Efficacy and safety profile of statins in patients with cancer: a systematic review of randomised controlled trials

PURPOSE: A growing body of preclinical and observational research suggests that statins have potential as a therapeutic strategy in patients with cancer. This systematic review of randomised controlled trials (RCTs) in patients with solid tumours aimed to determine the efficacy of statin therapy on mortality outcomes, their safety profile and the risk of bias of included studies. METHODS: Full-text articles comparing statin therapy versus control in solid tumours and reporting mortality outcomes were identified from Medline and Embase from conception to February 2020. A systematic review with qualitative (primarily) and quantitative synthesis was conducted. This systematic review was prospectively registered (Prospero registration CRD42018116364). RESULTS: Eleven trials of 2165 patients were included. Primary tumour sites investigated included lung, colorectal, gastro-oesophageal, pancreatic and liver. Most trials recruited patients with advanced malignancy and used sub-maximal statin doses for relatively short durations. Aside from one trial which demonstrated benefit with allocation to pravastatin 40 mg in hepatocellular carcinoma, the remaining ten trials did not demonstrate efficacy with statins. The pooled hazard ratio for all-cause mortality with allocation to pravastatin in patients with hepatocellular carcinoma in two trials was 0.69 (95% confidence interval CI 0.30-1.61). Study estimates were imprecise. There were no clinically important differences in statin-related adverse events between groups. Overall, included trials were deemed low risk of bias. CONCLUSION: The trial evidence is not sufficiently robust to confirm or refute the efficacy and safety of statins in patients with solid malignant tumours. Study and patient characteristics may explain this uncertainty. The potential role of high-dose statins in adjuvant settings deserves further research

Gene Therapy Developments for Pompe Disease

Pompe disease is an inherited neuromuscular disorder caused by deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). The most severe form is infantile-onset Pompe disease, presenting shortly after birth with symptoms of cardiomyopathy, respiratory failure and skeletal muscle weakness. Late-onset Pompe disease is characterized by a slower disease progression, primarily affecting skeletal muscles. Despite recent advancements in enzyme replacement therapy management several limitations remain using this therapeutic approach, including risks of immunogenicity complications, inability to penetrate CNS tissue, and the need for life-long therapy. The next wave of promising single therapy interventions involves gene therapies, which are entering into a clinical translational stage. Both adeno-associated virus (AAV) vectors and lentiviral vector (LV)-mediated hematopoietic stem and progenitor (HSPC) gene therapy have the potential to provide effective therapy for this multisystemic disorder. Optimization of viral vector designs, providing tissue-specific expression and GAA protein modifications to enhance secretion and uptake has resulted in improved preclinical efficacy and safety data. In this review, we highlight gene therapy developments, in particular, AAV and LV HSPC-mediated gene therapy technologies, to potentially address all components of the neuromuscular associated Pompe disease pathology

Protocol for a feasibility randomised controlled trial of Screening and Enhanced Risk management for Vascular Event-related Decline in Memory (SERVED Memory)

INTRODUCTION: Stroke is a leading cause of death and disability. The development of dementia after stroke is common. Vascular risk factors (VRF) which contribute to stroke risk can also contribute to cognitive decline, especially in vascular dementia (VaD). There is no established treatment for VaD, therefore strategies for prevention could have major health resource implications. This study was designed to assess whether patients with early cognitive decline after stroke/transient ischaemic attack (TIA) can be easily identified and whether target-driven VRF management can prevent progression to dementia.  OBJECTIVES: The primary objective is to establish the feasibility of recruitment and retention of patients with early cognitive decline to a randomised controlled trial of enhanced VRF management. Secondary objectives include: (a) to determine the potential clinical benefit of the intervention; (b) to estimate the sample size for a future definitive multicentre randomised controlled trial; (c) to inform a future economic evaluation; (d) to explore the link between VRF control and the incidence of cognitive impairment on longitudinal follow-up in a UK population after stroke/TIA with current routine management.  METHODS: 100 patients with cognitive decline poststroke/TIA will be recruited from stroke services at the Norfolk and Norwich University Hospital. After collection of baseline data, they will be randomised to intervention (3 monthly follow-up with enhanced management) or control (treatment as usual by the general practitioner). At 12 months outcomes (repeat cognitive testing, VRF assessment) will be assessed. A further 100 patients without cognitive decline will be recruited to a parallel observational group from the same site. At 12 months they will have repeat cognitive testing.  ETHICS AND DISSEMINATION: Ethical approval has been granted in England. Dissemination is planned via publication in peer-reviewed medical journals and presentation at relevant conferences.  TRIAL REGISTRATION NUMBER: 42688361; Pre-results

