Low-dose Aspirin Research Articles

Thromboxane biosynthesis and future events in diabetes: the ASCEND trial.

Thromboxane (TX) A2, released by activated platelets, plays an important role in atherothrombosis. Urinary 11-dehydro-TXB2 (U-TXM), a stable metabolite reflecting the whole-body TXA2 biosynthesis, is reduced by ∼70% by daily low-dose aspirin. The U-TXM represents a non-invasive biomarker of in vivo platelet activation and is enhanced in patients with diabetes. This study assessed whether U-TXM is associated with the risk of future serious vascular events or revascularizations (SVE-R), major bleeding, or cancer in patients with diabetes. The U-TXM was measured pre-randomization to aspirin or placebo in 5948 people with type 1 or 2 diabetes and no cardiovascular disease, in the ASCEND trial. Associations between log U-TXM and SVE-R (n = 618), major bleed (n = 206), and cancer (n = 700) during 6.6 years of follow-up were investigated by Cox regression; comparisons of these associations with the effects of randomization to aspirin were made. Higher U-TXM was associated with older age, female sex, current smoking, type 2 diabetes, higher body size, urinary albumin/creatinine ratio of ≥3 mg/mmol, and higher estimated glomerular filtration rate. After adjustment for these, U-TXM was marginally statistically significantly associated with SVE-R and major bleed but not cancer [hazard ratios per 1 SD higher log U-TXM (95% confidence interval): 1.09 (1.00-1.18), 1.16 (1.01-1.34), and 1.06 (0.98-1.14)]. The hazard ratio was similar to that implied by the clinical effects of randomization to aspirin for SVE-R but not for major bleed. The U-TXM was log-linearly independently associated with SVE-R in diabetes. This is consistent with the involvement of platelet TXA2 in diabetic atherothrombosis.

Effect of Low-Dose Aspirin on the Elderly.

Aspirin is a recognized and affordable antiplatelet medicine. Low amounts of aspirin have been used to prevent cardiovascular events, and it is still widely used for primary and secondary stroke prevention. The purpose of this review article is to evaluate the effects of using low doses of aspirin among elderly people. Although taking large dosages of aspirin (500 mg daily) reduces the long-term risk of colorectal cancer, its effectiveness for long-term prevention may be limited by adverse effects. Studies have assessed the relationship between aspirin dosage, incidence, and death in patients withcolorectal cancer. Research has indicated that those with diabetes mellitus have an increased risk of cardiovascular events. Low amounts of aspirin have been used to prevent cardiovascular events. However, there is uncertainty regarding the potential benefits and risks associated with preventing the development ofcardiovascular problems inindividuals with diabetes. The use of aspirin lowers the risk of occlusive vascular events but raises the possibility of bleeding. More attention should be paid to reducing inappropriate aspirin usage in light of its prevalence, particularly among older persons, as the substantial continuous usage of thisdrug increases the chances of bleeding.

Managing pre-existing diabetes prior to and during pregnancy.

Women with pre-existing diabetes who are planning a pregnancy ideally should receive high-quality, multidisciplinary preconception care in a specialist centre; this has been shown to improve pregnancy outcomes. Optimising glycaemic management is essential prior to conception and throughout pregnancy and breastfeeding to minimise adverse events. Low-dose aspirin is recommended from 12 weeks gestation for prevention of pre-eclampsia. Breastfeeding is highly advantageous in women with pre-existing diabetes; women often need additional support with establishment and maintenance of breastfeeding. High-quality postpartum care and effective contraception are essential.

The effects of low-dose aspirin on preterm birth: a systematic review and meta-analysis of randomized controlled trials.

