Aspirin for prophylactic use in the primary prevention of cardiovascular disease and cancer : a systematic review and overview of reviews

Background: Prophylactic aspirin has been considered to be beneficial in reducing the risks of heart disease and cancer. However, potential benefits must be balanced against the possible harm from side effects, such as bleeding and gastrointestinal (GI) symptoms. It is particularly important to know the risk of side effects when aspirin is used as primary prevention - that is when used by people as yet free of, but at risk of developing, cardiovascular disease (CVD) or cancer. In this report we aim to identify and re-analyse randomised controlled trials (RCTs), systematic reviews and meta-analyses to summarise the current scientific evidence with a focus on possible harms of prophylactic aspirin in primary prevention of CVD and cancer. Objectives: To identify RCTs, systematic reviews and meta-analyses of RCTs of the prophylactic use of aspirin in primary prevention of CVD or cancer. To undertake a quality assessment of identified systematic reviews and meta-analyses using meta-analysis to investigate study-level effects on estimates of benefits and risks of adverse events; cumulative meta-analysis; exploratory multivariable meta-regression; and to quantify relative and absolute risks and benefits. Methods: We identified RCTs, meta-analyses and systematic reviews, and searched electronic bibliographic databases (from 2008 September 2012) including MEDLINE, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, NHS Centre for Reviews and Dissemination, and Science Citation Index. We limited searches to publications since 2008, based on timing of the most recent comprehensive systematic reviews. Results: In total, 2572 potentially relevant papers were identified and 27 met the inclusion criteria. Benefits of aspirin ranged from 6% reduction in relative risk (RR) for all-cause mortality [RR 0.94, 95% confidence interval (CI) 0.88 to 1.00] and 10% reduction in major cardiovascular events (MCEs) (RR 0.90, 95% CI 0.85 to 0.96) to a reduction in total coronary heart disease (CHD) of 15% (RR 0.85, 95% CI 0.69 to 1.06). Reported pooled odds ratios (ORs) for total cancer mortality ranged between 0.76 (95% CI 0.66 to 0.88) and 0.93 (95% CI 0.84 to 1.03). Inclusion of the Women's Health Study changed the estimated OR to 0.82 (95% CI 0.69 to 0.97). Aspirin reduced reported colorectal cancer (CRC) incidence (OR 0.66, 95% CI 0.90 to 1.02). However, including studies in which aspirin was given every other day raised the OR to 0.91 (95% CI 0.74 to 1.11). Reported cancer benefits appeared approximately 5 years from start of treatment. Calculation of absolute effects per 100,000 patient-years of follow-up showed reductions ranging from 33 to 46 deaths (all-cause mortality), 60-84 MCEs and 47-64 incidents of CHD and a possible avoidance of 34 deaths from CRC. Reported increased RRs of adverse events from aspirin use were 37% for GI bleeding (RR 1.37, 95% CI 1.15 to 1.62), between 54% (RR 1.54, 95% CI 1.30 to 1.82) and 62% (RR 1.62, 95% CI 1.31 to 2.00) for major bleeds, and between 32% (RR 1.32, 95% CI 1.00 to 1.74) and 38% (RR 1.38, 95% CI 1.01 to 1.82) for haemorrhagic stroke. Pooled estimates of increased RR for bleeding remained stable across trials conducted over several decades. Estimates of absolute rates of harm from aspirin use, per 100,000 patient-years of follow-up, were 99-178 for non-trivial bleeds, 46-49 for major bleeds, 68-117 for GI bleeds and 8-10 for haemorrhagic stroke. Meta-analyses aimed at judging risk of bleed according to sex and in individuals with diabetes were insufficiently powered for firm conclusions to be drawn. Limitations: Searches were date limited to 2008 because of the intense interest that this subject has generated and the cataloguing of all primary research in so many previous systematic reviews. A further limitation was our potential over-reliance on study-level systematic reviews in which the person-years of follow-up were not accurately ascertainable. However, estimates of number of events averted or incurred through aspirin use calculated from data in study-level meta-analyses did not differ substantially from estimates based on individual patient data-level meta-analyses, for which person-years of follow-up were more accurate (although based on less-than-complete assemblies of currently available primary studies). Conclusions: We have found that there is a fine balance between benefits and risks from regular aspirin use in primary prevention of CVD. Effects on cancer prevention have a long lead time and are at present reliant on post hoc analyses. All absolute effects are relatively small compared with the burden of these diseases. Several potentially relevant ongoing trials will be completed between 2013 and 2019, which may clarify the extent of benefit of aspirin in reducing cancer incidence and mortality. Future research considerations include expanding the use of IPD meta-analysis of RCTs by pooling data from available studies and investigating the impact of different dose regimens on cardiovascular and cancer outcomes