Effect of Antiplatelet Therapy (Aspirin + Dipyridamole Versus Clopidogrel) on Mortality Outcome in Ischemic Stroke

The optimal regimen of antiplatelet therapy for secondary prevention in noncardioembolic ischemic stroke remains controversial. We aimed to determine which regimen was associated with the greatest reduction in adverse outcomes. We analysed prospectively collected data from the Norfolk and Norwich University Hospital Stroke Register (NNUHSR). The sample population consisted of 3,572 participants (mean age 74.96 ± 12.67) with ischemic stroke, who were consecutively admitted between 2003-2015. Patients were placed on one of three antiplatelet regimens at hospital discharge; aspirin monotherapy, aspirin plus dipyridamole and clopidogrel. Clopidogrel and aspirin plus dipyridamole was compared to aspirin. A direct comparison between clopidogrel and aspirin plus dipyridamole was also performed. Outcomes included all-cause mortality and a combined endpoint of all-cause mortality and incidence of major adverse cardiac events (stroke or myocardial infarction). Cox-regression models adjusted for potential confounders at the following time periods after discharge; 0-90 days, 91-365 days and 1-3 years. Aspirin plus dipyridamole was associated with a lower risk of mortality at 0-90 days; HR 0.62 (0.43-0.91). Clopidogrel was associated with a lower risk of mortality at 1-3 years; HR of 0.39 (0.26-0.60). Similar HRs were observed for the the corresponding time points in the composite outcome. In conclusion Patients with non-cardioembolic stroke may gain maximum benefit from aspirin plus dipyridamole initially (≤1 year) with a subsequent switch to clopidogrel, with regard to mortality and MACE outcomes

Impact of hemoglobin levels and anemia on mortality in acute stroke: analysis of UK regional registry data, systematic review and meta-analysis

Background: The impact of hemoglobin levels and anemia on stroke mortality remains controversial. We aimed to systematically assess this association and quantify the evidence. Methods and Results: We analysed data from a cohort of 8,013 stroke patients (mean (sd) 77.81±11.83 years) consecutively admitted over 11 years (January 2003–May 2015) using a UK Regional Stroke Register. The impact of hemoglobin levels and anemia on mortality was assessed by sex-specific values at different time points (7-day, 14-day, 1-month, 3-month, 6-month, 1 year), using multiple regression models controlling for confounders. Anemia was present in 24.5% of the cohort on admission and was associated with increased odds of mortality at most of the time points examined up to 1 year following stroke. The association was less consistent for males with hemorrhagic stroke. Elevated haemoglobin was also associated with increased mortality, mainly within the first month. We then conducted a systematic review using the EMBASE and Medline databases. Twenty studies met the inclusion criteria. When combined with the cohort from the current study, this gave a pooled population of 29,943 patients with stroke. The evidence base was quantified in a meta-analysis. Anemia on admission was found to be associated with an increased risk of mortality in both ischemic stroke (8 studies); OR 1.97(1.56– 2.47) and hemorrhagic stroke (4 studies); OR 1.46(1.23–1.74). Conclusions: There is strong evidence that patients with anemia have increased mortality in stroke. Targeted interventions in this patient population may improve outcomes and therefore require further evaluation

