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

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Coupled Ocean-Atmosphere Summer Intraseasonal Oscillation over the Bay of Bengal

This study shows the active role of subsurface ocean temperature in the evolution of coupled intra-seasonal oscillation (ISO) in the Bay of Bengal (BoB) using multi-satellite observations and ocean analysis product. Satellite-derived humidity profiles obtained from the atmospheric infrared sounder (AIRS) show that intense rains over the BoB are associated with the moistening (drying) in the lower and mid-troposphere during the active (break) phase of summer intraseasonal oscillation (ISO). Anomalous moistening in the mid-troposphere up to 500 hPa ahead of the maximum precipitation band over north BoB gives a precursor signal for the northward movement of the rain band. During the active (break) phase, the upper-tropospheric positive (negative) temperature anomaly ahead of the maximum rain band also sets a precondition by heating the mid- to upper troposphere. Daily subsurface temperature from Global Ocean Data Assimilation System (GODAS) analysis show that during the active phase, tropospheric moistening (drying) coincides with the subsurface warm (cold) temperature up to 200-m depth. The upper ocean warms uniformly by \~ 1 degrees C during the active phase as compared to the break phase in the entire BoB. The presence of a thin warm layer below the maximum rain band creates an environment conducive to sustaining the active phase on the ISO time scale. A positive sea surface temperature (SST) anomaly along with upper ocean warming ahead of a rain band in the north BoB in association with lower and mid-tropospheric moistening sets a precondition for the northward movement of the rain band. The anomalous warming (cooling) in the thermocline is associated with deeper (shallower) thermocline depth 23 degrees isotherms (D23)] and coincides with the mixed-layer warmin

Identification and Development of Therapeutics for COVID-19

After emerging in China in late 2019, the novel Severe acute respiratory syndrome-like coronavirus 2 (SARS-CoV-2) spread worldwide and as of early 2021, continues to significantly impact most countries. Only a small number of coronaviruses are known to infect humans, and only two are associated with the severe outcomes associated with SARS-CoV-2: Severe acute respiratory syndrome-related coronavirus, a closely related species of SARS-CoV-2 that emerged in 2002, and Middle East respiratory syndrome-related coronavirus, which emerged in 2012. Both of these previous epidemics were controlled fairly rapidly through public health measures, and no vaccines or robust therapeutic interventions were identified. However, previous insights into the immune response to coronaviruses gained during the outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) have proved beneficial to identifying approaches to the treatment and prophylaxis of novel coronavirus disease 2019 (COVID-19). A number of potential therapeutics against SARS-CoV-2 and the resultant COVID-19 illness were rapidly identified, leading to a large number of clinical trials investigating a variety of possible therapeutic approaches being initiated early on in the pandemic. As a result, a small number of therapeutics have already been authorized by regulatory agencies such as the Food and Drug Administration (FDA) in the United States, and many other therapeutics remain under investigation. Here, we describe a range of approaches for the treatment of COVID-19, along with their proposed mechanisms of action and the current status of clinical investigation into each candidate. The status of these investigations will continue to evolve, and this review will be updated as progress is made

Coral reef resilience differs among islands within the Gulf of Mannar, southeast India, following successive coral bleaching events

We used a 12-yr data set of benthic cover (2005–2017), spanning two bleaching events, to assess changes in benthic cover and coral community composition along 21 islands within Gulf of Mannar (GoM), southeast India. Overall, between 2005 and 2017 reefs had a simultaneous decrease in relative coral cover (avg. =  − 36%) and increase in algal cover (avg. =  + 45%). Changes in benthic cover were not consistent among islands, ranging from − 34 to + 5% for coral cover and from − 0.3 to + 50% for algae. There was a spatial gradient in coral mortality, which increased among islands from west to east. However, there was a disconnect between coral loss and subsequent increases in algae. Algal cover increased more on islands in west GoM where coral loss was minimal. Environmental co-factors (coral cover, percent bleaching, degree heating weeks, fish densities, Chl-a, pollution) explained > 50% of the benthic cover responses to successive bleaching. Coral survival was favored on islands with higher fish densities and chlorophyll-a levels, and increases in algal cover were associated with higher measures of pollution from terrestrial runoff. Coral morphotypes differed in their response following successive bleaching resulting in changes in the relative abundance of different coral morphotypes. Existing climate projections (RCP8.5) indicate a 22-yr gap in the onset of annual severe bleaching (ASB) for reefs in the east versus west GoM, and ASB was ameliorated for all reefs under the RCP4.5 projections. There is limited knowledge of the resilience of GoM reefs, and this study identifies coral morphotypes and reefs that are most likely to recover or decline from successive bleaching, in the context of forecasts of the frequency of future bleaching events in GoM

Coral reef resilience differs among islands within the Gulf of Mannar, southeast India, following successive coral bleaching events

We used a 12-yr data set of benthic cover (2005�2017), spanning two bleaching events, to assess changes in benthic cover and coral community composition along 21 islands within Gulf of Mannar (GoM), southeast India. Overall, between 2005 and 2017 reefs had a simultaneous decrease in relative coral cover (avg. = ? 36%) and increase in algal cover (avg. = + 45%). Changes in benthic cover were not consistent among islands, ranging from ? 34 to + 5% for coral cover and from ? 0.3 to + 50% for algae. There was a spatial gradient in coral mortality, which increased among islands from west to east. However, there was a disconnect between coral loss and subsequent increases in algae. Algal cover increased more on islands in west GoM where coral loss was minimal. Environmental co-factors (coral cover, percent bleaching, degree heating weeks, fish densities, Chl-a, pollution) explained > 50% of the benthic cover responses to successive bleaching. Coral survival was favored on islands with higher fish densities and chlorophyll-a levels, and increases in algal cover were associated with higher measures of pollution from terrestrial runoff. Coral morphotypes differed in their response following successive bleaching resulting in changes in the relative abundance of different coral morphotypes. Existing climate projections (RCP8.5) indicate a 22-yr gap in the onset of annual severe bleaching (ASB) for reefs in the east versus west GoM, and ASB was ameliorated for all reefs under the RCP4.5 projections. There is limited knowledge of the resilience of GoM reefs, and this study identifies coral morphotypes and reefs that are most likely to recover or decline from successive bleaching, in the context of forecasts of the frequency of future bleaching events in GoM. � 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.Climate projections for GoM were done under the Third NATCOM (National Communication) to the United Nations Framework Convention on Climate Change (UNFCCC) project of Ministry of Environment, Forest and Climate Change (MoEF & CC), Government of India�(GOI). The authors are thankful to the MoEF & CC,�GOI; Tamil Nadu Forest Department (TNFD), Government of Tamil Nadu (GOTN); Department of Environment, GOTN; Gulf of Mannar Biosphere Reserve Trust, GOTN; Coral Reef Degradation in Indian Ocean, Sweden; and V.O.Chidambaranar Port Trust (VOCPT), GOI for funding support. Thanks are also due to Chief Wildlife Warden, TNFD; Wildlife Warden, Gulf of Mannar Marine National Park (GOMMNP), GOTN; and Chairman, VOCPT, GOI, for research permissions to carry out coral reef surveys and monitoring within the Marine National Park and harbour area and to Suganthi Devadason Marine Research Institute for logistical support.�Any use of trade, firm, or product names is for descriptive purposes only and does not imply endorsement by the U.S. Government.Scopu