Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation

Controlled release of the hammerhead ribozyme from biodegradable PLGA encapsulation

Due to the character of the original source materials and the nature of batch digitization, quality control issues may be present in this document. Please report any quality issues you encounter to [email protected], referencing the URI of the item.Includes bibliographical references (leaves 111-120).Issued also on microfiche from Lange Micrographics.The hammerhead ribozyme is a well-characterized motif that can catalyze the cleavage of a phosphodiester bond in a substrate-RNA backbone. This cleavage activity finds potential applications in ribozyme gene therapy by targeting the mRNA that code for proteins associated with diseases. Successful applications of this strategy have been demonstrated in treatment of AIDS, cancer and Alzheimer's disease. It is therefore of interest to be able to deliver the hammerhead ribozyme as a drug for therapeutic applications. PLGA (Poly-Lactide-co-Glyolide) is an FDA approved and extensively characterized biodegradable controlled release system for drug delivery. These copolymer systems are preferred over conventional modes as they release the drug at a constant rate and are more patient compliant. This work explores the drug delivery aspects of the hammerhead ribozyme from two kinds of PLGA formulations, which have a ratio of lactide to glycolide of 65:35 and 85:15. The encapsulation has been done by a pressure quench method using supercritical CO₂, a technique not explored so far for nucleic acids. Studies done in this work reveal that the ribozyme can be encapsulated and released in its active form from a PLGA formulation, in a controlled fashion. However, it is observed that slowing down the rate of release is associated with greater degradation of RNA and a reduction in activity, particularly in a formulation with increased lactide content. These effects are attributed to the acidic pH generated in the polymer environment during degradation. The three-dimensional conformation of the hammerhead ribozyme is known to be critical for its activity. Electron Paramagnetic Resonance (EPR) spectroscopy using site-directed-spin-labeling (SDSL) of the ribozyme, with nitroxide labels covalently attached to the 5'-ends of stems I and III, has been explored as a tool for conformational analysis of the ribozyme, in view of extending the studies to probe the ribozyme for conformational changes in the polymer microenvironment. The results of these studies suggest that the distances between the 5'-ends of stems I and III are greater than 25 A[] as predicted by crystallographic studies. There is also evidence for the two-step folding mechanism predicted from fluorescence studies. It is expected that the two facets explored in the current work can contribute towards achieving an efficient drug delivery vehicle for the hammerhead ribozyme, and probing conformational changes related to its activity

Prevention of diabetes in rural India with a telemedicine intervention

Background : Diabetes care is not presently available, accessible, or affordable to people living in rural areas in developing countries, such as India. The Chunampet Rural Diabetes Prevention Project (CRDPP) was conceived with the aim of implementing comprehensive diabetes screening, prevention, and treatment using a combination of telemedicine and personalized care in rural India.Methods : This project was undertaken in a cluster of 42 villages in and around the Chunampet village in the state of Tamil Nadu in southern India. A telemedicine van was used to screen for diabetes and its complications using retinal photography, Doppler imaging, biothesiometry, and electrocardiography using standardized techniques. A rural diabetes center was set up to provide basic diabetes care.Results : Of the total 27,014 adult population living in 42 villages, 23,380 (86.5%) were screened for diabetes, of which 1138 (4.9%) had diabetes and 3410 (14.6%) had prediabetes. A total of 1001 diabetes subjects were screened for complications (response rate of 88.0%). Diabetic retinopathy was detected in 18.2%, neuropathy in 30.9%, microalbuminuria in 24.3%, peripheral vascular disease in 7.3%, and coronary artery disease in 10.8%. The mean hemoglobin A1c levels among the diabetes subjects in the whole community decreased from9.3 ± 2.6% to 8.5 ± 2.4% within 1 year. Less than 5% of patients needed referral for further management to the tertiary diabetes hospital in Chennai

Causes and predictors of mortality in Asian Indians with and without diabetes-10 year follow-up of the Chennai Urban Rural Epidemiology Study (CURES - 150).

BACKGROUND:The incidence and prevalence of diabetes is increasing worldwide and it is the fifth leading cause of mortality accounting for over 3.8 million deaths annually. Despite the enormity of the diabetes-related health burdens, very few studies have evaluated the factors associated with mortality among people with diabetes in India. We sought to study the causes and predictors of mortality among urban Asian Indians with and without diabetes. METHODS AND FINDINGS:Of 2273 adults (27,850 person-years of follow-up) from the 10-year follow-up of the Chennai Urban Rural Epidemiology Study (CURES), the cause of death could be ascertained in 552 individuals out of the 671 who had died (response rate 82.3%). Verbal autopsy was obtained from the family members of the deceased and this was adjudicated by trained physicians. The age-standardized mortality rate was 28.2 (95%CI 25.9-30.6) per 100,000 population. Mortality rates were significantly higher in individuals with diabetes compared to those without [27.9(95% CI 25.5-30.6) vs. 8.0 (6.6-9.9) per 1000 person years]. Compared to individuals of normal body mass index, underweight individuals had higher risk of mortality (Hazard ratio 1.49; 95% CI 1.11-2.0), whereas overweight and obese individuals did not show a higher risk. The population-attributable risk for all-cause mortality in the entire study cohort was highest for ischemic heart disease and diabetes. The excess mortality attributable to diabetes was highest in the age group of 51 to 70 years, and was mostly accounted for by renal disease (Rate ratio 5.68, 95%CI 2.43-6.23), ischemic heart disease (4.23,2.78-6.67), and cerebrovascular disease (4.00,1.87-9.81). CONCLUSION:Underweight (but not overweight or obesity) was strongly associated with mortality in this Asian Indian population. Ischemic heart disease and diabetes contributed the most to risk for all cause mortality. Excess mortality due to diabetes was higher in relatively younger individuals and was mostly accounted for by renal disease