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Frailty is associated with neutrophil dysfunction which is correctable with phosphoinositol-3-kinase inhibitors.
No full textNeutrophil dysfunction has been described with age, appears exaggerated in infection, with altered phosphoinositol signalling a potential mechanism. However, functional ageing is heterogeneous. Frailty is a negative health status and is more common in older adults. We hypothesised that neutrophil migration may be compromised in frailty, associated with the degree of frailty experienced by the older person. We compared measures of frailty, neutrophil function and systemic inflammation in forty young and seventy-seven older community dwelling adults in the United Kingdom. Systemic neutrophils exhibited an age-associated reduction in the accuracy of migration (chemotaxis) which was further blunted with frailty. The degree of migratory inaccuracy correlated with physical (adjusted hand grip strength) and cognitive (Stroop test) markers of frailty. Regression analysis demonstrated that age, Charlson Co-morbidity Index and Frailty Index were able to predict neutrophil chemotaxis. Reduced chemotaxis of neutrophils from frail adults could be reversed using selective PI3K inhibitors. Exposure of neutrophils from young adults to plasma from chronically inflamed frail older adults could not recapitulate the migratory deficit in vitro and there were no relationships with systemic inflammation and neutrophil dysfunction. Frailty exaggerated the neutrophil deficits seen with advanced age but aspects of the frailty-associated deficit in neutrophil function are rescuable and thus potentially form a therapeutic target to improve outcomes from infection in older adults
What is the UK Public Searching for? A Correlation Analysis of Google Trends Search Terms and Cosmetic Surgery in the UK.
No full textINTRODUCTION
Search engine optimisation (SEO) in plastic surgery practice is crucial for increasing web traffic. Knowing what patients are searching for online can help plastic surgeons understand public interest, enhance patient engagement, and improve service provision. This study analyses the correlation between Google Trends (GT) search activity and the number of cosmetic procedures carried out in the UK.
METHODS
GT search term data were analysed for popularity of use and geographical variation in the UK. Pearson's correlation coefficient was used to analyse GT data against the number of cosmetic surgery procedures undertaken in the UK in the corresponding year and with 1-year time lag.
RESULTS
GT score was higher for most colloquial search terms, such as "tummy tuck" compared to "abdominoplasty" (GT score 59 vs 6), but "otoplasty" was higher than "ear correction" (GT score 55 vs 19). Geographical variation showed that London ranked first in proportional search term activity for "brow lift" and Birmingham for "tummy tuck". There was statistically significant positive correlation for three search terms and the number of corresponding surgeries undertaken. This increased to nine search terms when analysed with a 1-year time lag.
CONCLUSION
These results highlight the trends in online search activity in the UK and their correlation with cosmetic procedures. The higher number of significant correlations with 1-year time lag may reflect the patient's decision-making journey to undergo cosmetic surgery. These results can be utilised for SEO, thus leading to a better-informed public and more robust practice building.
LEVEL OF EVIDENCE V
This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266
The Immunological Basis of Liver Allograft Rejection.
No full textLiver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies
The effects of oral corticosteroids on lung function, type-2 biomarkers and patient-reported outcomes in stable asthma: A systematic review and meta-analysis.
No full textBACKGROUND
Several studies have investigated the physiological effect of OCS in stable asthma, however these have included heterogeneous populations and outcomes. This paper is the first to combine their results.
METHODS
We searched Medline, Embase and Web of Science databases for studies reporting the impact of OCS on FEV, FVC, blood eosinophils, fractional exhaled nitric oxide (FeNO), Asthma Control Questionnaire (ACQ) score or Asthma Quality Of Life Questionnaire (AQLQ) score in stable asthma. We extracted data on the correlates of OCS response.
