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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 -
Annals of Allergy, Asthma & Immunology... Mar 2024The 22-item sino-nasal outcome test (SNOT-22) is a frequently used patient-recorded outcome measure in patients with chronic rhinosinusitis with nasal polyps (CRSwNPs)....
BACKGROUND
The 22-item sino-nasal outcome test (SNOT-22) is a frequently used patient-recorded outcome measure in patients with chronic rhinosinusitis with nasal polyps (CRSwNPs). Objective findings of nasal polyps and paranasal sinus inflammation are frequently graded using nasal polyp score (NPS) and Lund-Mackay Score (LMS), respectively.
OBJECTIVE
To evaluate a novel, abbreviated, rhinology-focused, five-domain SNOT-5 questionnaire because we had anecdotally noticed a relative disconnect between SNOT-22 and endoscopy and imaging scores.
METHODS
We performed a retrospective, cross-sectional, single-center review of patients with CRSwNPs who had filled out a SNOT-22, along with post hoc-derived SNOT-5 scores, which were then assessed in relation to NPS and LMS.
RESULTS
A total of 129 patients were included in the analysis. SNOT-5 but not SNOT-22 scores significantly correlated vs either NPS (P < .005) and LMS (P < .001), whereas only SNOT-5 differed significantly when comparing the cohort's lowest and highest tertiles for mean LMS: 11.8 vs 16.8 (95% CI, 1.5-8.4; P < .01) and for mean NPS 12.4 vs 15.6 (95% CI, 0.5-5.9; P < .05).
CONCLUSION
In a retrospective, real-life cohort study of CRSwNP, there was a relative disconnect between the significant association of SNOT-5 but not SNOT-22 in relation to objective endoscopy and imaging measures. We, therefore, propose that further prospective intervention studies are indicated in CRSwNP to evaluate the SNOT-5 score including establishing the minimal clinically important difference.
Topics: Humans; Nasal Polyps; Sino-Nasal Outcome Test; Cohort Studies; Retrospective Studies; Cross-Sectional Studies; Rhinosinusitis; Rhinitis; Sinusitis; Chronic Disease; Endoscopy
PubMed: 37984707
DOI: 10.1016/j.anai.2023.11.011 -
Prostaglandins, Leukotrienes, and... Dec 2023A recent trial showed that high-dose docosahexaenoic acid (high-DHA) supplementation of infants born <29 weeks' gestation improves intelligence quotient (IQ) at five... (Randomized Controlled Trial)
Randomized Controlled Trial
Subgroup analyses of a randomized trial of DHA supplementation for infants born preterm with assessments of cognitive development up to 7-years of age: What happens in infants born <29 weeks' gestation?
A recent trial showed that high-dose docosahexaenoic acid (high-DHA) supplementation of infants born <29 weeks' gestation improves intelligence quotient (IQ) at five years' corrected age. However, this finding has not been detected by other trials of DHA, which either did not measure IQ or included more mature infants. We analyzed the subgroup of 204 infants born <29 weeks' from our earlier randomized trial of high-DHA (∼1 % total fatty acids) or standard-DHA (∼ 0.3 % total fatty acids). Participants were assessed for cognition at 18 months, and IQ and behavior at seven years' corrected age. No group differences were detected for mean cognitive, IQ or behavior scores. At 18 months, 18.8 % of children in the high-DHA group had a cognitive score <85, compared with 31.1 % of children in the standard-DHA group, but at seven years there was no difference. Although an underpowered post-hoc subgroup analysis, this study provides limited support to recommendations that infants born <29 weeks' gestation require supplemental DHA.
Topics: Infant, Newborn; Infant; Child; Female; Humans; Docosahexaenoic Acids; Infant, Premature; Dietary Supplements; Cognition; Fatty Acids
PubMed: 37979339
DOI: 10.1016/j.plefa.2023.102593 -
Plants (Basel, Switzerland) Oct 2023Identifying a congenially targeted production environment and understanding the effects of genotype by environmental interactions on the adaption of chickpea genotypes...