To conduct a systematic review and meta-analysis of all randomized controlled trials (RCTs) that evaluated the efficacy of low-dose aspirin (LDA, ≤ 160mg/day) on preventing preterm birth (PB). Five databases were screened from inception until June 25, 2023. The RCTs were assessed for quality according to Cochrane's risk of bias tool. The endpoints were summarized as risk ratio (RR) with 95% confidence interval (CI). Overall, 40 RCTs were analyzed. LDA significantly decreased the risk of PB < 37weeks (RR: 0.91, 95% CI 0.87, 0.96, p < 0.001, moderate certainty of evidence) with low between-study heterogeneity (I2 = 23.2%, p = 0.11), and PB < 34weeks (RR: 0.78, 95% CI 0.61, 0.99, p = 0.04, low certainty of evidence) with high between-study heterogeneity (I2 = 58.3%, p = 0.01). There were no significant differences between both groups regarding the risk of spontaneous (RR: 0.94, 95% CI 0.83, 1.07, p = 0.37) and medically indicated (RR: 1.28, 95% CI 0.87, 1.88, p = 0.21) BP < 37weeks. Sensitivity analysis revealed robustness for all outcomes, except for the risk of PB < 34weeks. For PB < 37weeks and PB < 34weeks, publication bias was detected based on visual inspection of funnel plots for asymmetry and statistical significance for Egger's test (p = 0.009 and p = 0.0012, respectively). LDA can significantly reduce the risk of PB < 37 and < 34weeks. Nevertheless, further high-quality RCTs conducted in diverse populations, while accounting for potential confounding factors, are imperative to elucidate the optimal aspirin dosage, timing of initiation, and treatment duration for preventing preterm birth and to arrive at definitive conclusions.

Aspirin administration from early pregnancy versus initiation after 11 weeks of gestation for prevention of pre-eclampsia in high-risk pregnant women: Study protocol for randomized controlled trial.

Pre-eclampsia (PE) is a multiorgan disorder that affects 2-5% of all pregnant women. Present recommendations for when to start aspirin in high-risk women are after 11 wk of gestation. We present a protocol to investigate the effectiveness of aspirin use from early pregnancy, which is a randomized controlled trial to assess whether prescribed low-dose aspirin from early pregnancy reduces the prevalence of early and late-onset PE. Additionally, to compare the effectiveness of aspirin administration before and after 11 wk in reducing the occurrence of PE? All pregnancies at risk of PE, according to demographic and midwifery history, who are referred to the Maternal-Fetal Clinic of Tehran University hospital, Tehran, Iran were invited to take part in the trial. The outcomes of pregnancy and newborns will be gathered and analyzed. The first registration for the pilot study was in January 2023, and the participants were recognized as high-risk for PE. In addition, enrollment in the main study will begin as of October 2023.

First-trimester preterm preeclampsia prediction model for prevention with low-dose aspirin.

Preeclampsia (PE) is a major maternal and fetal threat. Previous risk-scoring methods in guidelines lacked precision. The Fetal Medicine Foundation (FMF) proposed a first-trimester PE screening model using Bayes' theorem. FMF prediction model combines maternal characteristics and medical/obstetrical history to determine prior risk and further incorporate maternal blood pressure, maternal serum biomarkers, and uterine Doppler pulsatility index expressed as multiples of the median (MoM) to estimate posterior risk. Low-dose aspirin is one ofthe potential PE prevention strategies. Initiating it before 16 weeks is crucial. Aspirin's antiplatelet and anti-inflammatory properties align with PE's pathophysiology. Dosing and resistance warrant further study, but a standard regimen of 150 mg nightly, starting before 16 weeks, is widely supported. Clinical trials, including ASPRE, affirm aspirin's role in PE prevention. Starting aspirin based on FMF screening significantly reduces preterm PE and associated complications. Emerging research explores predictors like maternal ophthalmic arterial waveform. Regional variations, especially in Asian populations, are considered. Machine learning and AI show promise, but examiner expertise remains essential for accurate prediction. In conclusion, integrating FMF's first-trimester PE screening with low-dose aspirin offers a promising strategy. Further advancements may enhance precision and broaden prevention efforts.

Low-dose aspirin use and risk of ovarian cancer: a combined analysis from two nationwide studies in Denmark and Sweden.