RESULTS
61 studies, comprising 1608 patients, were included. FEV was improved by 9% (95% CI: 7, 11). There were stronger increases in FEV among those with a mean baseline FEV<60% predicted (19%, 95% CI: 13, 24). Despite these improvements, substantial residual impairment remained after treatment. Blood eosinophils were reduced by 76% (95% CI: 63, 88) with larger decreases in studies of corticosteroid-naïve patients (93%, 95% CI: 73,100). Sputum eosinophils were reduced by 89% (95% CI: 79, 98) while FeNO was decreased by 35% (95% CI: 28, 41). ACQ scores were reduced by 20% (95% CI: 11, 29). Patients with higher baseline lung function impairment, sputum eosinophils, blood eosinophils and FeNO had improved OCS response.
INTERPRETATION
OCS consistently improves lung function, reduces markers of type-2 inflammation, and alleviates asthma symptoms. However, substantial residual impairment remained following treatment and mean improvements were below the minimally important clinically difference. Patients with increased markers of type-2 inflammation are more responsive to treatment, suggesting these should be used to better target OCS use
Spironolactone in Atrial Fibrillation With Preserved Cardiac Fraction: The IMPRESS-AF Trial.
No full textBackground Patients with permanent atrial fibrillation have poor outcomes, exercise capacity, and quality of life even on optimal anticoagulation. Based on mechanistic and observational data, we tested whether the mineralocorticoid receptor antagonist spironolactone can improve exercise capacity, E/e' ratio, and quality of life in patients with permanent atrial fibrillation and preserved ejection fraction. Methods and Results The double-masked, placebo-controlled IMPRESS-AF (Improved Exercise Tolerance in Heart Failure With Preserved Ejection Fraction by Spironolactone on Myocardial Fibrosis in Atrial Fibrillation) trial (NCT02673463) randomized 250 stable patients with permanent atrial fibrillation and preserved left ventricular ejection fraction to spironolactone 25 mg daily or placebo. Patients were followed for 2 years. The primary efficacy outcome was peak oxygen consumption on cardiopulmonary exercise testing at 2 years. Secondary end points included 6-minute walk distance, E/e' ratio, quality of life, and hospital admissions. Spironolactone therapy did not improve peak oxygen consumption at 2 years (14.0 mL/min per kg [SD, 5.4]) compared with placebo (14.5 [5.1], adjusted treatment effect, -0.28; 95% CI, -1.27 to 0.71]; =0.58). The findings were consistent across all sensitivity analyses. There were no differences in the 6-minute walking distance (adjusted treatment effect, -8.47 m; -31.9 to 14.9; =0.48), E/e' ratio (adjusted treatment effect, -0.68; -1.52 to 0.17, =0.12), or quality of life (=0.74 for EuroQol-5 Dimensions, 5-level version quality of life questionnaire and =0.84 for Minnesota Living with Heart Failure). At least 1 hospitalization occurred in 15% of patients in the spironolactone group and 23% in the placebo group (=0.15). Estimated glomerular filtration rate was reduced by 6 mL/min in the spironolactone group with <1-unit reduction in controls (<0.001). Systolic blood pressure was reduced by 7.2 mm Hg (95% CI, 2.2-12.3) in the spironolactone group versus placebo (=0.005). Conclusions Spironolactone therapy does not improve exercise capacity, E/e' ratio, or quality of life in patients with chronic atrial fibrillation and preserved ejection fraction. Registration UTL: https://www.clinicaltrial.gov; Unique identifier: NCT02673463. EudraCT number 2014-003702-33
COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study.
No full textBACKGROUND
Patients with cancer are purported to have poor COVID-19 outcomes. However, cancer is a heterogeneous group of diseases, encompassing a spectrum of tumour subtypes. The aim of this study was to investigate COVID-19 risk according to tumour subtype and patient demographics in patients with cancer in the UK.
