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1.
Helen C. Fraser Valerie Kuan Ronja Johnen Magdalena Zwierzyna Aroon D. Hingorani Andreas Beyer Linda Partridge 《Aging cell》2022,21(4)
Genetic, environmental, and pharmacological interventions into the aging process can confer resistance to multiple age‐related diseases in laboratory animals, including rhesus monkeys. These findings imply that individual mechanisms of aging might contribute to the co‐occurrence of age‐related diseases in humans and could be targeted to prevent these conditions simultaneously. To address this question, we text mined 917,645 literature abstracts followed by manual curation and found strong, non‐random associations between age‐related diseases and aging mechanisms in humans, confirmed by gene set enrichment analysis of GWAS data. Integration of these associations with clinical data from 3.01 million patients showed that age‐related diseases associated with each of five aging mechanisms were more likely than chance to be present together in patients. Genetic evidence revealed that innate and adaptive immunity, the intrinsic apoptotic signaling pathway and activity of the ERK1/2 pathway were associated with multiple aging mechanisms and diverse age‐related diseases. Mechanisms of aging hence contribute both together and individually to age‐related disease co‐occurrence in humans and could potentially be targeted accordingly to prevent multimorbidity. 相似文献
2.
Pete Beckman Kamil Iskra Kazutomo Yoshii Susan Coghlan Aroon Nataraj 《Cluster computing》2008,11(1):3-16
We investigate operating system noise, which we identify as one of the main reasons for a lack of synchronicity in parallel
applications. Using a microbenchmark, we measure the noise on several contemporary platforms and find that, even with a general-purpose
operating system, noise can be limited if certain precautions are taken. We then inject artificially generated noise into
a massively parallel system and measure its influence on the performance of collective operations. Our experiments indicate
that on extreme-scale platforms, the performance is correlated with the largest interruption to the application, even if the
probability of such an interruption on a single process is extremely small. We demonstrate that synchronizing the noise can
significantly reduce its negative influence.
相似文献
Aroon NatarajEmail: |
3.
Michael V. Holmes Tina Shah Christine Vickery Liam Smeeth Aroon D. Hingorani Juan P. Casas 《PloS one》2009,4(12)
Background
Studies of the genetic basis of drug response could help clarify mechanisms of drug action/metabolism, and facilitate development of genotype-based predictive tests of efficacy or toxicity (pharmacogenetics).Objectives
We conducted a systematic review and field synopsis of pharmacogenetic studies to quantify the scope and quality of available evidence in this field in order to inform future research.Data Sources
Original research articles were identified in Medline, reference lists from 24 meta-analyses/systematic reviews/review articles and U.S. Food and Drug Administration website of approved pharmacogenetic tests.Study Eligibility Criteria, Participants, and Intervention Criteria
We included any study in which either intended or adverse response to drug therapy was examined in relation to genetic variation in the germline or cancer cells in humans.Study Appraisal and Synthesis Methods
Study characteristics and data reported in abstracts were recorded. We further analysed full text from a random 10% subset of articles spanning the different subclasses of study.Results
From 102,264 Medline hits and 1,641 articles from other sources, we identified 1,668 primary research articles (1987 to 2007, inclusive). A high proportion of remaining articles were reviews/commentaries (ratio of reviews to primary research approximately 25∶1). The majority of studies (81.8%) were set in Europe and North America focussing on cancer, cardiovascular disease and neurology/psychiatry. There was predominantly a candidate gene approach using common alleles, which despite small sample sizes (median 93 [IQR 40–222]) with no trend to an increase over time, generated a high proportion (74.5%) of nominally significant (p<0.05) reported associations suggesting the possibility of significance-chasing bias. Despite 136 examples of gene/drug interventions being the subject of ≥4 studies, only 31 meta-analyses were identified. The majority (69.4%) of end-points were continuous and likely surrogate rather than hard (binary) clinical end-points.Conclusions and Implications of Key Findings
The high expectation but limited translation of pharmacogenetic research thus far may be explained by the preponderance of reviews over primary research, small sample sizes, a mainly candidate gene approach, surrogate markers, an excess of nominally positive to truly positive associations and paucity of meta-analyses. Recommendations based on these findings should inform future study design to help realise the goal of personalised medicines.Systematic Review Registration Number
Not Registered 相似文献4.
