Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001). Interpretation: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial

Background: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.Methods: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16,

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

Changes introduced in the open reading frame of bovine viral diarrhea virus during serial infection of pregnant swine

Bovine viral diarrhea virus (BVDV) is one of the most economically important viruses of cattle, but this pathogen is also able to infect pigs, camelids, and a wide range of domestic and wild ruminants. BVDV isolates circulating in animal populations are genetically and antigenically highly diverse. Acute BVDV infections in cattle cause the introduction of many substitutions in the viral genome. Serial infection of pregnant sheep with a BVDV-1b isolate of bovine origin was also associated with great numbers of substitutions. To our knowledge, genomic changes arising during BVDV infections in swine have not been investigated. The purpose of this study was to investigate the changes occurring in the open reading frame (ORF) of BVDV during serial infection of pregnant swine with a BVDV isolate of bovine origin. The BVDV-1b isolate AU526 was serially passaged in six pregnant gilts, two of which gave birth to live piglets congenitally infected with BVDV. The complete ORF sequences of 14 BVDV isolates obtained from pregnant gilts and their piglets were determined. Their analysis revealed that serial transmission of AU526 in pregnant swine resulted in many genomic changes. All isolates of porcine origin shared 32 nucleotide and 12 amino acid differences with the virus inoculum AU526. These changes were detected after a single passage in pregnant swine and were conserved during the subsequent five passages. Amino acid changes occurred primarily in genomic regions encoding the BVDV structural proteins E2 and E rns . These results suggest that BVDV infections in pregnant swine may contribute significantly to the genetic variability of BVDV and lead to the appearance of adaptive changes

Identification of Conserved Amino Acid Substitutions During Serial Infection of Pregnant Cattle and Sheep With Bovine Viral Diarrhea Virus

Bovine viral diarrhea virus (BVDV) is an economically important pathogen of cattle that can also infect a wide range of domestic and wild species including sheep, goats, deer, camelids, and pigs. BVDV isolates are genetically highly diverse and previous work demonstrated that many substitutions were introduced in the viral genome during acute infections in cattle. In contrast, only limited information exists regarding changes occurring during BVDV infections in species other than cattle. The purpose of this study was to determine the changes introduced in the open reading frame (ORF) of the BVDV genome during serial infection of pregnant cattle and sheep with an isolate of bovine origin. Serial experimental inoculations were performed in six pregnant heifers and six pregnant ewes using BVDV-1b isolate AU526 in the first heifer and ewe, and serum from the preceding acutely infected dam thereafter. Complete ORF sequences were determined for 23 BVDV-1b isolates including AU526, one isolate from each pregnant dam, and one isolate from each BVDV-positive offspring born to these dams. Sequence comparison revealed that greater numbers of substitutions occurred during serial infection of pregnant sheep than of pregnant cattle. Furthermore, multiple host-specific amino acid changes were gradually introduced and conserved. These changes were more abundant in ovine isolates and occurred primarily in the E2 coding region. These results suggest that BVDV infections in heterologous species may serve as a significant source of viral genetic diversity and may be associated with adaptive changes

Experimental infection of pregnant goats with bovine viral diarrhea virus (BVDV) 1 or 2

International audienceInfections with bovine viral diarrhea virus (BVDV) of the genus pestivirus, family Flaviviridae, are not limited to cattle but occur in various artiodactyls. Persistently infected (PI) cattle are the main source of BVDV. Persistent infections also occur in heterologous hosts such as sheep and deer. BVDV infections of goats commonly result in reproductive disease, but viable PI goats are rare. Using 2 BVDV isolates, previously demonstrated to cause PI cattle and white-tailed deer, this study evaluated the outcome of experimental infection of pregnant goats. Pregnant goats (5 goats/group) were intranasally inoculated with BVDV 1b AU526 (group 1) or BVDV 2 PA131 (group 2) at approximately 25–35 days of gestation. The outcome of infection varied considerably between groups. In group 1, only 3 does became viremic, and 1 doe gave birth to a stillborn fetus and a viable PI kid, which appeared healthy and shed BVDV continuously. In group 2, all does became viremic, 4/5 does aborted, and 1 doe gave birth to a non-viable PI kid. Immunohistochemistry demonstrated BVDV antigen in tissues of evaluated fetuses, with similar distribution but reduced intensity as compared to cattle. The genetic sequence of inoculated viruses was compared to those from PI kids and their dam. Most nucleotide changes in group 1 were present during the dam’s acute infection. In group 2, a similar number of mutations resulted from fetal infection as from maternal acute infection. Results demonstrated that BVDV may cause reproductive disease but may also be maintained in goats

Non-aqueous electrolyte solutions in chemistry and modern technology

In this paper a brief survey is given of the properties of non-aqueous electrolyte solutions and their applications in chemistry and technology without going into the details of theory. Specific solvent-solute interactions and the role of the solvent beyond its function as a homogenous isotropic medium are stressed. Taking into account Parker's statement1) ldquoScientists nowadays are under increasing pressure to consider the relevance of their research, and rightly sordquo we have included examples showing the increasing industrial interest in non-aqueous electrolyte solutions. The concepts and results are arranged in two parts. Part A concerns the fundamentals of thermodynamics, transport processes, spectroscopy and chemical kinetics of non-aqueous solutions and some applications in these fields. Part B describes their use in various technologies such as high-energy batteries, non-emissive electro-optic displays, photoelectrochemical cells, electrodeposition, electrolytic capacitors, electro-organic synthesis, metallurgic processes and others. Four Appendices are added. Appendix A gives a survey on the most important non-aqueous solvents, their physical properties and correlation parameters, and the commonly used abbreviations. Appendices B and C show the mathematical background of the general chemical model. The Symbols and abbreviations of the text are listed and explained in Appendix D