METHODS
We compared adult patients with cancer enrolled in the UK Coronavirus Cancer Monitoring Project (UKCCMP) cohort between March 18 and May 8, 2020, with a parallel non-COVID-19 UK cancer control population from the UK Office for National Statistics (2017 data). The primary outcome of the study was the effect of primary tumour subtype, age, and sex and on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) prevalence and the case-fatality rate during hospital admission. We analysed the effect of tumour subtype and patient demographics (age and sex) on prevalence and mortality from COVID-19 using univariable and multivariable models.
FINDINGS
319 (30·6%) of 1044 patients in the UKCCMP cohort died, 295 (92·5%) of whom had a cause of death recorded as due to COVID-19. The all-cause case-fatality rate in patients with cancer after SARS-CoV-2 infection was significantly associated with increasing age, rising from 0·10 in patients aged 40-49 years to 0·48 in those aged 80 years and older. Patients with haematological malignancies (leukaemia, lymphoma, and myeloma) had a more severe COVID-19 trajectory compared with patients with solid organ tumours (odds ratio [OR] 1·57, 95% CI 1·15-2·15; p<0·0043). Compared with the rest of the UKCCMP cohort, patients with leukaemia showed a significantly increased case-fatality rate (2·25, 1·13-4·57; p=0·023). After correction for age and sex, patients with haematological malignancies who had recent chemotherapy had an increased risk of death during COVID-19-associated hospital admission (OR 2·09, 95% CI 1·09-4·08; p=0·028).
INTERPRETATION
Patients with cancer with different tumour types have differing susceptibility to SARS-CoV-2 infection and COVID-19 phenotypes. We generated individualised risk tables for patients with cancer, considering age, sex, and tumour subtype. Our results could be useful to assist physicians in informed risk-benefit discussions to explain COVID-19 risk and enable an evidenced-based approach to national social isolation policies.
FUNDING
University of Birmingham and University of Oxford
Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial.
No full textBACKGROUND
Preoperative anaemia affects a high proportion of patients undergoing major elective surgery and is associated with poor outcomes. We aimed to test the hypothesis that intravenous iron given to anaemic patients before major open elective abdominal surgery would correct anaemia, reduce the need for blood transfusions, and improve patient outcomes.
METHODS
In a double-blind, parallel-group randomised trial, we recruited adult participants identified with anaemia at preoperative hospital visits before elective major open abdominal surgery at 46 UK tertiary care centres. Anaemia was defined as haemoglobin less than 130 g/L for men and 120 g/L for women. We randomly allocated participants (1:1) via a secure web-based service to receive intravenous iron or placebo 10-42 days before surgery. Intravenous iron was administered as a single 1000 mg dose of ferric carboxymaltose in 100 mL normal saline, and placebo was 100 mL normal saline, both given as an infusion over 15 min. Unblinded study personnel prepared and administered the study drug; participants and other clinical and research staff were blinded to treatment allocation. Coprimary endpoints were risk of the composite outcome of blood transfusion or death, and number of blood transfusions from randomisation to 30 days postoperatively. The primary analysis included all randomly assigned patients with data available for the primary endpoints; safety analysis included all randomly assigned patients according to the treatment received. This study is registered, ISRCTN67322816, and is closed to new participants.
FINDINGS
Of 487 participants randomly assigned to placebo (n=243) or intravenous iron (n=244) between Jan 6, 2014, and Sept 28, 2018, complete data for the primary endpoints were available for 474 (97%) individuals. Death or blood transfusion occurred in 67 (28%) of the 237 patients in the placebo group and 69 (29%) of the 237 patients in the intravenous iron group (risk ratio 1·03, 95% CI 0·78-1·37; p=0·84). There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group (rate ratio 0·98, 95% CI 0·68-1·43; p=0·93). There were no significant differences between the two groups for any of the prespecified safety endpoints.
INTERPRETATION
Preoperative intravenous iron was not superior to placebo to reduce need for blood transfusion when administered to patients with anaemia 10-42 days before elective major abdominal surgery.
FUNDING
UK National Institute of Health Research Health Technology Assessment Program