Low-dose Aspirin Treatment Research Articles

Effect of aspirin on deaths associated with sepsis in healthy older people (ANTISEPSIS): a randomised, double-blind, placebo-controlled primary prevention trial

Sepsis is a serious global health issue and a major cause of death and disability. The availability of a simple, community-based preventive strategy could substantially reduce the burden of sepsis. We aimed to establish whether low-dose aspirin reduced deaths or hospital admissions associated with sepsis in older people. ANTISEPSIS was a substudy of ASPREE (a randomised controlled primary prevention trial of low-dose aspirin [100 mg per day] compared with placebo in community dwelling older adults conducted in Australia and the USA), with the Australian cohort included in the ANTISEPSIS substudy. Inclusion criteria were participants aged at least 70 years who did not have major illnesses. Participants were block randomised (1:1) via a centralised web portal and stratified by general practice and age. Participants, investigators, and staff were masked to the intervention. Teams of clinical specialist investigators assessed potential sepsis events to establish if they satisfied the primary endpoint of death associated with sepsis. The analyses were by intention-to-treat with univariate survival analysis methods, the log-rank test, and Cox proportional hazards regression. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000349741. Between March 10, 2010, and Dec 24, 2014, of 20 288 individuals assessed for eligibility, 16 703 participants aged 70 years and older at trial entry were enrolled and followed up for a median of 4·6 years (IQR 3·6-5·6). 8322 (49·8%) participants were assigned to receive aspirin and 8381 (50·2%) to placebo. 203 deaths were considered to be associated with sepsis. Univariate analysis showed similar rates of death associated with sepsis in the two study groups (hazard ratio for aspirin vs placebo 1·08, 95% CI 0·82-1·43; p=0·57). Adverse events were previously reported in the ASPREE trial. Daily low-dose aspirin treatment did not reduce deaths associated with sepsis in community dwelling older adults. Our findings do not support the use of aspirin as a primary prevention strategy to reduce the burden of sepsis in this population. National Health and Medical Research Council of Australia, National Institutes of Health, Monash University.

Is It Time to Recommend Low-Dose Aspirin Treatment for the Prevention of Hepatocellular Carcinoma?

Is It Time to Recommend Low-Dose Aspirin Treatment for the Prevention of Hepatocellular Carcinoma?

Differential expression of glycoprotein IV on monocyte subsets following high-fat diet feeding and the impact of short-term low-dose aspirin treatment

ObjectiveTo assess the levels of glycoprotein GPIV (CD36) expression on peripheral blood monocyte subsets, in a mouse model of glucose intolerance. Moreover, to determine the effect of; low-dose aspirin (LDA) alone, LDA combined with metformin, or clopidogrel alone, on the expression of CD36 on subsets of circulating monocytes. MethodThe study consisted of two experimental phases. In experiment one, the mice (n = 14) were randomised to receive a low-fat diet (LFD) or a high-fat diet (HFD) for eight weeks. Whereas the secondary phase of the experiment, comprised of twenty-four HFD-fed mice treated with LDA alone (3 mg/kg), or in combination with metformin (150 mg/kg), or clopidogrel alone (10 mg/kg) for six weeks. The surface expression of CD36 on monocytes was measured using flow cytometry. ResultThe levels of CD36 expression on monocytes were upregulated in the HFD-fed compared to LFD-fed group (p < 0.05). In addition, HFD group showed; no significant changes in body weight (p = 0.3848), however, blood glucose (p = 0.0002) and insulin (p = 0.0360) levels were markedly increased following HFD-feeding. Interestingly, all treatments reduced the expression of CD36 on monocytes, decreased fasting blood glucose levels (p = 0.0024) and increased circulating monocyte levels (p = 0.0217) when compared to the untreated HFD group. Moreover, treatment with LDA alone increased basophils levels (p = 0.0272), while when combined with metformin showed an improved effect in enhancing eosinophil levels (p = 0.0302). ConclusionHFD-feeding increased the expression of CD36 on monocyte subsets. LDA as a monotherapy or combined with metformin was as effective as clopidogrel monotherapy, in downregulating the expression of CD36 on monocyte subsets. These treatments may be of relevance in preventing cardiovascular complications associated with impaired glucose tolerance.