Studies on association between low-dose aspirin use and ovarian cancer risk were mostly based on self-reported medication use and few had large enough sample size to investigate the potential modification effect by ovarian cancer risk factors. In these two nationwide nested case-control studies among the Danish and Swedish female population, 11,874 women with ovarian cancer (30-84 years old) (Denmark: 7328 diagnosed in 2000-2019, Sweden: 4546 diagnosed in 2010-2018) were randomly age- matched with 473,960 female controls (293,120 from Denmark, and 181,840 from Sweden). We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) and combined the estimates based the fixed-effect assumption. Effect modification by inflammation-related risk factors and by indication (cardiovascular disease, CVD) were also investigated. Ever use of low-dose aspirin was not strongly associated with the overall risk of ovarian cancer (OR = 0.97; 95%CI: 0.92-1.03). However, the association differed according to parity (nulliparous: OR = 0.80, 95%CI: 0.70-0.92; parous: OR = 1.00, 95%CI: 0.94-1.07; p-interaction = 0.0024), and according to history of CVD (no CVD: OR = 0.91, 95%CI: 0.82-1.00; ever CVD: OR = 1.05, 95%CI: 0.97-1.13; p-interaction =0.0204). Low-dose aspirin use was associated with a decreased ovarian cancer risk especially in nulliparous women and in women without CVD diagnosis.

EFEKTIFITAS PEMBERIAN ASPIRIN DOSIS RENDAH UNTUK MENCEGAH PREEKLAMSIA DI RSPAL DR. RAMELAN SURABAYA

Background: Preeclampsia is a multisystem disorder in pregnancy. In developing countries, cases of preeclampsia are 7 times higher than in developed countries with a prevalence of 1.8%−18%. First-trimester screening needs to be done in detecting preeclampsia in every pregnant woman and preeclampsia prevention strategies with aspirin have proven effective in previous studies.&#x0D; Research Objectives: To determine the effectiveness of low-dose aspirin administration to prevent preeclampsia at dr. Ramelan for the period 13 June 2019 – 30 September 2021.&#x0D; Research Methods: The research design used in this study was descriptive using a retrospective cohort study. Researchers used secondary data in the form of patient medical records with a total sample of 118 patients.&#x0D; Results: From a total sample of 118 people, 30.5% had preeclampsia and 66.1% of patients who were given low-dose aspirin.&#x0D; Conclusion: Pregnant women who experienced preeclampsia after being given low-dose aspirin were recorded in 31 of 78 patients (39.7%) and pregnant women who experienced preeclampsia when not given low-dose aspirin were recorded in 5 of 40 patients (12.5%).&#x0D;

Low-dose aspirin initiation rates in appropriate candidates at an academic residency program in the midwest

Low-dose aspirin initiation rates in appropriate candidates at an academic residency program in the midwest

Nebulization of low-dose aspirin ameliorates Huntington's pathology in N171-82Q transgenic mice.

Huntington Disease (HD), a devastating hereditary neurodegenerative disorder, is caused by expanded CAG trinucleotide repeats in the huntingtin gene (Htt) on chromosome 4. Currently, there is no effective therapy for HD. Although aspirin, acetylsalicylic acid, is one of the most widely-used analgesics throughout the world, it has some side effects. Even at low doses, oral aspirin can cause gastrointestinal symptoms, such as heartburn, upset stomach, or pain. Therefore, to bypass the direct exposure of aspirin to stomach, here, we described a new mode of use of aspirin and demonstrated that nebulization of low-dose of aspirin (10 μg/mouse/d=0.4 mg/kg body wt/d roughly equivalent to 28 mg/adult human/d) alleviated HD pathology in N171-82Q transgenic mice. Our immunohistochemical and western blot studies showed that daily aspirin nebulization significantly reduced glial activation, inflammation and huntingtin pathology in striatum and cortex of N171-82Q mice. Aspirin nebulization also protected transgenic mice from brain volume shrinkage and improved general motor behaviors. Collectively, these results highlight that nebulization of low-dose aspirin may have therapeutic potential in the treatment of HD.

Antiplatelet resistance among a cohort of patients at risk of atherosclerotic cardiovascular diseases in Jos, Nigeria

