus groups. Focus groups were audio-recorded, transcribed verbatim, and analysed using thematic analysis. Results. GPs recognised the need for the early treatment of RA and identified that facilitating appropriate access to care was important. However, not all held the view that a delay in help seeking was a clinically significant issue. Furthermore, many were concerned that the early symptoms of RA were often non-specific, and that current knowledge about the nature of symptoms at disease onset was inadequate to inform the content of a help-seeking campaign. They argued that a campaign might not be able to specifically target those who need to present urgently. Poorly designed campaigns were suggested to have a negative impact on GPs’ workloads, and would “clog up” the referral pathway for genuine cases of RA. Conclusions. GPs were supportive of strategies to improve access to Rheumatological care and increase public awareness of RA symptoms. However, they have identified important issues that need to be considered in developing a public health campaign that forms part of an overall strategy to reduce time to treatment for patients with new onset RA. This study highlights the value of gaining GPs’ perspectives before launching health promotion campaigns

Data Resource Profile: The Virtual Cardio-Oncology Research Initiative (VICORI) linking national English cancer registration and cardiovascular audits

Background: Cancer and cardiovascular disease (CVD) are the most common causes of morbidity and mortality worldwide. Improvements in treatment strategies for both CVD and cancer have resulted in significant improvements in survival and, as a result, there is an increasing population of patients who now live with both conditions.1–3 It is well known that cancer and its treatment increase the risk of CVD.4–6 Yet a detailed understanding of the underlying relationship between these two conditions and their respective treatments, including both positive and negative modulation of risk, is lacking. This is partly because few cohorts have been large enough to conduct detailed investigations. To address this, the Virtual Cardio-Oncology Research Initiative (VICORI) has linked national cardiac and cancer registries to create a resource of a larger scale and with longer follow-up than typical investigator-led studies

Case-ascertainment of acute myocardial infarction hospitalizations in cancer patients: A cohort study using English linked electronic health data

Aims: To assess the recording and accuracy of acute myocardial infarction (AMI) hospital admissions between two electronic health record databases within an English cancer population over time and understand the factors that affect case-ascertainment. Methods and results: We identified 112 502 hospital admissions for AMI in England 2010-2017 from the Myocardial Ischaemia National Audit Project (MINAP) disease registry and hospital episode statistics (HES) for 95 509 patients with a previous cancer diagnosis up to 15 years prior to admission. Cancer diagnoses were identified from the National Cancer Registration Dataset (NCRD). We calculated the percentage of AMI admissions captured by each source and examined patient characteristics associated with source of ascertainment. Survival analysis assessed whether differences in survival between case-ascertainment sources could be explained by patient characteristics. A total of 57 265 (50.9%) AMI admissions in patients with a prior diagnosis of cancer were captured in both MINAP and HES. Patients captured in both sources were younger, more likely to have ST-segment elevation myocardial infarction and had better prognosis, with lower mortality rates up to 9 years after AMI admission compared with patients captured in only one source. The percentage of admissions captured in both data sources improved over time. Cancer characteristics (site, stage, and grade) had little effect on how AMI was captured. Conclusion: MINAP and HES define different populations of patients with AMI. However, cancer characteristics do not substantially impact on case-ascertainment. These findings support a strategy of using multiple linked data sources for observational cardio-oncological research into AMI

Social validity of randomised controlled trials in health services research and intellectual disabilities: a qualitative exploration of stakeholder views

<p>Abstract</p> <p>Background</p> <p>Randomised controlled trials (RCTs) are the gold standard of evidence-based practice in medicine but they have had limited influence in the field of intellectual disabilities. Previous literature suggests that participants and professionals have limited tolerance for this type of research methodology. However, it is not known how well service users, carers and other health professionals understand and accept the need for RCTs, and why it is important for individuals with intellectual disabilities to be included in this kind of research.</p> <p>Methods</p> <p>We examined individual perceptions of RCTs in 51 participants (18 carers, 6 service users and 27 professionals) using semi-structured interviews. A framework approach was adopted in the analysis of data.</p> <p>Results</p> <p>We found that participants had concerns about capacity and resource allocation but held positive views towards this type of research methodology. Understanding of the principles behind RCTs was poor amongst service users and a minority of carers, but mediated by previous exposure to research for professionals.</p> <p>Conclusions</p> <p>The social validity of RCTs in intellectual disabilities may be compromised by lack of understanding of the design and the on-going concerns about obtaining informed consent especially in incapacitated adults. However, the overall finding that the need for this form of research was seen in a positive light suggests that there is a turning point in the perceptions of stakeholders working in intellectual disabilities services. We recommend that researchers include on-going education on RCT design during trials, tailoring it to all stakeholders with emphasis on strong service user and care involvement. This could be a pivotal element in improving acceptability of, and recruitment to RCTs.</p