Identifying a congenially targeted production environment and understanding the effects of genotype by environmental interactions on the adaption of chickpea genotypes is essential for achieving an optimal yield stability. Different models like additive main effect and multiplicative interactions (AMMI 1, AMM2), weighted average absolute scores of BLUPs (WAASB), and genotype plus genotype-environment (GGE) interactions were used to understand their suitability in the precise estimation of variance and their interaction. Our experiment used genotypes that represent the West Asia-North Africa (WANA) region. This trial involved two different sowing dates, two distinct seasons, and three different locations, resulting in a total of 12 environments. Genotype IG 5871(G1) showed a lower heat susceptibility index (HSI) across environments under study. The first four interactions principal component axis (IPCA) explain 93.2% of variations with significant genotype-environment interactions. Considering the AMMI stability value (ASV), the genotypes IG5862(G7), IG5861(G6), ILC239(G40), IG6002(G26), and ILC1932(G39), showing ASV scores of 1.66, 1.80, 2.20, 2.60, and 2.84, respectively, were ranked as the most stable and are comparable to the weighted average absolute scores of BLUPs (WAASB) ranking of genotypes. The which-won-where pattern of genotype plus genotype-environment (GGE) interactions suggested that the target environment consists of one mega environment. IG5866(G10), IG5865(G9), IG5884(G14), and IG5862(G7) displayed higher stability, as they were nearer to the origin. The genotypes that exhibited a superior performance in the tested environments can serve as ideal parental lines for heat-stress tolerance breeding programs. The weighted average absolute scores of BLUPs (WAASB) serve as an ideal tool to discern the variations and identify the stable genotype among all methods.
PubMed: 37960048
DOI: 10.3390/plants12213691 -
Aging Clinical and Experimental Research Dec 2023The workload associated with caring for a person with dementia (PwD) could negatively affect informal caregivers' physical and mental health. According to the recent...
Psychobiological effects of an eHealth psychoeducational intervention to informal caregivers of persons with dementia: a pilot study during the COVID-19 pandemic in Italy.
BACKGROUND
The workload associated with caring for a person with dementia (PwD) could negatively affect informal caregivers' physical and mental health. According to the recent literature, there is a need for studies testing the implementation of affordable and accessible interventions for improving caregivers' well-being.
AIMS
This study aimed to explore the feasibility and effectiveness of an 8 week eHealth psychoeducation intervention held during the COVID-19 pandemic in Italy in reducing the psychological burden and neuroendocrine markers of stress in caregivers of PwD.
METHODS
Forty-one informal caregivers of PwD completed the eHealth psychoeducation intervention. Self-reported (i.e., caregiver burden, anxiety symptoms, depressive symptoms, and caregiver self-efficacy) and cortisol measurements were collected before and after the intervention.
RESULTS
Following the intervention, the caregivers' self-efficacy regarding the ability to respond to disruptive behaviours improved (t = - 2.817, p = 0.007), anxiety and burden levels decreased (state anxiety: t = 3.170, p = 0.003; trait anxiety: t = 2.327, p = 0.025; caregiver burden: t = 2.290, p = 0.027), while depressive symptoms and cortisol levels did not change significantly. Correlation analyses showed that the increase in self-efficacy was positively associated with the improvement of caregiver burden from pre- to post-intervention (r = 0.386, p = 0.014). The intervention had a low rate of dropout (n = 1, due to the patient's death) and high levels of appreciation.
DISCUSSION
The positive evidence and participation rate support the feasibility and effectiveness of the proposed eHealth psychoeducational intervention to meet the need for knowledge of disease management and possibly reduce detrimental effects on caregivers' psychological well-being.
CONCLUSION
Further placebo-controlled trials are needed to test the generalizability and specificity of our results.