Risk of lower gastrointestinal bleeding and colorectal neoplasms following initiation of low-dose aspirin: a Danish population-based cohort study

ObjectiveAspirin may increase the risk of lower gastrointestinal bleeding (LGIB) from precursors of colorectal cancer (CRC). We investigated whether use of low-dose aspirin, through initiation of LGIB, may lead patients...

Elevated T-helper 2 cytokine levels in high fat diet-fed C57BL/6 mice are attenuated by short-term 6-week treatment with a combination of low-dose aspirin and metformin

ObjectiveTo evaluate T-helper cytokine responses in a short-term high fat diet (HFD) induced impaired glucose metabolism. To further evaluate the modulation of T-helper 1 (Th1) and T-helper 2 (Th2) cytokines using short-term low-dose aspirin in combination with metformin. DesignTwo experiments were carried out in this study in order to evaluate the T-helper cytokine profiles in a state of impaired glucose metabolism. A total of 28 six-week-old male C57BL/6 mice were used in this study. In the first experiment, mice were fed either a high fat diet or low fat diet for a duration of 10 weeks. We then determined the Th1, Th2 and T-helper 17 (Th17) cytokine profiles. In the second experiment, we evaluated whether the short term 6-week treatment with low-dose aspirin in combination with metformin modulates T-helper cytokine profiles of the HFD-fed mice. MeasurementsIn the first experiment, we measured the body weights, blood glucose levels, insulin levels, lipid profiles and haematological parameters. We further performed oral glucose tolerance testing following an 8-hour fast and serum Th1, Th2 and Th17 cytokine levels were also determined following short-term 8-week diet-feeding and 6-week low-dose aspirin and combined metformin with low-dose aspirin treatment. ResultsHigh fat diet-feeding caused a marked increase in circulating peripheral blood lymphocytes, which was attenuated by short-term low-dose aspirin treatment. Moreover, the HFD feeding resulted in 2-fold increase in total cholesterol and a 4-fold increase in low-density lipoprotein cholesterol when compared to the low-fat diet-fed group (p < 0.05). In the high fat diet group, impaired glucose metabolism was associated with skewed Th2 responses without alterations in the Th1 and Th17 cytokine profiles. Interestingly the short-term treatment with low-dose aspirin showed no effect on the selected T-helper 1 cytokine IFN-Ƴ (P > 0.05). While the combination of low-dose aspirin with metformin considerably reduced the levels of serum IFN-Ƴ (P < 0.05). Furthermore low-dose aspirin treatment showed the modest attenuation of the selected Th2 cytokines, IL-10 and IL-13 when compared to low-dose aspirin with metformin (P < 0.01). ConclusionThe early immunological and metabolic changes that occur in a state impaired glucose tolerance are accompanied by the increased production of Th2 cell cytokines. The short-term treatment using low-dose aspirin combined with metformin may provide therapeutic benefits in preventing complications associated with dysregulated Th2 cell responses.

Effects of chronic low-dose aspirin treatment on tumor prevention in three mouse models of intestinal tumorigenesis.

Although early detection and treatment of colorectal cancer (CRC) have improved, it remains a significant health‐care problem with high morbidity and mortality. Data indicate that long‐term intake of low‐dose aspirin reduces the risk of CRC; however, the mechanisms underlying this chemopreventive effect are still unclear. Different mouse models for inflammation‐associated, sporadic, and hereditary CRC were applied to assess the efficacy and mechanism of low‐dose aspirin on tumor prevention. An initial dosing study performed in healthy mice indicates that aspirin at a dose of 25 mg/kg/d has a similar pharmacodynamic effect as low‐dose aspirin treatment in human subjects (100 mg/d). Chronic low‐dose aspirin treatment suppresses colitis‐associated and to a lesser extent spontaneous tumorigenesis in mice. Aspirin's antitumor effect is most pronounced in a preventive approach when aspirin administration starts before the tumor‐initiating genotoxic event and continues for the duration of the experiment. These effects are not associated with alterations in cell proliferation, apoptosis, or activation of signaling pathways involved in CRC. Aspirin‐induced reduction in tumor burden is accompanied by inhibition of thromboxane B2 formation, indicating reduced platelet activation. Aspirin treatment also results in decreased colonic prostaglandin E2 formation and tumor angiogenesis. With respect to colitis‐triggered tumorigenesis, aspirin administration is associated with a reduction in inflammatory activity in the colon, as indicated by decreased levels of pro‐inflammatory mediators, and tumor‐associated iNOS‐positive macrophages. Our results suggest that low‐dose aspirin represents an effective antitumor agent in the context of colon tumorigenesis primarily due to its well‐established cyclooxygenase inhibition effects.