A Nutraceutical Industry: Policy Implications for Future Directions

Food Consumption/Nutrition/Food Safety,

Aspirin in primary prevention of cardiovascular disease and cancer : a systematic review of the balance of evidence from reviews of randomized trials

Background: Aspirin has been recommended for primary prevention of cardiovascular disease (CVD) and cancer, but overall benefits are unclear. We aimed to use novel methods to re-evaluate the balance of benefits and harms of aspirin using evidence from randomised controlled trials, systematic reviews and meta-analyses. Methods and Findings: Data sources included ten electronic bibliographic databases, contact with experts, and scrutiny of reference lists of included studies. Searches were undertaken in September 2012 and restricted to publications since 2008. Of 2,572 potentially relevant papers 27 met the inclusion criteria. Meta-analysis of control arms to estimate event rates, modelling of all-cause mortality and L'Abbé plots to estimate heterogeneity were undertaken. Absolute benefits and harms were low: 60-84 major CVD events and 34-36 colorectal cancer deaths per 100,000 person-years were averted, whereas 46-49 major bleeds and 68-117 gastrointestinal bleeds were incurred. Reductions in all-cause mortality were minor and uncertain (Hazard Ratio 0.96; 95% CI: 0.90-1.02 at 20 years, Relative Risk [RR] 0.94, 95% CI: 0.88-1.00 at 8 years); there was a non-significant change in total CVD (RR 0.85, 95% CI: 0.69-1.06) and change in total cancer mortality ranged from 0.76 (95% CI: 0.66-0.88) to 0.93 (95% CI: 0.84-1.03) depending on follow-up time and studies included. Risks were increased by 37% for gastrointestinal bleeds (RR 1.37, 95% CI: 1.15-1.62), 54%-66% for major bleeds (Rate Ratio from IPD analysis 1.54, 95% CI: 1.30-1.82, and RR 1.62, 95% CI: 1.31-2.00), and 32%-38% for haemorrhagic stroke (Rate Ratio from IPD analysis 1.32; 95% CI: 1.00-1.74; RR 1.38; 95% CI: 1.01-1.82). Conclusions: Findings indicate small absolute effects of aspirin relative to the burden of these diseases. When aspirin is used for primary prevention of CVD the absolute harms exceed the benefits. Estimates of cancer benefit rely on selective retrospective re-analysis of RCTs and more information is needed

Evaluation of Barley Genotypes Against Spot Blotch Disease in Inner Tarai Region of Nepal

Spot blotch caused by Bipolaris sorokiniana (Sacc. in Sorok.) Shoem. is an important disease of barley (Hordeum vulgare L.). A total of 126 barley genotypes received from Hill Crops Research Program, Kabre, Dolakha having SoluUwa as a susceptible check and Bonus as a resistant check were evaluated as barley disease screening nursery (BDSN) under natural epiphytotic condition at National Maize Research Program, Rampur, Chitwan during winter seasons of 2017 and 2018. The nursery was planted in augmented design. The resistant and susceptible checks were repeated and planted after each 10 tested entries. The unit plot size was 2 rows of one meter length for each genotype planted continuously with 25cm row to row spacing. The seed rate was 100 kg/ha. The recommended fertilizer dose of 23:30:0 N:P2O5:K2O kg/ha was applied. The double digit scale (00 to 99) was used to measure overall foliar infection on the whole plant during flowering, soft dough and hard dough stages. Other agronomic practices were followed as per recommendation. Genotypes B86019-1K-3K-0K3, ACC 2087, ACC 2441, ACC GHv-06816, ACC 1597, ACC 1612, ACC 2059 and ACC 2032 were resistant against spot blotch disease. Similarly, 32 barley genotypes were moderately resistant and rest of the tested genotypes were susceptible to the disease. The selected resistant barley genotypes can be used in crossing program and/or promoted for further testing to develop spot blotch resistant varieties for inner Tarai region of Nepal

Tpz1TPP1 SUMOylation reveals evolutionary conservation of SUMO-dependent Stn1 telomere association

Elongation of the telomeric overhang by telomerase is counteracted by synthesis of the complementary strand by the CST complex, CTC1(Cdc13)/Stn1/Ten1. Interaction of budding yeast Stn1 with overhang-binding Cdc13 is increased by Cdc13 SUMOylation. Human and fission yeast CST instead interact with overhang-binding TPP1/POT1. We show that the fission yeast TPP1 ortholog, Tpz1, is SUMOylated. Tpz1 SUMOylation restricts telomere elongation and promotes Stn1/Ten1 telomere association,and a SUMO-Tpz1 fusion protein has increased affinity for Stn1. Our data suggest that SUMO inhibits telomerase through stimulation of Stn1/Ten1 action by Tpz1, highlighting the evolutionary conservation of the regulation of CST function by SUMOylation

The exosome journey: from biogenesis to uptake and intracellular signalling.

