The synthesis of complex organic molecules requires several stages, from ideation to execution, that require time and effort investment from expert chemists. Here, we report a step toward a paradigm ...of chemical synthesis that relieves chemists from routine tasks, combining artificial intelligence-driven synthesis planning and a robotically controlled experimental platform. Synthetic routes are proposed through generalization of millions of published chemical reactions and validated in silico to maximize their likelihood of success. Additional implementation details are determined by expert chemists and recorded in reusable recipe files, which are executed by a modular continuous-flow platform that is automatically reconfigured by a robotic arm to set up the required unit operations and carry out the reaction. This strategy for computer-augmented chemical synthesis is demonstrated for 15 drug or drug-like substances.
In a randomized, double-blind, placebo-controlled phase 3 trial of the ChAdOx1 nCoV-19 vaccine in over 32,000 participants from the United States, Chile, and Peru, the incidence of serious adverse ...effects was low (including no cases of vaccine-induced immune thrombotic thrombocytopenia) and the vaccine efficacy was 74%. Efficacy was documented in a range of demographic subgroups.
In recent years, Asian lineage Zika virus (ZIKV) strains emerged to cause pandemic outbreaks associated with a high rate of congenital ZIKV syndrome (CZVS). The reasons for the enhanced spread and ...severe disease caused by newly emerging strains are not fully understood. Here we compared viral sequences, viral replication, and innate immune signaling induction of three different ZIKV strains derived from African and Asian lineages and West Nile virus, another flavivirus. We found pronounced differences in activation of innate immune signaling and inhibition of viral replication across ZIKV strains. The newly emerged Asian ZIKV strain Brazil Fortaleza 2015, which is associated with a higher rate of neurodevelopmental disorders like microcephaly, induced much weaker and delayed innate immune signaling in infected cells. However, superinfection studies to assess control of innate immune signaling induced by Sendai virus argue against an active block of IRF3 activation by the Brazilian strain of ZIKV and rather suggest an evasion of detection by host cell pattern recognition receptors. Compared to the Asian strain FSS13025 isolated in Cambodia, both ZIKV Uganda MR766 and ZIKV Brazil Fortaleza appear less sensitive to the interferon-induced antiviral response. ZIKV infection studies of cells lacking the different RIG-I-like receptors identified RIG-I as the major cytosolic pattern recognition receptor for detection of ZIKV.
Zika Virus (ZIKV), discovered in 1947, is divided into African and Asian lineages. Pandemic outbreaks caused by currently emerging Asian lineage strains are accompanied by high rates of neurological disorders and exemplify the global health burden associated with this virus. Here we compared virological and innate immunological aspects of two ZIKV strains from the Asian lineage, an emerging Brazilian strain and a less-pathogenic Cambodian strain, and the prototypic African lineage ZIKV strain from Uganda. Compared to the replication of other ZIKV strains, the replication of ZIKV Brazil was less sensitive to the antiviral actions of interferon (IFN), while infection with this strain induced weaker and delayed innate immune responses
Our data suggest that ZIKV Brazil directs a passive strategy of innate immune evasion that is reminiscent of a stealth virus. Such strain-specific properties likely contribute to differential pathogenesis and should be taken into consideration when choosing virus strains for future molecular studies.
Summary Background Clinical effectiveness of previous regimens to treat Plasmodium vivax infection have been hampered by compliance. We aimed to assess the dose–response, safety, and tolerability of ...single-dose tafenoquine plus 3-day chloroquine for P vivax malaria radical cure. Methods In this double-blind, randomised, dose-ranging phase 2b study, men and women (aged ≥16 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to <100 000 per μL blood) were enrolled from community health centres and hospitals across seven sites in Brazil, Peru, India, and Thailand. Patients with glucose-6-phosphate dehydrogenase enzyme activity of less than 70% were excluded. Eligible patients received chloroquine (days 1–3) and were randomly assigned (1:1:1:1:1:1) by a computer-generated randomisation schedule to receive single-dose tafenoquine 50 mg, 100 mg, 300 mg, or 600 mg, primaquine 15 mg for 14 days, or chloroquine alone. Randomisation was stratified by baseline parasite count (≤7500 and >7500 per μL blood). The primary efficacy endpoint was relapse-free efficacy at 6 months from initial dose (ie, clearance of initial infection without subsequent microscopically confirmed infection), analysed by intention to treat. This study is registered with ClinicalTrials.gov , number NCT01376167. Findings Between Sept 19, 2011, and March 25, 2013, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg n=55, 100 mg n=57, 300 mg n=57, 600 mg n=56; or to chloroquine plus primaquine n=50; or chloroquine alone n=54). Relapse-free efficacy at 6 months was 57·7% (95% CI 43–70) with tafenoquine 50 mg, 54·1% (40–66) with tafenoquine 100 mg, 89·2% (77–95) with tafenoquine 300 mg, 91·9% (80–97) with tafenoquine 600 mg, 77·3% (63–87) with primaquine, and 37·5% (23–52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51·7% 95% CI 35–69, p<0·0001, with tafenoquine 300 mg and 54·5% 38–71, p<0·0001, with tafenoquine 600 mg), as did primaquine (treatment difference 39·9% 21–59, p=0·0004). Adverse events were similar between treatments. 29 serious adverse events occurred in 26 (8%) of 329 patients; QT prolongation was the most common serious adverse event (11 3% of 329), occurring in five (2%) of 225 patients receiving tafenoquine, four (8%) of 50 patients receiving primaquine, and two (4%) of 54 patients receiving chloroquine alone, with no evidence of an additional effect on QT of chloroquine plus tafenoquine coadministration. Interpretation Single-dose tafenoquine 300 mg coadministered with chloroquine for P vivax malaria relapse prevention was more efficacious than chloroquine alone, with a similar safety profile. As a result, it has been selected for further clinical assessment in phase 3. Funding GlaxoSmithKline, Medicines for Malaria Venture.