Impact of a Prior Cancer Diagnosis on Quality of Care and Survival Following Acute Myocardial Infarction: Retrospective Population-Based Cohort Study in England

BACKGROUND: An increasing proportion of patients with cancer experience acute myocardial infarction (AMI). We investigated differences in quality of AMI care and survival between patients with and without previous cancer diagnoses. METHODS: A retrospective cohort study using Virtual Cardio-Oncology Research Initiative data. Patients aged 40+ years hospitalized in England with AMI between January 2010 and March 2018 were assessed, ascertaining previous cancers diagnosed within 15 years. Multivariable regression was used to assess effects of cancer diagnosis, time, stage, and site on international quality indicators and mortality. RESULTS: Of 512 388 patients with AMI (mean age, 69.3 years; 33.5% women), 42 187 (8.2%) had previous cancers. Patients with cancer had significantly lower use of ACE (angiotensin-converting enzyme) inhibitors/angiotensin receptor blockers (mean percentage point decrease [mppd], 2.6% [95% CI, 1.8–3.4]) and lower overall composite care (mppd, 1.2% [95% CI, 0.9–1.6]). Poorer quality indicator attainment was observed in patients with cancer diagnosed in the last year (mppd, 1.4% [95% CI, 1.8–1.0]), with later stage disease (mppd, 2.5% [95% CI, 3.3–1.4]), and with lung cancer (mppd, 2.2% [95% CI, 3.0–1.3]). Twelve-month all-cause survival was 90.5% in noncancer controls and 86.3% in adjusted counterfactual controls. Differences in post-AMI survival were driven by cancer-related deaths. Modeling improving quality indicator attainment to noncancer patient levels showed modest 12-month survival benefits (lung cancer, 0.6%; other cancers, 0.3%). CONCLUSIONS: Measures of quality of AMI care are poorer in patients with cancer, with lower use of secondary prevention medications. Findings are primarily driven by differences in age and comorbidities between cancer and noncancer populations and attenuated after adjustment. The largest impact was observed in recent cancer diagnoses (<1 year) and lung cancer. Further investigation will determine whether differences reflect appropriate management according to cancer prognosis or whether opportunities to improve AMI outcomes in patients with cancer exist

A novel somatic mutation implicates ATP6V0D1 in proinsulin processing

Context Prohormone convertase 1/3 (PC1/3), encoded by protein convertase subtilisin kexin type 1 (PCSK1), converts inactive prohormones into biologically active peptides. Somatic mutations of insulinomas are associated with genetic defects interfering with control of insulin secretion from pancreatic beta cells. However, somatic mutations in proinsulinomas have not been described. Objective We report a case of a proinsulinoma, with suppressed insulin and C-peptide levels. Methods A 70-year-old woman presented with a 20-year history of “blackouts.” During a 72-hour fast, blood glucose level dropped to 1.9 mmol/L with suppressed plasma insulin and C-peptide levels, but proinsulin levels were raised at 37 pmol/L (<10 pmol/L). Results Imaging revealed 3 distinct DOTATATE-avid pancreatic lesions. Laparoscopic spleen-preserving distal pancreatomy was performed. In view of discordant insulin, C-peptide, and proinsulin levels, whole exome sequencing analysis was performed on the tumor. In the somatic exome of the tumor, we found mutations in PCSK expression regulators, as well as a novel truncating somatic mutation in ATP6V0D1, a subunit of the ion pump that acidifies the β-cell compartments where the PCSKs act. Conclusion Appropriately suppressed insulin levels in the context of hypoglycemia do not always indicate the absence of a neuroendocrine islet cell tumor and proinsulin levels may be indicated to solidify the diagnosis. In the context of elevated proinsulin levels, low insulin and C-peptide levels might be explained by somatic mutations that likely implicate proinsulin processing within the tumor. Furthermore, we propose several mechanistic candidates, including ATP6V0D1. Experimental validation using cellular approaches may in future confirm pathomechanisms involved in this rare condition