5.
Teerasak Damrongrungruang Sujaree Phiphitaporn Nuttakul Salacheep Chonlada Sritragool Aroon Teerakapong Kittipitch Meesawat Anan Kruesubthaworn Chaiyapong Ruangsuwan Wilawan Weera-archakul 《Biochemistry and Biophysics Reports》2022
In photodynamic therapy, intermittent irradiation modes that incorporate an interval between pulses are believed to decrease the effect of hypoxia by permitting an interval of re-oxygenation. The effect of the irradiation intermittency factor (the ratio of the irradiation pulse time to the total irradiation time) on singlet oxygen formation and inflammatory cytokine production was examined using azulene as a photosensitizer. Effects of difference intermittency factor on singlet oxygen formation and inflammatory cytokine were examined. Azulene solutions (1/10 μM) were irradiated with a 638-nm 500 mW diode laser in fractionation (intermittency factor of 5 or 9) or continuous mode using 50 mW/cm2 at 4 or 8 J/cm2. Singlet oxygen measurement was performed using a dimethyl anthracene probe. Peripheral blood mononuclear cells (PBMC) were stimulated by 10 ng/ml rhTNF-α for 6 h, before addition of 1 and 10 μM azulene solutions and irradiation. PGE2 measurement was undertaken using a human PGE2 ELISA kit. Kruskal-Wallis with Dunn Bonferroni test was used for statistical analyses at p < 0.05.Irradiation of 1 μM azulene+4 J/cm2+intermittency factor of 9 increased singlet oxygen 3-fold (p < 0.0001). Irradiation of 10 μM azulene at either 4 J/cm2+intermittency of 9 or 8 J/cm2+intermittency factor of 5 reduced PGE2 expression in PBMCs to non-inflamed levels. Thus, at 50 mW/cm2, 10 μM azulene-mediated photodynamic therapy with a high intermittency factor and a low energy density generated sufficient singlet oxygen to suppress PGE2 in Inflamed PBMCs. 相似文献
6.
Background
A recent trial unexpectedly reported that atrial fibrillation, when defined as serious, occurred more often in participants randomized to an annual infusion of the relatively new parenteral bisphosphonate, zoledronic acid, than among those given placebo, but had limited power. Two subsequent population-based case-control studies of patients receiving a more established oral bisphosphonate, alendronic acid, reported conflicting results, possibly due to uncontrolled confounding factors.Methodology/Principal Findings
We used the United Kingdom General Practice Research Database to assess the risk of atrial fibrillation and flutter in women exposed to the oral bisphosphonates, alendronic acid and risedronate sodium. The self-controlled case-series method was used to minimise the potential for confounding. The age-adjusted incidence rate ratio for atrial fibrillation or flutter in individuals during their exposure to these oral bisphosphonates (n = 2195) was 1.07 (95% CI 0.94–1.21). The age-adjusted incidence rate ratio for alendronic acid (n = 1489) and risedronate sodium (n = 649) exposed individuals were 1.09 (95% CI 0.93–1.26) and 0.99 (95% CI 0.78–1.26) respectively. In post-hoc analyses, an increased risk of incident atrial fibrillation or flutter was detected for patients during their first few months of alendronic acid therapy.Conclusions/Significance
We found no robust evidence of an overall long-term increased risk of atrial fibrillation or flutter associated with continued exposure to the oral bisphosphonates, alendronic acid and risedronate sodium. A possible signal for an increase in risk during the first few months of therapy with alendronic acid needs to be re-assessed in additional studies. 相似文献7.