Tafenoquine is an investigational 8-aminoquinoline for the prevention of Plasmodium vivax relapse. Tafenoquine has a long half-life and the potential for more convenient dosing, compared with the ...currently recommended 14-day primaquine regimen.
This randomized, active-control, double-blind trial was conducted in Bangkok, Thailand. Seventy patients with microscopically confirmed P. vivax were randomized (2:1) to tafenoquine 400 mg once daily for 3 days or 2500 mg total dose chloroquine phosphate (1500 mg chloroquine base) given over 3 days plus primaquine 15 mg daily for 14 days. Patients were followed to day 120.
Day 28 adequate clinical response rate in the per-protocol population was 93% (40/43) (90%CI 83-98%) with tafenoquine, and 100% (22/22) (90%CI 87-100%) with chloroquine/primaquine. Day 120 relapse prevention was 100% (35/35) with tafenoquine (90%CI 92-100%), and 95% (19/20) (90%CI 78-100%) with chloroquine/primaquine. Mean (SD) parasite, gametocyte and fever clearance times with tafenoquine were 82.5 h (32.3), 49.1 h (33.0), and 41.1 h (31.4) versus 40.0 h (15.7), 22.7 h (16.4), and 24.7 h (17.7) with chloroquine/primaquine, respectively. Peak methemoglobin was 1.4-25.6% (median 7.4%, mean 9.1%) in the tafenoquine arm, and 0.5-5.9% (median 1.5%, mean 1.9%) in the chloroquine/primaquine arm. There were no clinical symptoms of methemoglobinemia in any patient.
Although there was no difference in efficacy in this study, the slow rate of parasite, gametocyte and fever clearance indicates that tafenoquine should not be used as monotherapy for radical cure of P. vivax malaria. Also, monotherapy increases the potential risk of resistance developing to this long-acting agent. Clinical trials of single-dose tafenoquine 300 mg combined with standard 3-day chloroquine or artemisinin-based combination therapy are ongoing.
Clinicaltrials.gov NCT01290601.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BackgroundWe report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial.MethodsAdults at increased risk of SARS-CoV-2 infection were randomized ...(2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR-positive (RT-PCR-positive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2-seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively.FindingsData cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the double-blind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen.ConclusionAZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median follow-up (AZD1222 group) of 6 months.Trial registrationClinicalTrials.gov NCT04516746.FundingAstraZeneca; US government.
Since the inception of the Canadian Cardiovascular Society heart failure (HF) guidelines in 2006, much has changed in the care for patients with HF. Over the past decade, the HF Guidelines Committee ...has published regular updates. However, because of the major changes that have occurred, the Guidelines Committee believes that a comprehensive reassessment of the HF management recommendations is presently needed, with a view to producing a full and complete set of updated guidelines. The primary and secondary Canadian Cardiovascular Society HF panel members as well as external experts have reviewed clinically relevant literature to provide guidance for the practicing clinician. The 2017 HF guidelines provide updated guidance on the diagnosis and management (self-care, pharmacologic, nonpharmacologic, device, and referral) that should aid in day-to-day decisions for caring for patients with HF. Among specific issues covered are risk scores, the differences in management for HF with preserved vs reduced ejection fraction, exercise and rehabilitation, implantable devices, revascularization, right ventricular dysfunction, anemia, and iron deficiency, cardiorenal syndrome, sleep apnea, cardiomyopathies, HF in pregnancy, cardio-oncology, and myocarditis. We devoted attention to strategies and treatments to prevent HF, to the organization of HF care, comorbidity management, as well as practical issues around the timing of referral and follow-up care. Recognition and treatment of advanced HF is another important aspect of this update, including how to select advanced therapies as well as end of life considerations. Finally, we acknowledge the remaining gaps in evidence that need to be filled by future research.
