Sex disparities in efficacy in covid-19 vaccines: A systematic review and meta-analysis

Sex differences in adaptive and innate immune responses have been shown to occur and anecdotal reports suggest that vaccine efficacy and safety may be sex-dependent. We investigated the influence of sex on the efficacy of COVID-19 vaccines through a systematic review and meta-analysis of clinical trials on COVID-19 vaccines. The safety profile of COVID-19 vaccines was also investigated. A systematic review included eligible articles published in three databases and three websites. A meta-analysis of available data, stratified by sex, was conducted. Statistical analysis was performed using the Hartung\u2013Knapp\u2013Sidik\u2013Jonkman method, as well as influence and heterogeneity analysis. Pooled analysis showed significantly higher efficacy, measured as the rate of new COVID-19 cases, in men compared to women in the vaccine group (OR = 0.67, 95% CI 0.48\u20130.94). No sex differences were found in the rate of new cases in the control group (OR = 0.92, 95% CI 0.78\u20131.09). Safety profiles derived from pharmacovigilance reports appear to indicate increased toxicity in women. In conclusion, evidence of a potential role of sex in COVID-19 vaccine efficacy was described. It strengthens the need to include sex as a core variable in the clinical trial design of COVID-19 vaccines

Population structure and evolution of resistance to acetolactate synthase (ALS)-inhibitors in Amaranthus tuberculatus in Italy

6openInternationalBothBackground: Before 2010, Amaranthus tuberculatus (Moq.) J. D. Sauer was barely known to farmers and stakeholders in Italy. Since then, several populations resistant to acetolactate synthase (ALS)-inhibiting herbicides have been collected. In most populations, a known target site resistance-endowing mutation was found, a Trp to Leu substitution at position 574 of the ALS gene, but it was unclear whether they had evolved resistance independently or not. The aims of the work were (i) to elucidate the population structure of Italian ALS-resistant A. tuberculatus populations, and (ii) to analyze the ALS haplotypes of the various populations to determine whether resistance arose multiple times independently. Results: In order to determine the population structure of eight A. tuberculatus populations, eight previously described microsatellite loci were used. Two ancestors were found: three populations derived from one, and five from the other. In the 4-kb ALS region of the genome, including the 2-kb coding region, 389 single nucleotide polymorphisms were found. In silico haplotype estimation was used to reconstruct the sequence of three distinct haplotypes carrying the Trp574Leu mutation. In addition, no mutation was found in 83% of plants of a single population. Conclusions: (i) Resistance must have arisen independently at least three times; (ii) at least one population was already resistant to ALS inhibitors when introduced in Italy; (iii) a single haplotype with a Trp574Leu mutation was shared among six populations, probably because of broad seed dispersal; and (iv) one population likely evolved nontarget site ALS inhibitors resistance.openMilani, A.; Lutz, U.; Galla, G.; Scarabel, L.; Weigel, D.; Sattin, M.Milani, A.; Lutz, U.; Galla, G.; Scarabel, L.; Weigel, D.; Sattin, M

Rare genetic variant burden in DPYD predicts severe fluoropyrimidine-related toxicity risk

Preemptive targeted pharmacogenetic testing of candidate variations in DPYD is currently being used to limit toxicity associated with fluoropyrimidines. The use of innovative next generation sequencing (NGS) approaches could unveil additional rare (minor allele frequency <1%) genetic risk variants. However, their predictive value and management in clinical practice are still controversial, at least partly due to the challenges associated with functional analyses of rare variants. The aim of this study was to define the predictive power of rare DPYD variants burden on the risk of severe fluoropyrimidine-related toxicity. The DPYD coding sequence and untranslated regions were analyzed by NGS in 120 patients developing grade 3–5 (NCI-CTC vs3.0) fluoropyrimidine-related toxicity and 104 matched controls (no-toxicity). The functional impact of rare variants was assessed using two different in silico predictive tools (i.e., Predict2SNP and ADME Prediction Framework) and structural modeling. Plasma concentrations of uracil (U) and dihydrouracil (UH2) were quantified in carriers of the novel variants. Here, we demonstrate that the burden of rare variants was significantly higher in patients with toxicity compared to controls (p = 0.007, Mann-Whitney test). Carriers of at least one rare missense DPYD variant had a 16-fold increased risk in the first cycle and an 11-fold increased risk during the entire course of chemotherapy of developing a severe adverse event compared to controls (p = 0.013 and p = 0.0250, respectively by multinomial regression model). Quantification of plasmatic U/UH2 metabolites and in silico visualization of the encoded protein were consistent with the predicted functional effect for the novel variations. Analysis and consideration of rare variants by DPYD-sequencing could improve prevention of severe toxicity of fluoropyrimidines and improve patients’ quality of life

Broad Resistance to ACCase Inhibiting Herbicides in a Ryegrass Population Is Due Only to a Cysteine to Arginine Mutation in the Target Enzyme