Objectives: Patients with atherosclerotic cardiovascular diseases (ASCVDs) are predisposed to atherothrombosis and ischemic phenomena. Antiplatelets mitigate this but not consistently, as these ischemic events still occur despite their administration. This is called antiplatelet resistance. We sought to see how much of this occurs in our patients since its rate is bound to differ from place to place. The burden of antiplatelet resistance has not been determined in our environment. Material and Methods: Patients at risk of ASCVD who were receiving antiplatelet treatments were invited to participate in this study. They were enrolled first into a two week wash out phase, after which baseline aggregometry and full blood count were done. They were then given either Aspirin or Clopidogrel for four weeks and had the same blood work-up repeated. The Aggregometer was used to determine the platelet aggregability at these different times. If the second set showed &gt;10% reduction from baseline, such patients were adjudged sensitive. A reduction &lt;10% of the first value defined resistance. Results: Twenty patients (15 F/5 M) were in Group 1 and received a low dose of Aspirin (75 mg), the age range of 42–76 years, with a mean (standard deviation [SD]) of 60.75 (10.45). Twenty-six were in Group 2 (18 F/8 M) and received low dose clopidogrel (75 mg), with an age range of 23–87 years and a mean (SD) of 58.08 (14.18). Fifteen (75%) were sensitive in Group 1 (Aspirin) with 25% resistant. For Clopidogrel, 14 (53.85%) were sensitive and 12 (46.15%) resistant. In a few cases, the aggregability actually increased paradoxically on treatment. Conclusion: Antiplatelet resistance also occurs in our environment; it is worse for Clopidogrel than for Aspirin. These are people who, despite being on antiplatelets, would go on to develop these atherothrombotic ischemic phenomena. Efforts to identify the predictors of this phenomenon of resistance and work out effective counteractions should be encouraged.

The impact of antiphospholipid antibodies/antiphospholipid syndrome on systemic lupus erythematosus.

aPLs are a major determinant of the increased cardiovascular risk in patients with SLE. They adversely affect clinical manifestations, damage accrual and prognosis. Apart from the antibodies included in the 2006 revised classification criteria for APS, other non-classical aPLs might help in identifying SLE patients at increased risk of thrombotic events. The best studied are IgA anti-β2-glycoprotein I, anti-domain I β2-glycoprotein I and aPS-PT. Major organ involvement includes kidney and neuropsychiatric systems. aPL/APS severely impacts pregnancy outcomes. Due to increased thrombotic risk, these patients require aggressive cardiovascular risk factor control. Primary prophylaxis is based on low-dose aspirin in high-risk patients. Warfarin is the gold-standard drug for secondary prophylaxis.

Editor's Choice – Revascularisation for Peripheral Artery Disease in France: Implications for the Implementation of VOYAGER-PAD

The VOYAGER-PAD trial demonstrated the interest in dual pathway inhibition (DPI) (low dose rivaroxaban plus aspirin) to reduce limb and cardiovascular events after revascularisation for peripheral artery disease (PAD), but its applicability in clinical practice has not yet been assessed. This study aimed to assess the number of patients revascularised in France for PAD and to estimate the proportion of those matching the VOYAGER-PAD trial selection criteria. A secondary objective was to examine the prognosis of revascularised patients in a real world setting. This observational retrospective study was conducted on the national hospital discharge database and included all patients with PAD who underwent lower extremity revascularisation for PAD (without lower extremity revascularisation in the two years prior to inclusion) from 1 January 2016 to 31 December 2019. Available VOYAGER-PAD selection criteria were then applied to the study population. In total, 180 870 patients were included (mean age 72.0 ± 12.2 years, 30.9% female), with approximately 45000 patients revascularised annually. Among them, 90 379 (50.0%) matched the VOYAGER-PAD trial criteria (VOYAGER-PAD eligible subgroup; mean age 69.8 ± 12.1 years, 29.5% female). In the study population and the VOYAGER-PAD eligible subgroup, 33.9% and 26.6% of patients had diabetes, 28.1% and 19.9% had chronic coronary artery disease, and 14.6% and 5.7% had renal failure, respectively. Overall, 73.1% of study patients were treated by an endovascular approach (75.5% in the VOYAGER-PAD eligible subgroup). In patients with more than one year of follow up, 45.4% of study patients and 36.0% of the VOYAGER-PAD eligible subgroup experienced a limb or cardiovascular event. The median time until the first event and in hospital death was 4.8months and 7.8 months, respectively (6.7 months and 12.9 months in the VOYAGER-PAD eligible subgroup). The burden of PAD for revascularisation and secondary events is considerable. One half of revascularised patients in France are eligible for DPI therapy. Those patients are younger, with fewer comorbidities, and better outcomes.

Low-Dose Aspirin and Prevention of Colorectal Cancer: Evidence From a Nationwide Registry-Based Cohort in Norway.