Pregnancy success rate and response to heparins and/or aspirin differ in women with antiphospholipid antibodies according to their Global AntiphosPholipid Syndrome Score

BackgroundThe current treatment to prevent pregnancy morbidity (PM) associated with antiphospholipid antibodies (aPL) is based on the use of low dose aspirin and low molecular weight heparin (henceforth defined as standard of care (SoC) treatment). Despite the SoC, up to 30% of women with aPL continue to have pregnancy complications. The global antiphospholipid syndrome (APS) score (GAPSS) is a tool to quantify the risk for the aPL-related clinical manifestations. In this study, we investigated the individual clinical response to SoC in women with aPL after stratifying them according to their GAPSS. MethodsOne-hundred-fourty-three women (352 pregnancies) with aPL ever pregnant treated with SoC therapy were included. The patients GAPSS was then grouped according to the patients’ GAPSS into low risk (< 6), medium risk (6–11), and high risk (≥12). ResultsThe live birth rate was 70.5% (248 out of the 352 pregnancies), 45 patients (31%) experienced at least one event of PM, defined as early or late.Patients were stratified according to GAPSS values, in order to identify a low risk group (GAPSS <6, n = 72), a medium risk group (GAPSS 6–11, n = 66) and a high risk group (GAPSS ≥12, n = 5).When considering patients who ever experienced any PM while treated with SoC, all patients in the high risk group experienced PM, while patients in the medium group had a significant higher rate of PM when compared to the low risk group [29 (43.9%) patients V.s. 11 (15.3%), respectively; p < 0.001]. When analysing the number of pregnancies in the three groups, patients in the high risk group had significantly lower live birth rates, when compared to the other groups [11 (40.7%) live births vs. 100 (62.1%) and 137 (82.5%), respectively; p < 0.05]. Furthermore, patients with medium risk group also had significantly lower live birth rates, when compared to the lower risk group (p < 0.001). ConclusionsGAPSS might be a valuable tool for to identify patients with a higher likelihood of response to SoC.

Comparative analysis of the impact on pregnancy of low-dose aspirin, low-molecular-weight heparine and combined treatment objectified by values of Doppler velocimetry

Introduction. The fact that thrombophilia is a factor involved in the pathogenesis of preeclampsia is a hypothesis supported bidirectionally by numerous contradictory results; however, it is estimated that approximately 40% of patients with preeclampsia have a thrombophilic substrate. Most valid studies do not support an association between inherited thrombophilia and preeclampsia, intrauterine growth restriction or spontaneous abortion, thus implicitly not supporting the prophylactic anticoagulant treatment with low-molecular-weight heparin (LMWH) for the prevention of the aforementioned conditions. Materials and method. We selected pregnant women with developing or spontaneous discontinued pregnancy undergoing anticoagulant or antiplatelet treatment. In the context where clear protocols for the administration of anticoagulants in pregnancy have not yet been established, we aimed to perform a comparative analysis of the clinical and anamnestic aspects on which the indication of treatment with antiplatelet, anticoagulant or the two combined in pregnancy were based and the impact on placental function by comparative analysis of the values of the Doppler measurements for the uterine, umbilical and average cerebral arteries of the patients included in the three study groups. Results. Spontaneous abortions or intrauterine fetal death in the antecedents was the main criterion for recommending antiplatelet, anticoagulant or combined treatment. In the presence of a personal history of thrombotic events, the combined treatment of LMWH and low-dose aspirin was chosen. We did not obtain a significant difference in the frequency of spontaneous pregnancy loss between the three study groups, the proportion of this condition being similar. Conclusions. The combined treatment of LMWH and low-dose aspirin in pregnancy was significantly correlated with the values of the resistance and pulsatility index of the uterine arteries closest to the normal values, with an average pulsatility index lower than 1, in particular for the left uterine artery, compared to the results obtained for the single treatment with low-dose aspirin or LMWH.