BACKGROUND: The design of sustainable weed management strategies requires a good understanding of the mechanisms by which weeds evolve resistance to herbicides. Here we have conducted a study on the mechanism of resistance to ACCase inhibiting herbicides in a Lolium multiflorum population (RG3) from the UK. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of plant phenotypes and genotypes showed that all the RG3 plants (72%) that contained the cysteine to arginine mutation at ACCase codon position 2088 were resistant to ACCase inhibiting herbicides. Whole plant dose response tests on predetermined wild and mutant 2088 genotypes from RG3 and a standard sensitive population indicated that the C2088R mutation is the only factor conferring resistance to all ten ACCase herbicides tested. The associated resistance indices ranged from 13 for clethodim to over 358 for diclofop-methyl. Clethodim, the most potent herbicide was significantly affected even when applied on small mutant plants at the peri-emergence and one leaf stages. CONCLUSION/SIGNIFICANCE: This study establishes the clear and unambiguous importance of the C2088R target site mutation in conferring broad resistance to ten commonly used ACCase inhibiting herbicides. It also demonstrates that low levels "creeping", multigenic, non target site resistance, is not always selected before single gene target site resistance appears in grass weed populations subjected to herbicide selection pressure

Herbicide resistance-endowing ACCase gene mutations in hexaploid wild oat (Avena fatua): insights into resistance evolution in a hexaploid species

Many herbicide-resistant weed species are polyploids, but far too little about the evolution of resistance mutations in polyploids is understood. Hexaploid wild oat (Avena fatua) is a global crop weed and many populations have evolved herbicide resistance. We studied plastidic acetyl-coenzyme A carboxylase (ACCase)-inhibiting herbicide resistance in hexaploid wild oat and revealed that resistant individuals can express one, two or three different plastidic ACCase gene resistance mutations (Ile-1781-Leu, Asp-2078-Gly and Cys-2088-Arg). Using ACCase resistance mutations as molecular markers, combined with genetic, molecular and biochemical approaches, we found in individual resistant wild-oat plants that (1) up to three unlinked ACCase gene loci assort independently following Mendelian laws for disomic inheritance, (2) all three of these homoeologous ACCase genes were transcribed, with each able to carry its own mutation and (3) in a hexaploid background, each individual ACCase resistance mutation confers relatively low-level herbicide resistance, in contrast to high-level resistance conferred by the same mutations in unrelated diploid weed species of the Poaceae (grass) family. Low resistance conferred by individual ACCase resistance mutations is likely due to a dilution effect by susceptible ACCase expressed by homoeologs in hexaploid wild oat and/or differential expression of homoeologous ACCase gene copies. Thus, polyploidy in hexaploid wild oat may slow resistance evolution. Evidence of coexisting non-target-site resistance mechanisms among wild-oat populations was also revealed. In all, these results demonstrate that herbicide resistance and its evolution can be more complex in hexaploid wild oat than in unrelated diploid grass weeds. Our data provide a starting point for the daunting task of understanding resistance evolution in polyploids

Base molecular para resistência a fluazifop-p-butyl em capim-camalote (rottboellia cochinchinensis) da Costa Rica

Rottboellia cochinchinensis is an annual grass weed species known as itchgrass, or “caminadora” in America´s Spanish speaking countries, and has become a major and troublesome weed in several crops. The application of fluazifop-P-butyl at recommended rates (125 g a.i. ha-1) was observed to be failing to control itchgrass in a field in San José, Upala county, Alajuela province, Costa Rica. Plants from the putative resistant R. cochinchinensis population survived fluazifop-P-butyl when treated with 250 g a.i. ha-1 (2X label rate) at the three- to four-leaf stage under greenhouse conditions. PCR amplification and sequencing of partial carboxyl transferase domain (CT) of the acetyl-CoA carboxylase (ACCase) gene were used to determine the molecular mechanism of resistance. A single non-synonymous point mutation from TGG (susceptible plants) to TGC (putative resistant plants) that leads to a Trp-2027-Cys substitution was found. This Trp-2027-Cys mutation is known to confer resistance to all aryloxyphenoxyproprionate (APP) herbicides to which fluazifop-P-butyl belongs. To the best of our knowledge, this is the first report of fluazifop-P-butyl resistance and a mutation at position 2027 for a Costa Rican R. cochinchinensis population.Rottboellia cochinchinensis, espécie de planta daninha anual conhecida como capim-camalote, ou “caminadora”, em países de língua espanhola das Américas, tornou-se uma planta daninha significativa e problemática em diversas culturas. Observou-se que a aplicação de fluazifop-p-butyl nas doses recomendadas (125 g i.a. ha-1) não conseguiu controlar capim-camalote em uma região em San José, condado de Upala, província de Alajuela, Costa Rica. As plantas da população supostamente resistente de R. cochinchinensis sobreviveram a fluazifop-p-butyl quando tratadas com 250 g i.a. ha-1 (2X a dose do rótulo) na fase de três a quatro folhas em condições de estufa. Amplificação e sequenciamento de reação em cadeia da polimerase de domínio de transferase de ácido carboxílico parcial (TC) do gene acetil-CoA carboxilase (ACCase) foram utilizados para determinar o mecanismo molecular de resistência. Foi encontrada uma mutação de ponto não sinônimo individual de TGG (plantas suscetíveis) para TGC (plantas supostamente resistentes) que conduz a uma substituição de Trp-2027-Cys. Sabe-se que essa mutação de Trp-2027-Cys confere resistência a todos os herbicidas ariloxifenoxipropionatos (AFP) a que fluazifop-p-butyl pertence. Pelo visto, este é o primeiro relato de resistência a fluazifop-p-butyl de uma mutação na posição 2027 para uma população costarriquenha de R. cochinchinensisWest Florida Research and Education Center, University of Florida/[]//United States of AmericaUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Agroalimentarias::Estación Experimental Agrícola Fabio Baudrit Moreno (EEAFBM