To examine the association between low-dose aspirin use and risk of colorectal cancer (CRC). In this nationwide cohort study, we identified individuals aged 50 years or older residing for 6 months or more in Norway in 2004-2018 and obtained data from national registers on drug prescriptions, cancer occurrence, and sociodemographic factors. Multivariable Cox regression models were used to estimate the association between low-dose aspirin use and CRC risk. In addition, we calculated the number of CRC potentially averted by low-dose aspirin use. We included 2,186,390 individuals. During the median follow-up of 10.9 years, 579,196 (26.5%) used low-dose aspirin, and 38,577 (1.8%) were diagnosed with CRC. Current use of aspirin vs never use was associated with lower CRC risk (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.84-0.90). The association was more pronounced for metastatic CRC (HR 0.79; 95% CI 0.74-0.84) than regionally advanced (HR 0.89; 95% CI 0.85-0.92) and localized CRC (HR 0.93; 95% CI 0.87-1.00; P heterogeneity = 0.001). A significant trend was found between duration of current use and CRC risk: HR 0.91 (95% CI 0.86-0.95) for <3 years, HR 0.85 (0.80-0.91) for ≥3 and <5 years, and HR 0.84 (0.80-0.88) for ≥5 years of use vs never use ( P trend < 0.001). For past use, HR were 0.89 (95% CI 0.84-0.94) for <3 years, 0.90 (0.83-0.99) for ≥3 and <5 years, and 0.98 (0.91-1.06) for ≥5 years since last use vs never use ( P -trend < 0.001). We estimated that aspirin use averted 1,073 cases of CRC (95% CI 818-1,338) in the study period. In this nationwide cohort, use of low-dose aspirin was associated with a lower risk of CRC.

Integrating evidence and causal mapping of factors that influence medication decision-making by pregnant women at risk of hypertensive disorder: protocol for a scoping review

IntroductionIn 2018, the American College of Obstetricians and Gynecologists recommended low-dose aspirin to prevent the onset of pre-eclampsia among women who were at high risk. Factors influencing women’s acceptance of...

Digital gangrene: can be the first manifestation of essential thrombocythemia? a case report

Introduction and importance: Essential thrombocythemia (ET) is a rare chronic myeloproliferative hematologic disorder, leading to an elevated platelet count. Two-thirds of patients are asymptomatic during their lifetime, while others may experience symptoms like redness, congestion, and erythromelalgia after long symptom-free intervals. Case presentation: The authors present a rare instance of a 55-year-old female who, despite receiving aspirin and losartan treatment, eventually developed digital gangrene. In further work-ups, she had an elevated platelet count and a positive JAK 2 mutation. Her platelet count was reduced throughout treatment with aspirin, hydroxyurea, and heparin, which was followed by the necrotic tip of her index finger being surgically debrided. Clinical discussion: Significant symptoms, such as severe acrocyanosis and even peripheral gangrene, can be treated with a single dose of aspirin. Daily aspirin consumption withstanding, this case developed the severe form of ET. In addition, while thrombocytosis predisposes patients to thrombotic complications in theory, there is little evidence to support a correlation between absolute platelet count and thrombosis. Conclusion: The initial symptom of ET could be such severe and uncommon that may develop arterial acral thrombosis despite previous daily low-dose aspirin consumption.

Persistent pulmonary hypertension of the newborn infant (PPHN) due to premature closure of the ductus arteriosus (DA)

Abstract Objectives To describe the course of an infant with persistent pulmonary hypertension of the newborn (PPHN) secondary to premature closure of the ductus arteriosus (DA), a very rare phenomenon which can lead to adverse clinical outcomes. Case presentation A term infant was diagnosed with severe PPHN with echocardiographic features noted at 6 h after birth which included supra-systemic pulmonary pressures, severe isolated right ventricle (RV) hypertrophy, poor RV dysfunction and no ductal flow in the context of a structurally normal heart. There was maternal use of low-dose aspirin in pregnancy due to preeclampsia. There is a known association between use of prostaglandin synthase inhibitors such as aspirin with ductal closure leading to increased RV pressure. Treatment was commenced with positive pressure ventilation, inhaled nitric oxide (iNO) and milrinone. There was a limited response to iNO necessitating increasing the concentration of milrinone with a marked improvement in oxygenation. Following commencement of sildenafil, inhaled nitric oxide was gradually weaned and stopped in the third week and the infant extubated. The infant was discharged home on oral sildenafil at four weeks of age with no respiratory or feeding support. Echocardiographic features of raised right sided pressures persisted, but with reduced RV hypertrophy and septal flattening and improved RV function. Oral sildenafil was subsequently weaned and stopped at four months of age. Conclusions A severe form of PPHN due to premature closure of the DA requires early discussion with the cardiologist. The use of milrinone and sildenafil can lead to a favourable outcome.