Anticardiolipin Positivity Is Highly Associated With Intrauterine Growth Restriction in Women With Antiphospholipid Syndrome.

The purpose of our study was to evaluate pregnancy outcomes of women with antiphospholipid antibodies (aPL) positivity and assess risk factors associated with adverse pregnancy outcomes. Pregnant women with aPL positivity were enrolled prospectively in China from January 2017 to March 2020. Treatment of low-dose aspirin and low molecular weight heparin were given. Pregnancy outcomes and coagulation function were recorded and compared with normal pregnancies. Multivariable logistic regression was performed to identify risk factors associated to intrauterine growth restriction (IUGR). 270 pregnant women, including 44 diagnosed as Antiphospholipid syndrome (APS), 91 as non-criteria APS (NCAPS) and 135 normal cases as control, were enrolled in the study. The live birth rate in aPL carriers and APS group was 97% and 95.5%, respectively. Adverse pregnancy outcomes did not show significant difference between aPL carriers and normal pregnancies, and between APS and NCAPS, except for IUGR. The incidence of IUGR was significantly higher in aPL carriers than normal pregnancies, and in APS patients than NCAPS (P < 0.05). After controlling for age, in vitro fertilization (IVF), pregnancy losses related to APS and treatment, anticardiolipin (aCL) positivity was the only variable significantly associated with IUGR, with an adjusted odds ratio of 4.601 (95% CI, 1.205-17.573). Better pregnant outcomes of aPL positive women, include APS and NCAPS, were achieved in our study with treatment based on low-dose aspirin (LDA) plus low molecular weight heparin (LMWH). The incidence of IUGR was still higher in them, and aCL positivity was the only one risk factor associated with IUGR.

All-cause mortality following low-dose aspirin treatment for patients with high cardiovascular risk in remote Australian Aboriginal communities: an observational study

ObjectivesTo evaluate the benefit and risk of low-dose acetylsalicylic acid (aspirin) in patients from remote Aboriginal communities in the Northern Territory, Australia.DesignRetrospective cohort study using primary care and hospital data...

Low-Dose Aspirin Treatment Attenuates Male Rat Salt-Sensitive Hypertension via Platelet Cyclooxygenase 1 and Complement Cascade Pathway.

BackgroundThe role of platelets in the development of vascular inflammation and endothelial dysfunction in the pathogenesis of hypertension is well established at this time. Aspirin is known to relieve pain, decrease fever, reduce inflammation, impair platelet aggregation, and prevent clotting, yet its effect in the context of salt‐sensitive hypertension remains unclear. The present study investigated the importance of aspirin in inhibiting the abnormal activation of platelets and promoting the normal function of the vascular endothelium in a rat model of salt‐sensitive hypertension.Method and ResultsDahl salt‐sensitive rats and salt‐resistant rats were fed a normal‐salt diet (4% NaCl), a high‐salt diet (8% NaCl), or a high‐salt diet with aspirin gavage (10 mg/kg per day) for 8 weeks. Blood pressure, platelet activation, vascular function, inflammatory response, and potential mechanism were measured. Low‐dose aspirin (10 mg/kg per day) decreased the high‐salt diet–induced elevation of blood pressure, platelet activation, leukocyte infiltration, and leukocyte–platelet aggregation (CD45+CD61+), as well as vascular endothelial and renal damage. These effects were related to the ability of aspirin to prevent the adhesion of leukocytes to endothelial cells via inhibition of the platelet cyclooxygenase 1 but not the cyclooxygenase 2 pathway. Aspirin also reversed the high‐salt diet–induced abnormal activation of complement and coagulation cascades in platelets.ConclusionsThese results highlight a new property of aspirin in ameliorating vascular endothelial dysfunction induced by platelet activation, which may be beneficial in the treatment of salt‐sensitive hypertension.

