Drugs affecting the renin-angiotensin system and survival from cancer: a population based study of breast, colorectal and prostate cancer patient cohorts

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) are commonly prescribed to the growing number of cancer patients (more than two million in the UK alone) often to treat hypertension. However, increased fatal cancer in ARB users in a randomized trial and increased breast cancer recurrence rates in ACEI users in a recent observational study have raised concerns about their safety in cancer patients. We investigated whether ACEI or ARB use after breast, colorectal or prostate cancer diagnosis was associated with increased risk of cancer-specific mortality. METHODS: Population-based cohorts of 9,814 breast, 4,762 colorectal and 6,339 prostate cancer patients newly diagnosed from 1998 to 2006 were identified in the UK Clinical Practice Research Datalink and confirmed by cancer registry linkage. Cancer-specific and all-cause mortality were identified from Office of National Statistics mortality data in 2011 (allowing up to 13 years of follow-up). A nested case–control analysis was conducted to compare ACEI/ARB use (from general practitioner prescription records) in cancer patients dying from cancer with up to five controls (not dying from cancer). Conditional logistic regression estimated the risk of cancer-specific, and all-cause, death in ACEI/ARB users compared with non-users. RESULTS: The main analysis included 1,435 breast, 1,511 colorectal and 1,184 prostate cancer-specific deaths (and 7,106 breast, 7,291 colorectal and 5,849 prostate cancer controls). There was no increase in cancer-specific mortality in patients using ARBs after diagnosis of breast (adjusted odds ratio (OR) = 1.06 95% confidence interval (CI) 0.84, 1.35), colorectal (adjusted OR = 0.82 95% CI 0.64, 1.07) or prostate cancer (adjusted OR = 0.79 95% CI 0.61, 1.03). There was also no evidence of increases in cancer-specific mortality with ACEI use for breast (adjusted OR = 1.06 95% CI 0.89, 1.27), colorectal (adjusted OR = 0.78 95% CI 0.66, 0.92) or prostate cancer (adjusted OR = 0.78 95% CI 0.66, 0.92). CONCLUSIONS: Overall, we found no evidence of increased risks of cancer-specific mortality in breast, colorectal or prostate cancer patients who used ACEI or ARBs after diagnosis. These results provide some reassurance that these medications are safe in patients diagnosed with these cancers

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment (Review)

BACKGROUND: It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non‐pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis. OBJECTIVES: To evaluate the cognitive effects, non‐cognitive effects, duration and safety of non‐pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments). SEARCH METHODS: We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015. SELECTION CRITERIA: Randomised controlled trials (RCTs) of non‐pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult‐onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non‐melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied. DATA COLLECTION AND ANALYSIS: Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta‐analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well‐being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes. MAIN RESULTS: Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer‐assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed‐ and immediate‐ memory), subjectively reported cognitive function and mental well‐being. Compensatory strategy training demonstrated improvements on objectively assessed delayed‐, immediate‐ and verbal‐memory, self‐reported cognitive function and spiritual quality of life (QoL). The meta‐analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well‐being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) ‐0.59 to 0.83; I(2)= 67%) or two months post‐intervention (SMD ‐ 0.21, 95% CI ‐0.89 to 0.47; I(2) = 63%) or on mental well‐being two months post‐intervention (SMD ‐0.38, 95% CI ‐1.10 to 0.34; I(2) = 67%). Lower mental well‐being immediately post‐intervention appeared to be observed in patients who received compensatory strategy training compared to wait‐list controls (SMD ‐0.57, 95% CI ‐0.98 to ‐0.16; I(2) = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear. AUTHORS' CONCLUSIONS: Overall, the, albeit low‐quality evidence may be interpreted to suggest that non‐pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi‐site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer

Effect of a Web-Based Behavior Change Program on Weight Loss and Cardiovascular Risk Factors in Overweight and Obese Adults at High Risk of Developing Cardiovascular Disease: Randomized Controlled Trial.

Web-based programs are a potential medium for supporting weight loss because of their accessibility and wide reach. Research is warranted to determine the shorter- and longer-term effects of these programs in relation to weight loss and other health outcomes

Effectiveness of prosthodontic interventions and survival of remaining teeth in adult patients with shortened dental arches - a systematic review Journal of Dentistry

ObjectivesA systematic review of randomised and non-randomised controlled trials was conducted to evaluate studies of the effectiveness of different tooth replacement strategies in adult patients with shortened dental arches. The objectives of the review were to determine the survival rates of different prosthodontic interventions, the risk of tooth loss with and without prosthodontic interventions, and the impact of different tooth replacement strategies on oral-health related quality of life (OHRQoL).MethodsThe protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO CRD42017064851), and the review was conducted in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).ResultsThe search strategy identified 112 potentially relevant publications; 22 from Medline (OVID), 54 from EMBASE (OVID), 35 from CENTRAL, one from the authors’ knowledge of the subject area, and none from OpenSIGLE. Ten articles were included in this systematic review. Of these, four were analyses of different outcomes from a multicentre randomized controlled trial in Germany, whilst one study was the pilot phase for this trial. Two further randomized controlled trials were included from the United Kingdom and Republic of Ireland. The remaining articles were reports of prospective cohort studies from Denmark and the Netherlands.Conclusionsthere is currently insufficient evidence to recommend one tooth replacement strategy over another in adult patients with reduced dentitions.Clinical significanceThere is a need for further research as there are insufficient numbers of good quality randomised controlled trials currently available. Authors should be encouraged to adhere to CONSORT guidelines for randomized controlled trials, and report findings in such a way that facilitates future meta-analysis.<br/