Depuis la parution des Lignes directrices sur l’insuffisance cardiaque (IC) de la Société canadienne de cardiologie en 2006, les soins aux patients atteints de ce trouble ont connu d’importants changements. Au cours de la dernière décennie, le Comité des lignes directrices sur l’IC a publié des mises à jour périodiques. Toutefois, en raison des changements importants qui sont survenus, le Comité des lignes directrices a jugé qu’il était nécessaire de procéder à une réévaluation exhaustive des recommandations sur la prise en charge de l’IC afin de produire un ensemble complet de lignes directrices à jour. Les membres des comités primaire et secondaire sur l’IC de la Société canadienne de cardiologie, ainsi que des spécialistes externes, ont passé en revue la littérature pertinente afin d’indiquer aux cliniciens la marche à suivre. Les lignes directrices de 2017 donnent des indications sur le diagnostic et la prise en charge (autosoins, traitements pharmacologiques et non pharmacologiques, dispositifs et orientation des patients) destinées à faciliter la prise de décisions quotidiennes en matière de soins aux patients atteints d’IC. Parmi les questions abordées figurent notamment les cotes de risque, les différences de prise en charge selon qu’il s’agit d’IC à fraction d’éjection préservée ou réduite, l’activité physique et la réadaptation, les dispositifs implantables, la revascularisation, la dysfonction ventriculaire droite, l’anémie et la carence en fer, le syndrome cardiorénal, l’apnée du sommeil, les cardiomyopathies, l’IC pendant la grossesse, la cardio-oncologie et la myocardite. Le comité a apporté une attention particulière aux stratégies et aux traitements visant à prévenir l’IC, à l’organisation des soins aux patients atteints d’IC, à la prise en charge des comorbidités, ainsi qu’à des questions pratiques concernant les délais d’orientation du patient et les soins de suivi. La reconnaissance et le traitement de l’IC au stade avancé, et notamment le choix des thérapies à ce stade et les considérations en matière de fin de vie, représentent un autre aspect important de cette mise à jour. Enfin, le comité reconnaît les lacunes dans les données probantes qui subsistent et devront être comblées par les recherches futures.
Intranasal vaccination may induce protective local and systemic immune responses against respiratory pathogens. A number of intranasal SARS-CoV-2 vaccine candidates have achieved protection in ...pre-clinical challenge models, including ChAdOx1 nCoV-19 (AZD1222, University of Oxford / AstraZeneca).
We performed a single-centre open-label Phase I clinical trial of intranasal vaccination with ChAdOx1 nCoV-19 in healthy adults, using the existing formulation produced for intramuscular administration.
Thirty SARS-CoV-2 vaccine-naïve participants were allocated to receive 5 × 109 viral particles (VP, n=6), 2 × 1010 VP (n=12), or 5 × 1010 VP (n=12). Fourteen received second intranasal doses 28 days later. A further 12 received non-study intramuscular mRNA SARS-CoV-2 vaccination between study days 22 and 46.
To investigate intranasal ChAdOx1 nCoV-19 as a booster, six participants who had previously received two intramuscular doses of ChAdOx1 nCoV-19 and six who had received two intramuscular doses of BNT162b2 (Pfizer / BioNTech) were given a single intranasal dose of 5 × 1010 VP of ChAdOx1 nCoV-19.
Objectives were to assess safety (primary) and mucosal antibody responses (secondary).
Reactogenicity was mild or moderate. Antigen-specific mucosal antibody responses to intranasal vaccination were detectable in a minority of participants, rarely exceeding levels seen after SARS-CoV-2 infection. Systemic responses to intranasal vaccination were typically weaker than after intramuscular vaccination with ChAdOx1 nCoV-19. Antigen-specific mucosal antibody was detectable in participants who received an intramuscular mRNA vaccine after intranasal vaccination. Seven participants developed symptomatic SARS-CoV-2 infection.
This formulation of intranasal ChAdOx1 nCoV-19 showed an acceptable tolerability profile but induced neither a consistent mucosal antibody response nor a strong systemic response.
AstraZeneca.
Tafenoquine (TQ), a new 8-aminoquinoline with activity against all stages of the Plasmodium vivax life cycle, is being developed for the radical cure of acute P. vivax malaria in combination with ...chloroquine. The efficacy and exposure data from a pivotal phase 2b dose-ranging study were used to conduct exposure-response analyses for TQ after administration to subjects with P. vivax malaria. TQ exposure (i.e., area under the concentration-time curve AUC) and region (Thailand compared to Peru and Brazil) were found to be statistically significant predictors of clinical response based on multivariate logistic regression analyses. After accounting for region/country, the odds of being relapse free at 6 months increased by approximately 51% (95% confidence intervals CI, 25%, 82%) for each 25-U increase in AUC above the median value of 54.5 μg · h/ml. TQ exposure was also a significant predictor of the time to relapse of the infection. The final parametric, time-to-event model for the time to relapse, included a Weibull distribution hazard function, AUC, and country as covariates. Based on the model, the risk of relapse decreased by 30% (95% CI, 17% to 42%) for every 25-U increase in AUC. Monte Carlo simulations indicated that the 300-mg dose of TQ would provide an AUC greater than the clinically relevant breakpoint obtained in a classification and regression tree (CART) analysis (56.4 μg · h/ml) in more than 90% of subjects and consequently result in a high probability of being relapse free at 6 months. This model-based approach was critical in selecting an appropriate phase 3 dose. (This study has been registered at ClinicalTrials.gov under registration no. NCT01376167.).
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