Molecular Targets of Aspirin and Prevention of Preeclampsia and Their Potential Association with Circulating Extracellular Vesicles during Pregnancy.

Uncomplicated healthy pregnancy is the outcome of successful fertilization, implantation of embryos, trophoblast development and adequate placentation. Any deviation in these cascades of events may lead to complicated pregnancies such as preeclampsia (PE). The current incidence of PE is 2–8% in all pregnancies worldwide, leading to high maternal as well as perinatal mortality and morbidity rates. A number of randomized controlled clinical trials observed the association between low dose aspirin (LDA) treatment in early gestational age and significant reduction of early onset of PE in high-risk pregnant women. However, a substantial knowledge gap exists in identifying the particular mechanism of action of aspirin on placental function. It is already established that the placental-derived exosomes (PdE) are present in the maternal circulation from 6 weeks of gestation, and exosomes contain bioactive molecules such as proteins, lipids and RNA that are a “fingerprint” of their originating cells. Interestingly, levels of exosomes are higher in PE compared to normal pregnancies, and changes in the level of PdE during the first trimester may be used to classify women at risk for developing PE. The aim of this review is to discuss the mechanisms of action of LDA on placental and maternal physiological systems including the role of PdE in these phenomena. This review article will contribute to the in-depth understanding of LDA-induced PE prevention.

Triple Antiphospholipid (aPL) Antibodies Positivity Is Associated With Pregnancy Complications in aPL Carriers: A Multicenter Study on 62 Pregnancies.

Objective: Antiphospholipid antibodies (aPL) are risk factors for thrombosis and adverse pregnancy outcomes (APO). The management of the so called “aPL carriers” (subjects with aPL positivity without the clinical criteria manifestations of APS) is still undefined. This study aims at retrospectively evaluating the outcomes and the factors associated with APO and maternal complications in 62 pregnant aPL carriers.Methods: Medical records of pregnant women regularly attending the Pregnancy Clinic of 3 Rheumatology centers from January 1994 to December 2015 were retrospectively evaluated. Patients with concomitant autoimmune diseases or other causes of pregnancy complications were excluded.Results: An aPL-related event was recorded in 8 out of 62 patients (12.9%) during pregnancy: 2 thrombosis and 6 APO. At univariate analysis, factors associated with pregnancy complications were acquired risk factors (p:0.008), non-criteria aPL manifestations (p:0.024), lupus-like manifestations (p:0.013), and triple positive aPL profile (p:0.001). At multivariate analysis, only the association with a triple aPL profile was confirmed (p:0.01, OR 21.3, CI 95% 1.84–247). Patients with triple aPL positivity had a higher rate of pregnancy complications, despite they were more frequently receiving combined treatment of low dose aspirin (LDA) and low molecular weight heparin (LMWH) at prophylactic dose.Conclusion: This study highlights the importance of risk stratification in pregnant aPL carriers, in terms of both immunologic and non-immunologic features. Combination treatment with LDA and LMWH did not prevent APO in some cases, especially in carriers of triple aPL positivity. Triple positive aPL carriers may deserve additional therapeutic strategies during pregnancy.

Trajectories of Adherence to Low-Dose Aspirin Treatment Among the French Population

Previous studies have shown that adherence to low-dose aspirin (LDA) is suboptimal. However, these studies were based on an average measure of adherence during follow-up, ignoring its dynamic process over time. We described the trajectories of adherence to LDA treatment among the French population over 3 years of follow-up. We identified a cohort of 11 793 new LDA users, aged ≥50 years in 2010, by using the French national health-care database. Patients included had at least 3 years of history in the database before study entry to exclude prevalent aspirin users and to assess baseline comorbidities. They were followed from the first date of LDA supply (the index date) until the first date among death, exit from the database, or 3 years after the index date. Adherence to LDA was assessed every 3 months by using the proportion of days covered (PDC) and dichotomized with a cutoff of PDC of 0.8. We used group-based trajectory modeling to identify trajectories of LDA adherence. Predictors of LDA adherence trajectory membership were identified by multinomial logistics regression. We identified 4 trajectories of adherence among new LDA users: the not-adherents (4737 [40.2%]), the delayed not-adherents (gradual decrease in adherence probability, 1601 [13.6%]), the delayed adherents (gradual increase in adherence probability, 1137 [9.6%]), and the persistent adherents (4318 [36.6%]). The probability of belonging to the not-adherent group was increased with female sex, low socioeconomic status, and polymedication and was reduced with a secondary indication for LDA use, such as diabetes, hypertension, and dementia, at least 4 consultations in the previous year, or 1 hospitalization or a cardiologist consultation in the 3 months before the index date. This study provides a dynamic picture of adherence behaviors among new LDA users and underlines the presence of critical trajectories that intervention could target to improve adherence.

