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Science Bulletin Dec 2023The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective...
The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike (S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the wild-type, B.1.1.7, B.1.351, B.1.617.2, and the newly emerging Omicron variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. Furthermore, our safety assessment of RQ3013 in NHP showed no observable adverse effects. These results provide strong support for the evaluation of RQ3013 in clinical trials and suggest that it may be a promising candidate for broad protection against COVID-19 and its variants.
Topics: Animals; Cricetinae; Mice; COVID-19; COVID-19 Vaccines; mRNA Vaccines; SARS-CoV-2; Primates; Immunogenicity, Vaccine; Broadly Neutralizing Antibodies; Antibodies, Viral
PubMed: 37993332
DOI: 10.1016/j.scib.2023.11.024 -
Nature Communications Nov 2023Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers...
Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition of these proteases and determine their complex structures with their respective targets. Furthermore, we show that applying inhibitors simultaneously that block both entry pathways has a synergistic antiviral effect. Notably, we devise a bispecific compound, 212-148, exhibiting the dual-inhibition ability of both TMPRSS2 and CTSL/CTSB, and demonstrate antiviral activity against various SARS-CoV-2 variants with different viral entry profiles. Our findings offer an alternative approach for the discovery of SARS-CoV-2 antivirals, as well as application for broad-spectrum treatment of viral pathogenic infections with similar entry pathways.
Topics: Humans; SARS-CoV-2; COVID-19; Antiviral Agents; Virus Internalization; Spike Glycoprotein, Coronavirus
PubMed: 37990007
DOI: 10.1038/s41467-023-42527-5 -
Nature Neuroscience Oct 2016Genome-wide association studies (GWAS) in psychiatry, once they reach sufficient sample size and power, have been enormously successful. The Psychiatric Genomics... (Review)
Review
Genome-wide association studies (GWAS) in psychiatry, once they reach sufficient sample size and power, have been enormously successful. The Psychiatric Genomics Consortium (PGC) aims for mega-analyses with sample sizes that will grow to >1 million individuals in the next 5 years. This should lead to hundreds of new findings for common genetic variants across nine psychiatric disorders studied by the PGC. The new targets discovered by GWAS have the potential to restart largely stalled psychiatric drug development pipelines, and the translation of GWAS findings into the clinic is a key aim of the recently funded phase 3 of the PGC. This is not without considerable technical challenges. These approaches complement the other main aim of GWAS studies, risk prediction approaches for improving detection, differential diagnosis, and clinical trial design. This paper outlines the motivations, technical and analytical issues, and the plans for translating PGC phase 3 findings into new therapeutics.
Topics: Animals; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Mental Disorders; Polymorphism, Single Nucleotide; Psychiatry; Risk Assessment
PubMed: 27786187
DOI: 10.1038/nn.4411 -
Cancers Dec 2022A tertiary lymphoid structure (TLS) is a special component in the immune microenvironment that is mainly composed of tumor-infiltrating lymphocytes (TILs), including T... (Review)
Review
A tertiary lymphoid structure (TLS) is a special component in the immune microenvironment that is mainly composed of tumor-infiltrating lymphocytes (TILs), including T cells, B cells, DC cells, and high endothelial venules (HEVs). For cancer patients, evaluation of the immune microenvironment has a predictive effect on tumor biological behavior, treatment methods, and prognosis. As a result, TLSs have begun to attract the attention of researchers as a new potential biomarker. However, the composition and mechanisms of TLSs are still unclear, and clinical detection methods are still being explored. Although some meaningful results have been obtained in clinical trials, there is still a long way to go before such methods can be applied in clinical practice. However, we believe that with the continuous progress of basic research and clinical trials, TLS detection and related treatment can benefit more and more patients. In this review, we generalize the definition and composition of TLSs, summarize clinical trials involving TLSs according to treatment methods, and describe possible methods of inducing TLS formation.
PubMed: 36497450
DOI: 10.3390/cancers14235968 -
Critical Care and Resuscitation :... Jun 2022The effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in patients who require unplanned invasive mechanical ventilation in an...
Protocol and statistical analysis plan for the mega randomised registry trial research program comparing conservative versus liberal oxygenation targets in adults receiving unplanned invasive mechanical ventilation in the ICU (Mega-ROX).
The effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in patients who require unplanned invasive mechanical ventilation in an intensive care unit (ICU) is uncertain and will be evaluated in the mega randomised registry trial research program (Mega-ROX). To summarise the protocol and statistical analysis plan for Mega-ROX. Mega-ROX is a 40 000-patient parallel-group, registry-embedded clinical trial in which adults who require unplanned invasive mechanical ventilation in an ICU will be randomly assigned to conservative or liberal oxygen therapy. Within this overarching trial research program, three nested parallel randomised controlled trials will be conducted. These will include patients with suspected hypoxic ischaemic encephalopathy (HIE) following resuscitation from a cardiac arrest, patients with sepsis, and patients with non-HIE acute brain injuries or conditions. The primary outcome is in-hospital allcause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and proportion of patients discharged home. Mega-ROX will compare the effect of conservative versus liberal oxygen therapy on 90-day in-hospital mortality in critically ill adults who receive unplanned invasive mechanical ventilation in an ICU. The protocol and a pre-specified approach to analyses are reported here to mitigate analysis bias. Australian and New Zealand Clinical Trials Registry (ANZCTRN 12620000391976).
PubMed: 38045600
DOI: 10.51893/2022.2.OA4 -
Critical Care and Resuscitation :... Mar 2023The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults who have nonhypoxic ischaemic encephalopathy acute brain injuries and...
Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with nonhypoxic ischaemic acute brain injuries and conditions in the intensive care unit (Mega-ROX Brains).
BACKGROUND
The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults who have nonhypoxic ischaemic encephalopathy acute brain injuries and conditions and are receiving invasive mechanical ventilation in the intensive care unit (ICU) is uncertain.
OBJECTIVE
The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Brains trial.
DESIGN SETTING AND PARTICIPANTS
Mega-ROX Brains is an international randomised clinical trial, which will be conducted within an overarching 40,000-participant, registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We expect to enrol between 7500 and 9500 participants with nonhypoxic ischaemic encephalopathy acute brain injuries and conditions who are receiving unplanned invasive mechanical ventilation in the ICU.
MAIN OUTCOME MEASURES
The primary outcome is in-hospital all-cause mortality up to 90 d from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of participants discharged home.
RESULTS AND CONCLUSIONS
Mega-ROX Brains will compare the effect of conservative vs. liberal oxygen therapy regimens on 90-day in-hospital mortality in adults in the ICU with acute brain injuries and conditions. The protocol and planned analyses are reported here to mitigate analysis bias.
TRIAL REGISTRATION
Australian and New Zealand Clinical Trials Registry (ACTRN 12620000391976).
PubMed: 37876994
DOI: 10.1016/j.ccrj.2023.04.011 -
The European Respiratory Journal Dec 2020https://bit.ly/3o0K9kl
https://bit.ly/3o0K9kl
Topics: COVID-19; Evidence-Based Medicine; Humans; Methylprednisolone; Pandemics; SARS-CoV-2; Steroids
PubMed: 33361452
DOI: 10.1183/13993003.04116-2020 -
Circulation. Arrhythmia and... Nov 2020The field of cardiac electrophysiology has been on the cutting edge of advanced digital technologies for many years. More recently, medical device development through... (Review)
Review
The field of cardiac electrophysiology has been on the cutting edge of advanced digital technologies for many years. More recently, medical device development through traditional clinical trials has been supplemented by direct to consumer products with advancement of wearables and health care apps. The rapid growth of innovation along with the mega-data generated has created challenges and opportunities. This review summarizes the regulatory landscape, applications to clinical practice, opportunities for virtual clinical trials, the use of artificial intelligence to streamline and interpret data, and integration into the electronic medical records and medical practice. Preparation of the new generation of physicians, guidance and promotion by professional societies, and advancement of research in the interpretation and application of big data and the impact of digital technologies on health outcomes will help to advance the adoption and the future of digital health care.