Topics: Humans; Caregivers; Pilot Projects; Dementia; Hydrocortisone; Pandemics; COVID-19; Italy; Telemedicine; Quality of Life
PubMed: 37943404
DOI: 10.1007/s40520-023-02610-9 -
Gastroenterology Nursing : the Official...Providing education in medical procedures may ensure patients' compliance, reduce anxiety, and increase satisfaction. This randomized controlled research study was... (Randomized Controlled Trial)
Randomized Controlled Trial
Providing education in medical procedures may ensure patients' compliance, reduce anxiety, and increase satisfaction. This randomized controlled research study was conducted to determine the effect of video-assisted education on anxiety and satisfaction given before an endoscopic retrograde cholangiopancreatography procedure. A total of 70 patients participated between September 2017 and December 2018. Data were collected with the State-Trait Anxiety Inventory and the Visual Analogue Scale. Routine education was given to the control group, while routine education and video-assisted education were given to the intervention group. There was no difference between the state anxiety scores of the groups before the procedure ( p > .05). The state anxiety level of the intervention group was lower than that of the control group after the procedure ( p < .05). There was no significant difference between the trait anxiety scores of groups before and after the procedure ( p > .05). The postprocedure trait anxiety mean score of the intervention group decreased statistically significantly compared with the preprocedure mean score ( p < .05). The mean satisfaction score after the procedure was higher in the intervention group than in the control group ( p < .05). It was determined that video-assisted education decreased state and trait anxiety and increased satisfaction after the procedure.
Topics: Humans; Cholangiopancreatography, Endoscopic Retrograde; Anxiety; Anxiety Disorders; Personal Satisfaction; Patient Satisfaction
PubMed: 37935446
DOI: 10.1097/SGA.0000000000000781 -
Microbiology Spectrum Dec 2023Efficient strategies for HIV-1 cART-free virologic control are critical for ending the AIDS pandemic. The essential role of effector-memory CD8 T cells in controlling...
Efficient strategies for HIV-1 cART-free virologic control are critical for ending the AIDS pandemic. The essential role of effector-memory CD8 T cells in controlling viremia and eliminating virus-infected cells has made them a promising target for vaccine development. It has been previously reported that PD-1-based DNA vaccination was effective in inducing polyfunctional effector-memory CD8 T cells for AIDS virus control for 2 years in rhesus monkeys. This follow-up study extends the findings and shows that a viremia-free period of over 6 years was detected in two monkeys immunized with PD-1-based DNA vaccine against pathogenic SHIV infection in the absence of antiretroviral therapy. Long-term vaccine-induced memory T cell responses were detected. Our results warrant the clinical trials of PD-1-based DNA vaccines for achieving HIV-1 cART-free virologic control used either alone or in combination with other biomedical interventions.
Topics: Animals; Macaca mulatta; Simian Acquired Immunodeficiency Syndrome; CD8-Positive T-Lymphocytes; Simian Immunodeficiency Virus; Vaccines, DNA; Follow-Up Studies; Programmed Cell Death 1 Receptor; Vaccination; DNA; AIDS Vaccines
PubMed: 37921496
DOI: 10.1128/spectrum.03350-23 -
Current Stem Cell Research & Therapy Oct 2023The number of trials investigating mesenchymal stromal cells (MSCs) soars within 3 years which urges a study analysing emerging MSC treatment-related adverse events. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The number of trials investigating mesenchymal stromal cells (MSCs) soars within 3 years which urges a study analysing emerging MSC treatment-related adverse events.
AIM
To assess the safety of MSC therapy and provide solid evidence for clinical translation of MSC.
METHODS
A meta-analysis of randomized clinical trials (RCTs) published up to April 20th, 2023 was performed. Odds ratio (OR) and 95% confidential intervals (CIs) were used to display pooled results.
RESULTS
152 randomized clinical trials (RCTs) that incorporated 9228 individuals treated with MSCs from autologous or allogenic adipose tissue, bone marrow, Wharton's Jelly, and placenta tissue were included in the analysis. We discovered appropriate 21 MSC treatment-related adverse events (TRAEs), of which fever [OR, 1.61, 95% CI: 1.22-2.11, p<0.01] was the sole event that was closely associated with MSC therapy. MSCs also trended to lower the incidence rate of tachycardia [OR, 0.83, 95% CI: 0.64-1.09, p=0.14] and fatigue [OR, 0.18, 95% CI: 0.61-1.07, p=0.18]. A separate analysis of studies with long-term follow-up (more than 1 year) demonstrated the close relationship between MSCs and fever [OR, 1.75, 95% CI: 1.26-2.24, p<0.01]. The rest TRAEs did not associate themselves with MSC therapy. Dose-response was also conducted for fever, linearity was discovered between MSCs from allogeneic tissue and Wharton's Jelly and fever.
CONCLUSION
To date, our results suggest that fever is the only AE closely associated with MSCs.
PubMed: 37909436
DOI: 10.2174/011574888X179799231023060734 -
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