Olive-Derived Hydroxytyrosol Shows Anti-inflammatory Effect without Gastric Damage in Rats.

Hydroxytyrosol (HT) is a simple phenol compound present in olive oil. In a previous in vitro study, we showed that HT downregulated lipopolysaccharide-mediated expression of inducible nitric oxide synthase, cyclooxygenase-2 (COX-2), tumor necrosis factor alpha, and interleukin-1β, resulting in reduced nitric oxide and prostaglandin E2 production. In the present study, we aimed to determine whether HT suppresses COX-2-induced inflammation in a carrageenan-induced rat paw edema model. Additionally, we compared its activity with those of the selective COX-2 inhibitor, celecoxib for a comparative control, and a representative nonsteroidal anti-inflammatory drug (NSAID), indomethacin for a positive control. HT, celecoxib, and indomethacin significantly suppressed swelling in carrageenan-injected rat paws. Although HT was less effective than celecoxib and indomethacin, it had a delayed onset of action. Moreover, we evaluated whether HT aggravates gastric damage, which is a typical adverse effect associated with NSAIDs and COX-2 inhibitors under low dose aspirin (LDA) treatment, in an aspirin-induced gastric damage rat model. Unlike celecoxib and indomethacin, HT did not cause gastric damage when co-administered with aspirin. Our results indicate that HT exerts a delayed but sustained anti-inflammatory effect against COX-2-mediated inflammation. Finally, the combination of short-acting conventional anti-inflammatory drugs and long-acting HT can be considered a new, safe, and effective anti-inflammatory treatment modality even when continuously administered for a long period under LDA treatment.

Uterine Radial Artery Resistance Index Predicts Reproductive Outcome in Women with Recurrent Pregnancy Losses and Thrombophilia.

Uterine radial artery resistance index (URa-RI) by Doppler ultrasound may reflect the changes in the uteroplacental circulation and be associated with adverse events in early pregnancy. Recurrent pregnancy losses (RPL) are associated with thrombophilia, and anticoagulation treatment with low molecular weight heparin improves pregnancy outcome in women with RPL and thrombophilia. A retrospective cohort study was conducted in 139 pregnant women with 3 or more RPL and thrombophilia. The relationship between pregnancy outcome and dynamic changes of URa-RI was analyzed in 116 women who delivered a liveborn infant and 23 who miscarried the index pregnancy. Patients were on preconception low molecular weight heparin, low-dose aspirin (81mg per day), and prednisone treatment. URa-RI was measured during periovulation time, at the time of positive pregnancy test, and then repeated every two weeks until 32-week gestation or the time of miscarriage. The URa-RI at 8-week gestation was significantly higher in women who miscarried the index pregnancy than those who delivered alive born infant (0.51±0.08 vs. 0.42±0.03, P<0.001). Receiver operating characteristic curve analysis demonstrated that URa-RI of 8 wk gestation effectively distinguished women who miscarried from those who had a live birth with an area under the curve of 82.6% (95% CI 69.01-97.17). After adjusting for covariates including age, BMI, and number of miscarriages, multiple logistic regression models showed that each 0.1 unit increase of URa-RI of 8 wk gestation was associated with 18.70-point increase in the risk of miscarriage (OR19.70, 95%CI 4.26-91.1, P<0.001), and women with an URa-RI≥0.45 had an OR of 49.48 (95% CI 8.01-307.95; P<0.001) for miscarriage compared to those who had URa-RI<0.45. In women with RPL and inherited thrombophilia, increased URa-RI at 8-week gestation was associated with spontaneous abortion independent of other risk factors while they were on anticoagulation treatment.