Topics: Arrhythmias, Cardiac; Artificial Intelligence; Attitude of Health Personnel; Attitude to Computers; Clinical Trials as Topic; Diffusion of Innovation; Electrophysiologic Techniques, Cardiac; Health Knowledge, Attitudes, Practice; Humans; Mobile Applications; Patient Participation; Predictive Value of Tests; Prognosis; Remote Sensing Technology; Smartphone; Telemedicine; Wearable Electronic Devices
PubMed: 33021815
DOI: 10.1161/CIRCEP.120.007953 -
BMJ Open Jul 2022Secondary schools have the transformative potential to advance adolescent nutrition and provide a unique entry point for nutrition interventions to reach adolescents and...
Meals, Education, and Gardens for In-School Adolescents (MEGA): study protocol for a cluster randomised trial of an integrated adolescent nutrition intervention in Dodoma, Tanzania.
INTRODUCTION
Secondary schools have the transformative potential to advance adolescent nutrition and provide a unique entry point for nutrition interventions to reach adolescents and their families and communities. Integrated school nutrition interventions offer promising pathways towards improving adolescent nutrition status, food security and building sustainable skill sets.
METHODS AND ANALYSIS
The Meals, Education, and Gardens for In-School Adolescents (MEGA) project aims to implement and evaluate an integrated, school-based nutrition intervention package among secondary schools in the Chamwino District of Dodoma, Tanzania. MEGA is a cluster-randomised controlled trial, including six public secondary schools assigned to three different arms. Two schools will receive the full intervention package, including school meals, school gardens, nutrition education and community workshops. Two schools will receive the partial intervention package, including the school garden, nutrition education and community workshops. Two schools will serve as the controls and will not receive any intervention. The intervention will be implemented for one academic year. Baseline and end-line quantitative data collection will include 750 adolescents and 750 parents. The domains of outcomes for adolescents will include haemoglobin concentrations, anthropometry, educational outcomes and knowledge, attitudes and practices regarding nutrition, agriculture and health. The domains of outcomes for parents will include knowledge, attitudes and practices of nutrition, agriculture and health. End-line focus group discussions will be conducted among selected adolescents, parents and teachers to assess the facilitators and barriers associated with the intervention.
ETHICS AND DISSEMINATION
This study was approved by the Institutional Review Board at Harvard T.H. Chan School of Public Health (approval number: IRB20-1623), the Institutional Research Review Committee at the University of Dodoma (approval number: MA.84/261/02) and the Tanzania National Institute for Medical Research (approval number: NIMR/HO/R.8a/Vol. IX/3801). A manuscript with the research findings will be developed for publication. Local dissemination meetings will be held with key stakeholders.
TRIAL REGISTRATION NUMBER
NCT04788303.; ClinicalTrials.gov Identifier.
Topics: Adolescent; Educational Status; Gardens; Humans; Meals; Randomized Controlled Trials as Topic; School Health Services; Schools; Tanzania
PubMed: 35798513
DOI: 10.1136/bmjopen-2022-062085 -
Critical Care and Resuscitation :... Jun 2023The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis receiving unplanned invasive mechanical ventilation in the...
Protocol and statistical analysis plan for the mega randomised registry trial comparing conservative vs. liberal oxygenation targets in adults with sepsis in the intensive care unit (Mega-ROX Sepsis).
BACKGROUND
The effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis receiving unplanned invasive mechanical ventilation in the intensive care unit (ICU) is uncertain.
OBJECTIVE
The objective of this study was to summarise the protocol and statistical analysis plan for the Mega-ROX Sepsis trial.
DESIGN SETTING AND PARTICIPANTS
The Mega-ROX Sepsis trial is an international randomised clinical trial that will be conducted within an overarching 40,000-patient registry-embedded clinical trial comparing conservative and liberal ICU oxygen therapy regimens. We anticipate that between 10,000 and 13,000 patients with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU will be enrolled in this trial.
MAIN OUTCOME MEASURES
The primary outcome is in-hospital all-cause mortality up to 90 days from the date of randomisation. Secondary outcomes include duration of survival, duration of mechanical ventilation, ICU length of stay, hospital length of stay, and the proportion of patients discharged home.
RESULTS AND CONCLUSIONS
Mega-ROX Sepsis will compare the effect of conservative vs. liberal oxygen therapy on 90-day in-hospital mortality in adults with sepsis who are receiving unplanned invasive mechanical ventilation in the ICU. The protocol and a prespecified approach to analyses are reported here to mitigate analysis bias.
PubMed: 37876605
DOI: 10.1016/j.ccrj.2023.04.008