The use of exosomes in clinical settings is progressively becoming a reality, as clinical trials testing exosomes for diagnostic and therapeutic applications are generating remarkable interest from the scientific community and investors. Exosomes are small extracellular vesicles secreted by all cell types playing intercellular communication roles in health and disease by transferring cellular cargoes such as functional proteins, metabolites and nucleic acids to recipient cells. An in-depth understanding of exosome biology is therefore essential to ensure clinical development of exosome based investigational therapeutic products. Here we summarise the most up-to-date knowkedge about the complex biological journey of exosomes from biogenesis and secretion, transport and uptake to their intracellular signalling. We delineate the major pathways and molecular players that influence each step of exosome physiology, highlighting the routes of interest, which will be of benefit to exosome manipulation and engineering. We highlight the main controversies in the field of exosome research: their adequate definition, characterisation and biogenesis at plasma membrane. We also delineate the most common identified pitfalls affecting exosome research and development. Unravelling exosome physiology is key to their ultimate progression towards clinical applications. Video Abstract

Optical Studies of Zero-Field Magnetization of CdMnTe Quantum Dots: Influence of Average Size and Composition of Quantum Dots

We show that through the resonant optical excitation of spin-polarized excitons into CdMnTe magnetic quantum dots, we can induce a macroscopic magnetization of the Mn impurities. We observe very broad (4 meV linewidth) emission lines of single dots, which are consistent with the formation of strongly confined exciton magnetic polarons. Therefore we attribute the optically induced magnetization of the magnetic dots results to the formation of spin-polarized exciton magnetic polarons. We find that the photo-induced magnetization of magnetic polarons is weaker for larger dots which emit at lower energies within the QD distribution. We also show that the photo-induced magnetization is stronger for quantum dots with lower Mn concentration, which we ascribe to weaker Mn-Mn interaction between the nearest neighbors within the dots. Due to particular stability of the exciton magnetic polarons in QDs, where the localization of the electrons and holes is comparable to the magnetic exchange interaction, this optically induced spin alignment persists to temperatures as high as 160 K.Comment: 26 pages, 7 figs - submitted for publicatio

Community-Based Monitoring of Tigers in Nepal

Local citizens recruited and trained as bagh heralu (“tiger watchers”) helped us to collect information on the distribution of tiger throughout the Terai of Nepal. While the ultimate goal of the bagh heralu program was to map the current metapopulation of tigers in Nepal and to determine extent of breeding outside protected areas, the bagh heralu approach was useful not only because it facilitated data collection but also because it enhanced conservation efforts in multiple ways.Over the five years of the program, bagh heralu became knowledgeable about basic tiger biology and they became recognized in their communities as local tiger experts. Their knowledge of the ecological needs of tigers and strong local interest in the project increased discussions of tiger conservation in local communities throughout the lowlands. This case study indicates that the citizen monitoring programs has the potential to shift some of the responsibility for and economic benefits from biodiversity conservation from government agencies and non-governmental organizations to local communities, thus enhancing efforts to manage resources sustainably across entire landscapes. This case study serves as an example of a citizen monitoring project in a developing country and raises questions relevant to its possible expansion and to broader questions of citizen science in a developing country context

Resonant shifts of positronium energy levels in MgO powder

We report measurements of shifts in the frequencies of 13S1→23PJ and 23PJ→n3D/n3S transitions optically driven in positronium atoms while they are inside the open volumes of MgO smoke powder. The observed intervals are larger than the corresponding vacuum excitations, but, surprisingly, the transitions to Rydberg states are less strongly affected, and the energy shifts exhibit no dependence on the principal quantum number n of the final state. We attribute these shifts to resonant interactions between Ps atoms and MgO surfaces, mediated via spectrally overlapping MgO ultra violet (UV) photo-luminescent absorption bands. Since many insulating materials suitable for Ps confinement exhibit similar broadband UV absorption characteristics, the observed phenomena have implications for optical diagnostics and laser cooling schemes of relevance to studies of high-density Ps ensembles in insulating cavities, including the production of a Ps Bose-Einstein condensate