Low-dose aspirin protective effects are correlated with deregulation of HNF factor expression in the preeclamptic placentas from mice and humans

Aspirin (acetyl-salicylic acid) is one of the most ancient drugs of the human pharmacopeia. Nonetheless, its action at low doses is not well understood at the molecular level. One of the applications of low-dose aspirin treatment is the prevention of preeclampsia (PE) in patients at risk. Foeto-placental overexpression of the STOX1A transcription factor in mice triggers PE symptoms. Transcriptomic analysis of the placentas, showed that aspirin massively down-regulates genes of the coagulation and complement cascade, as well as genes involved in lipid transport. The genes modified by aspirin treatment are not the ones that are modified by STOX1 overexpression, suggesting that aspirin could act downstream, symptomatically on the preeclamptic disease. Bioinformatics analysis of the promoters of the deregulated genes showed that they are strongly enriched in HNF transcription factors-binding sites, in accordance with existing literature showing their roles as regulators of coagulation. Two of these transcription factors, Hnf1β and Hnf4α are found down-regulated by aspirin treatment. In parallel, we show that in human patient placentas, aspirin-induced deregulations of genes of the coagulation cascade are also observed. Finally, the expression of Hnf1β target sequences (Kif12, F2, Hnf4α promoters and a synthetic concatemer of the Hnf1β-binding site) were investigated by transfection in trophoblast cell models, with or without aspirin treatment and with or without STOX1A overexpression. In this model we observed that STOX1A and aspirin tended to synergize in the down-regulation of Hnf1β target genes in trophoblasts.

Teprenone improves gastric mucosal injury and dyspeptic symptoms in long-term nonsteroidal anti-inflammatory drug users.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a major cause of gastric mucosal lesions. In China, teprenone is frequently prescribed as a mucoprotective agent, but the literature regarding their efficacy is limited. Our purpose was to address the effects of teprenone on long-term NSAID-associated gastric mucosal lesions. This study examined 369 patients taking NSAIDs for at least 12weeks. Patients without gastroduodenal ulcer and without Helicobacter pylori infection on endoscopy at baseline were randomized to receive either NSAID plus teprenone (150mg/day) or NSAID only for 12weeks. Lanza scores were examined using endoscopy before and after treatment, and dyspeptic symptom scores are also analyzed. A total of 158 patients were randomized to the teprenone group (n=74) or the control group (n=84) for 12weeks. Seventy-one of patients in the teprenone group and 79 of patients in the control group were analyzed finally. After treatment, the Lanza scores and dyspeptic symptom scores decreased significantly in the teprenone group while increased in the control group (P<0.05). The changes of Lanza scores and dyspeptic symptom scores were higher in the teprenone group than in the control group (P<0.05). For subgroup analysis, the change in Lanza scores and dyspeptic symptom scores improved significantly in the teprenone group receiving long-term low-dose aspirin treatment, as well as in the teprenone group receiving other NSAIDs treatment (P<0.05). Teprenone may be an effective treatment choice of gastric mucosal injuries and dyspepsia symptoms in patients who used NSAIDs chronically without H.pylori infection or history of gastroduodenal ulcer.

Implementation and effects of risk-dependent obstetric care in the Netherlands: a clinical impact study Expect Study II