Pablo Perel Tim Clayton Doug G. Altman Peter Croft Ian Douglas Harry Hemingway Aroon Hingorani Katherine I. Morley Richard Riley Adam Timmis Danielle Van der Windt Ian Roberts for the PROGRESS Partnership 《PLoS medicine》2014,11(6)
Background
Haemorrhage is a common cause of death in trauma patients. Although transfusions are extensively used in the care of bleeding trauma patients, there is uncertainty about the balance of risks and benefits and how this balance depends on the baseline risk of death. Our objective was to evaluate the association of red blood cell (RBC) transfusion with mortality according to the predicted risk of death.Methods and Findings
A secondary analysis of the CRASH-2 trial (which originally evaluated the effect of tranexamic acid on mortality in trauma patients) was conducted. The trial included 20,127 trauma patients with significant bleeding from 274 hospitals in 40 countries. We evaluated the association of RBC transfusion with mortality in four strata of predicted risk of death: <6%, 6%–20%, 21%–50%, and >50%. For this analysis the exposure considered was RBC transfusion, and the main outcome was death from all causes at 28 days. A total of 10,227 patients (50.8%) received at least one transfusion. We found strong evidence that the association of transfusion with all-cause mortality varied according to the predicted risk of death (p-value for interaction <0.0001). Transfusion was associated with an increase in all-cause mortality among patients with <6% and 6%–20% predicted risk of death (odds ratio [OR] 5.40, 95% CI 4.08–7.13, p<0.0001, and OR 2.31, 95% CI 1.96–2.73, p<0.0001, respectively), but with a decrease in all-cause mortality in patients with >50% predicted risk of death (OR 0.59, 95% CI 0.47–0.74, p<0.0001). Transfusion was associated with an increase in fatal and non-fatal vascular events (OR 2.58, 95% CI 2.05–3.24, p<0.0001). The risk associated with RBC transfusion was significantly increased for all the predicted risk of death categories, but the relative increase was higher for those with the lowest (<6%) predicted risk of death (p-value for interaction <0.0001). As this was an observational study, the results could have been affected by different types of confounding. In addition, we could not consider haemoglobin in our analysis. In sensitivity analyses, excluding patients who died early; conducting propensity score analysis adjusting by use of platelets, fresh frozen plasma, and cryoprecipitate; and adjusting for country produced results that were similar.Conclusions
The association of transfusion with all-cause mortality appears to vary according to the predicted risk of death. Transfusion may reduce mortality in patients at high risk of death but increase mortality in those at low risk. The effect of transfusion in low-risk patients should be further tested in a randomised trial.Trial registration
www.ClinicalTrials.gov Please see later in the article for the Editors'' Summary NCT01746953相似文献8.
Leanne Bellamy Juan-Pablo Casas Aroon D Hingorani David J Williams 《BMJ (Clinical research ed.)》2007,335(7627):974
Objective To quantify the risk of future cardiovascular diseases, cancer, and mortality after pre-eclampsia.Design Systematic review and meta-analysis.Data sources Embase and Medline without language restrictions, including papers published between 1960 and December 2006, and hand searching of reference lists of relevant articles and reviews for additional reports.Review methods Prospective and retrospective cohort studies were included, providing a dataset of 3 488 160 women, with 198 252 affected by pre-eclampsia (exposure group) and 29 495 episodes of cardiovascular disease and cancer (study outcomes).Results After pre-eclampsia women have an increased risk of vascular disease. The relative risks (95% confidence intervals) for hypertension were 3.70 (2.70 to 5.05) after 14.1 years weighted mean follow-up, for ischaemic heart disease 2.16 (1.86 to 2.52) after 11.7 years, for stroke 1.81 (1.45 to 2.27) after 10.4 years, and for venous thromboembolism 1.79 (1.37 to 2.33) after 4.7 years. No increase in risk of any cancer was found (0.96, 0.73 to 1.27), including breast cancer (1.04, 0.78 to 1.39) 17 years after pre-eclampsia. Overall mortality after pre-eclampsia was increased: 1.49 (1.05 to 2.14) after 14.5 years.Conclusions A history of pre-eclampsia should be considered when evaluating risk of cardiovascular disease in women. This association might reflect a common cause for pre-eclampsia and cardiovascular disease, or an effect of pre-eclampsia on disease development, or both. No association was found between pre-eclampsia and future cancer. 相似文献
9.
Brunner EJ Kivimäki M Witte DR Lawlor DA Davey Smith G Cooper JA Miller M Lowe GD Rumley A Casas JP Shah T Humphries SE Hingorani AD Marmot MG Timpson NJ Kumari M 《PLoS medicine》2008,5(8):e155
Background
Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.Methods and Findings
We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29–1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52–0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007–0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25–0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.Conclusions
Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP. 相似文献10.
Kivimäki M Lawlor DA Smith GD Kumari M Donald A Britton A Casas JP Shah T Brunner E Timpson NJ Halcox JP Miller MA Humphries SE Deanfield J Marmot MG Hingorani AD 《PloS one》2008,3(8):e3013