Sequencing strategies and characterization of 721 vervet monkey genomes for future genetic analyses of medically relevant traits

Background We report here the first genome-wide high-resolution polymorphism resource for non-human primate (NHP) association and linkage studies, constructed for the Caribbean-origin vervet monkey, or African green monkey (Chlorocebus aethiops sabaeus), one of the most widely used NHPs in biomedical research. We generated this resource by whole genome sequencing (WGS) of monkeys from the Vervet Research Colony (VRC), an NIH-supported research resource for which extensive phenotypic data are available. Results We identified genome-wide single nucleotide polymorphisms (SNPs) by WGS of 721 members of an extended pedigree from the VRC. From high-depth WGS data we identified more than 4 million polymorphic unequivocal segregating sites; by pruning these SNPs based on heterozygosity, quality control filters, and the degree of linkage disequilibrium (LD) between SNPs, we constructed genome-wide panels suitable for genetic association (about 500,000 SNPs) and linkage analysis (about 150,000 SNPs). To further enhance the utility of these resources for linkage analysis, we used a further pruned subset of the linkage panel to generate multipoint identity by descent matrices. Conclusions The genetic and phenotypic resources now available for the VRC and other Caribbean-origin vervets enable their use for genetic investigation of traits relevant to human diseases

Association between different methods of assessing blood pressure variability and incident cardiovascular disease, cardiovascular mortality and all-cause mortality : a systematic review

Dr Smith is supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. Dr Choon-Hian Goh is supported by the University of Malaya Post Doctoral Research Fellowship scheme. No funding was received to undertake the conduct of this study.Peer reviewedPostprin

Functional and quality-of-life outcomes in geriatric patients with type-II dens fracture.

BACKGROUND: Dens fractures are relatively common in the elderly. The treatment of Type-II dens fractures remains controversial. The aim of this multicenter prospective cohort study was to compare outcomes (assessed with use of validated clinical measures) and complications of nonsurgical and surgical treatment of Type-II dens fractures in patients sixty-five years of age or older. METHODS: One hundred and fifty-nine patients with a Type-II dens fracture were enrolled in a multicenter prospective study. Subjects were treated either surgically (n = 101) or nonsurgically (n = 58) as determined by the treatment preferences of the treating physicians and the patients. The subjects were followed at six and twelve months with validated outcome measures, including the Neck Disability Index (NDI) and Short Form-36v2 (SF-36v2). Treatment complications were prospectively recorded. Statistical analysis was performed to compare outcome measures before and after adjustment for confounding variables. RESULTS: The two groups were similar with regard to baseline characteristics. The most common surgical treatment was posterior C1-C2 arthrodesis (eighty of 101, or 79%) while the most common nonsurgical treatment was immobilization with use of a hard collar (forty-seven of fifty-eight, or 81%). The overall mortality rate was 18% over the twelve-month follow-up period. At twelve months, the NDI had increased (worsened) by 14.7 points in the nonsurgical cohort (p \u3c 0.0001) compared with a nonsignificant increase (worsening) of 5.7 points in the surgical group (p = 0.0555). The surgical group had significantly better outcomes as measured by the NDI and SF-36v2 Bodily Pain dimension compared with the nonsurgical group, and these differences persisted after adjustment. There was no difference in the overall rate of complications, but the surgical group had a significantly lower rate of nonunion (5% versus 21% in the nonsurgical group; p = 0.0033). Mortality was higher in the nonsurgical group compared with the surgical group (annual mortality rates of 26% and 14%, respectively; p = 0.059). CONCLUSIONS: We demonstrated a significant benefit with surgical treatment of dens fractures as measured by the NDI, a disease-specific functional outcome measure. As a result of the nonrandomized nature of the study, the results are vulnerable to the effects of possible residual confounding. We recommend that elderly patients with a Type-II dens fracture who are healthy enough for general anesthesia be considered for surgical stabilization to improve functional outcome as well as the union and fusion rates