Introduction: This study will compare former obstetric care as usual Expect I with risk-dependent care using a prediction tool Expect II. The Expect I study externally validated 39 prediction models using data of 2,614 women prospectively included from 2013 to 2015. Clinically useful models were embedded in a prediction tool. At the same time, risk-dependent care paths were developed by gynaecologists and midwives of Limburg southern province of the Netherlands. In risk-dependent care antenatal care is tailored to the results of individual risk assessments. Furthermore, these care paths stimulate integrated obstetric care by intensifying the collaboration between midwives outpatient clinics and gynecologists hospitals. Risk-dependent care is currently embedded in Limburg. Methods: A multicenter prospective cohort study will be performed from 2017 to 2018, enrolling women who will receive risk-dependent obstetric care Expect II. Obstetric risk profiles will be calculated using a web-based prediction tool comprising validated prediction models. Primary outcomes are adherence of healthcare professionals and compliance of women to key recommendations which were inadequate in former care as usual; e.g. recommendations regarding calcium intake to all women Expect I: adequate calcium intake in 34% of women and low dose aspirin treatment to women with an elevated preeclampsia risk Expect I: actual use in the high-risk group: 1.5%. Secondary outcomes are patient satisfaction and healthcare costs. Health outcomes such as neonatal adverse events will be analyzed in the second part of the Expect II study using registry data of the region. Preliminary results: Seven months after introduction we estimate that our prediction tool is used in ~40% of all pregnant women in participating regions. At the moment, 150 women are included in our cohort. Recommendations about calcium intake during pregnancy were given to 112 women 74%, 91 of these women 61% reported the intention to comply with the recommendations received. In case of an elevated preeclampsia risk n=62 preventive aspirin treatment was recommended to 41 women 66%, 18 of these women 29% reported the intention to comply. Discussion: Implementing new guidelines takes time and requires an additional effort of healthcare professionals. Especially if these guidelines reorganize the logistic structure of healthcare and include new strategies such as a prediction tool. Conclusion: The preliminary results of this study indicate that risk-dependent care has already been implemented by a reasonable proportion of healthcare professionals. Furthermore, risk-dependent care combined with a web-based prediction tool appears to increase usage of preventive interventions. Lessons learned: Since this abstract reveals preliminary results it is too soon to draw conclusions about any lessons learned. Limitations: These results are based on preliminary data, thus a relatively large proportion of participants are included by healthcare professionals who immediately started using our tool. Therefore, the preliminary results may suffer from a selective response of healthcare professionals in the early stages of our study.

Low-dose aspirin treatment enhances the adhesion of preeclamptic decidual mesenchymal stem/stromal cells and reduces their production of pro-inflammatory cytokines.

Preeclampsia (PE) is a hypertensive disorder of human pregnancy. Low-dose aspirin (acetylsalicylic acid) (60-150mg/day) is used to prevent PE when taken early in pregnancy. The effect of aspirin on term PE remains uncertain. Abnormal placentation is a hallmark of PE and leads to increased placental oxidative stress, which triggers the release of anti-angiogenic factors that cause local damage to the decidual vasculature. The damage subsequently spreads systemically and culminates in maternal clinical symptoms. Decidua basalis mesenchymal stem/stromal cells (DMSCs) reside in a vascular microenvironment. In PE, DMSCs are exposed to abnormally high levels of oxidative stress and circulating inflammatory factors from the maternal blood. We previously showed that colony-forming unit ability and resistance to oxidative stress in DMSCs are reduced in MSCs derived from term PE pregnancies (PE-DMSCs). The action, if any, of aspirin on term PE-DMSCs has not been reported. In this study, aspirin (5μg/mL) was found to significantly increase PE-DMSC adhesion compared to untreated PE-DMSCs and gestation-matched control DMSCs (p value < 0.001) but had no effect on PE-DMSC proliferation. ELISA analysis showed that aspirin significantly decreased the production of inflammatory cytokines IFN-γ (p value < 0.05) and IL-8 (p value < 0.001) in PE-DMSCs. In addition, aspirin treatment increased the antioxidant capacity of PE-DMSCs compared with the untreated group (p value < 0.05). This study is the first to reveal a novel, beneficial action of aspirin on PE-DMSCs from term PE pregnancies by improving their adhesion, suppressing their production of pro-inflammatory cytokines production, and increasing their antioxidant capacity. KEY MESSAGES: Preeclampsia (PE) is a serious hypertensive disorder of pregnancy. The risk of PE is reduced by aspirin but the mechanism is poorly understood. Decidua basalis mesenchymal stem/stromal cells (DMSCs) are abnormal in PE. Aspirin treatment improves multiple functions of PE-DMSCs. Improved DMSC function may contribute to the beneficial effect of aspirin.