Platelets and Thrombotic Antiphospholipid Syndrome

Antiphospholipid antibody syndrome (APS) is an autoimmune disorder characterised by thrombosis and the presence of antiphospholipid antibodies (aPL): lupus anticoagulant and/or IgG/IgM anti-β2-glycoprotein I and anticardiolipin antibodies. APS carries significant morbidity for a relatively young patient population from recurrent thrombosis in any vascular bed (arterial, venous, or microvascular), often despite current standard of care, which is anticoagulation with vitamin K antagonists (VKA). Platelets have established roles in thrombosis at any site, and platelet hyperreactivity is clearly demonstrated in the pathophysiology of APS. Together with excess thrombin generation, platelet activation and aggregation are the common end result of all the pathophysiological pathways leading to thrombosis in APS. However, antiplatelet therapies play little role in APS, reserved as a possible option of low dose aspirin in addition to VKA in arterial or refractory thrombosis. This review outlines the current evidence and mechanisms for excessive platelet activation in APS, how it plays a central role in APS-related thrombosis, what evidence for antiplatelets is available in clinical outcomes studies, and potential future avenues to define how to target platelet hyperreactivity better with minimal impact on haemostasis.

Potential impact on using aspirin as the primary prevention of adverse pregnancy outcomes in twins conceived using ART

With the development of assisted reproductive technology, the number of twin pregnancies is increasing year by year. Given the increased risk of pregnancy complications associated with twin pregnancies, and the fact that these babies are rare and difficult to obtain through assisted reproductive technology, clinicians urgently require finding effective and safe drugs to improve pregnancy outcomes. Low-dose aspirin can not only promote placental blood supply, but also effectively anti-inflammatory. Whether Low-dose aspirin can effectively reduce the risk of pregnancy complications in this special group needs to be clarified. We therefore retrospectively analyzed 665 twin pregnancies from assisted reproduction technology, grouped according to aspirin use, and followed pregnancy outcomes to assess bleeding risk. Low-dose aspirin was found to be effective in preventing preeclampsia without a significant risk of bleeding. However, aspirin does not prevent specific complication in twin pregnancies and seems to have a better preventive effect only when the mother is under 30, which should alarm clinicians should not blindly using aspirin in this particular group.

A randomized, placebo-controlled crossover trial to assess the influence of body weight on aspirin-triggered specialized pro-resolving mediators: Protocol for the DISCOVER Study.

Low-dose aspirin is ineffective for primary prevention of cardiovascular events in people with body weight greater than 70kg. While the prevalent explanation for this is reduced platelet cyclooxygenase-1 (COX-1) inhibition at higher body weights, supporting data are limited, thereby demanding further investigation of the reason(s) underlying this observation. We propose that aspirin-mediated cyclooxygenase-2 (COX-2) acetylation and the resulting synthesis of 15-epi-lipoxin A4, a specialized pro-resolving mediator, is suboptimal in higher weight individuals, which may contribute to the clinical trial findings. To test this hypothesis, we are conducting a double-blind, placebo-controlled, randomized, mechanistic crossover trial. Healthy men and women exhibiting a wide range of body weights take 81mg aspirin and 325mg aspirin for 3 weeks each, following 3-week placebo run-in and wash-out phases. Our target sample size is 90 subjects, with a minimum of 72 completing all visits estimated to be necessary to achieve power adequate to test our primary hypothesis. Our primary endpoint is the difference in change in plasma 15-epi-lipoxin A4 occurring with each dose of aspirin. Secondary endpoints include lipid mediator profiles, serum bioactive lipid profiles, and other endpoints involved in the resolution of vascular inflammation. Study enrollment began in November 2021 and is ongoing. The results of this study will improve our understanding of the mechanisms underlying aspirin's role(s) in the prevention of adverse cardiovascular outcomes. They may also lead to additional studies with the potential to inform dosing strategies for patients based on body weight.