Common protocol for validation of the QCOVID algorithm across the four UK nations

Introduction The QCOVID algorithm is a risk prediction tool for infection and subsequent hospitalisation/death due to SARS-CoV-2. At the time of writing, it is being used in important policy-making decisions by the UK and devolved governments for combatting the COVID-19 pandemic, including deliberations on shielding and vaccine prioritisation. There are four statistical validations exercises currently planned for the QCOVID algorithm, using data pertaining to England, Northern Ireland, Scotland and Wales, respectively. This paper presents a common procedure for conducting and reporting on validation exercises for the QCOVID algorithm. Methods and analysis We will use open, retrospective cohort studies to assess the performance of the QCOVID risk prediction tool in each of the four UK nations. Linked datasets comprising of primary and secondary care records, virological testing data and death registrations will be assembled in trusted research environments in England, Scotland, Northern Ireland and Wales. We will seek to have population level coverage as far as possible within each nation. The following performance metrics will be calculated by strata: Harrell’s C, Brier Score, R2 and Royston’s D. Ethics and dissemination Approvals have been obtained from relevant ethics bodies in each UK nation. Findings will be made available to national policy-makers, presented at conferences and published in peer-reviewed journal

Technologies for the diagnosis of angle closure glaucoma (ACE): protocol of a prospective, multicentre, cross-sectional diagnostic study

INTRODUCTION: Angle-closure is responsible for half of all glaucoma blindness globally. Patients with suspected glaucoma require assessment of the drainage angle by an experienced clinician. The goal of this study is to evaluate the diagnostic performance and cost-effectiveness of two non-contact tests, anterior segment OCT (Optical Coherence Tomography) (AS-OCT) and limbal anterior chamber depth for patients referred to hospital with suspected angle closure compared with gonioscopy by ophthalmologist. METHODS AND ANALYSIS: Study design: prospective, multicentre, cross-sectional diagnostic accuracy study. INCLUSION CRITERIA: adults referred from community optometry to hospital with suspected angle closure. PRIMARY OUTCOME: Sensitivity and specificity. SECONDARY OUTCOMES: Positive/negative likelihood ratios, concordance, cost-effectiveness, proportion of patients requiring subsequent clinical assessment by ophthalmologist. SAMPLE SIZE: 600 individuals who have been referred with suspected angle closure from primary care (community optometry). We will have a 95% probability of detecting the true sensitivity of either test to within ±3.5% based on a sensitivity of 90%. The study would also have a 95% probability of detecting the true specificity of either test to within ±5%, assuming a specificity of 75%. ETHICS AND DISSEMINATION: Ethical Review Board approval was obtained. REC reference: 22/LO/0885. Our findings will be disseminated to those involved in eye care services. We will have a knowledge exchange event at the end of the study, published via the Health Technology Assessment web page and in specialist journals. The results will be presented at professional conferences and directly to patients via patient group meetings and the Glaucoma UK charity. TRIAL REGISTRATION NUMBER: ISRCTN15115867

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Common protocol for validation of the QCOVID algorithm across the four UK nations

Introduction: The QCOVID algorithm is a risk prediction tool for infection and subsequent hospitalisation/death due to SARS-CoV-2. At the time of writing, it is being used in important policy-making decisions by the UK and devolved governments for combatting the COVID-19 pandemic, including deliberations on shielding and vaccine prioritisation. There are four statistical validations exercises currently planned for the QCOVID algorithm, using data pertaining to England, Northern Ireland, Scotland and Wales, respectively. This paper presents a common procedure for conducting and reporting on validation exercises for the QCOVID algorithm. Methods and analysis: We will use open, retrospective cohort studies to assess the performance of the QCOVID risk prediction tool in each of the four UK nations. Linked datasets comprising of primary and secondary care records, virological testing data and death registrations will be assembled in trusted research environments in England, Scotland, Northern Ireland and Wales. We will seek to have population level coverage as far as possible within each nation. The following performance metrics will be calculated by strata: Harrell’s C, Brier Score, R2 and Royston's D. Ethics and dissemination: Approvals have been obtained from relevant ethics bodies in each UK nation. Findings will be made available to national policy-makers, presented at conferences and published in peer-reviewed journal

A2ML1 and otitis media : novel variants, differential expression, and relevant pathways

A genetic basis for otitis media is established, however, the role of rare variants in disease etiology is largely unknown. Previously a duplication variant within A2ML1 was identified as a significant risk factor for otitis media in an indigenous Filipino population and in US children. In this report exome and Sanger sequencing was performed using DNA samples from the indigenous Filipino population, Filipino cochlear implantees, US probands, Finnish, and Pakistani families with otitis media. Sixteen novel, damaging A2ML1 variants identified in otitis media patients were rare or low-frequency in population-matched controls. In the indigenous population, both gingivitis and A2ML1 variants including the known duplication variant and the novel splice variant c.4061 + 1 G>C were independently associated with otitis media. Sequencing of salivary RNA samples from indigenous Filipinos demonstrated lower A2ML1 expression according to the carriage of A2ML1 variants. Sequencing of additional salivary RNA samples from US patients with otitis media revealed differentially expressed genes that are highly correlated with A2ML1 expression levels. In particular, RND3 is upregulated in both A2ML1 variant carriers and high-A2ML1 expressors. These findings support a role for A2ML1 in keratinocyte differentiation within the middle ear as part of otitis media pathology and the potential application of ROCK inhibition in otitis media.Peer reviewe