The remarkable variability of response to vaccines against SARS-CoV-2 is apparent. The present study aims to estimate the extent to which the host genetic background contributes to this variability in terms of immune response and side effects following the administration of the BNT162b2 vaccine. We carried out a genome wide association study (GWAS) by genotyping 873 Italian healthcare workers who underwent anti-SARS-CoV-2 vaccination with the BNT162b2 vaccine and for whom information about anti-SARS-CoV-2 spike antibodies titers and vaccine side effects were available. The GWAS revealed a significant association between the HLA locus and the anti-SARS-CoV-2 Spike antibodies level at 2 months following the first dose of vaccine (SNP: rs1737060; p = 9.80 10-11 ). In particular, we observed a positive association between the antibody levels and the presence of the HLA-A*03:01 allele. The same allele was found associated with a 2-2.4-fold increased risk of experiencing specific side effects such as fever, chills and myalgia and a 1.5-1.8-fold increased risk of joint pain, nausea, fatigue, headache and asthenia, independently of age and sex. This study confirms that the heterogeneity in the immune response to the BNT162b2 vaccine and in its side effects are at least partially influenced by genetic variants. This information, integrated with individual biological and lifestyle-related correlates, could be of use in the definition of algorithms aimed at the identification of subjects in which the administration of additional vaccine doses would be particularly beneficial to maintain immunity against the virus.
Chemotherapy side effects (CSE) have a strong impact on patients' quality of life (QOL). To assess patient perceptions of CSE, their impact on QOL and doctor-patient communication regarding these aspects, a survey was conducted among Italian cancer patients. Patients at least 18 years of age, who received chemotherapy, were administered a dedicated questionnaire to assess their point of view on five domains: expectations about CSE and impact on QOL; doctor-patient communication about CSE; treatments to reduce the impact of CSE; sexual life; family relationships/activities and employment. A total of 761 patients participated. CSE had a considerable impact on patient QOL. Nausea/vomiting was the most feared adverse effect before initiating chemotherapy and the one most commonly experienced during treatment. Patients generally reported good doctor-patient communication regarding information about CSE. In almost all cases, the oncologists prescribed an antiemetic treatment, but the incidence of nausea/vomiting was high. Cancer and CSE severely affected sexual life, daily activities and employment. CSE had a strong negative impact on QOL. Good doctor-patient communication is essential. Improving antiemetic strategies may improve QOL. Doctors' ability to inform patients about delicate issues, such as the impact of CSE on sexual life, needs to be improved.
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Aquatic habitats, in which amphibians live, breed and develop, are easily contaminated by a range of pollutants, and in agricultural landscapes the likely exposure scenario is represented by pesticides1, 7. Many of these substances have been shown to exert their adverse effects through modulation and/or disruption of endocrine functions, and are known as endocrine disrupting chemicals (EDCs)2, 8,9,10,11. Given the crucial role of the endocrine system in the maintenance of numerous biological, physiological and behavioural functions, damage in any part of this complex system can lead to serious disease or death.
Over the past few years, fungicides use has significantly increased, especially in Europe, and as results of their repeated applications in agricultural practices they occur more frequently and/or in higher concentrations than other agrochemicals in all environmental compartments19,20,21,22,23 and references therein. In particular, fungicides are the most frequently detected agrochemicals in amphibian habitats and tissues24, 25. Available data indicate that fungicides, at environmentally relevant concentrations, can induce several harmful effects on amphibians, such as increased mortality and deformity1, 26, decreased and/or increased growth rate and development13, 15, 26, alteration of behaviour27, immunosuppression and lipid peroxidation28, 29. Most if not all of those harmful effects could be related to endocrine disturbance and a variety of fungicides are known or suspected to act as EDCs8,9,10,11, 15.
We recently demonstrated that a chronic exposure to pyrimethanil causes detrimental effects on survival, development, metamorphic traits, and body form in H. intermedia 26. However, in evaluating the effects of a toxicant in amphibians it is important to consider also lagged effects that may not become evident until metamorphosis2, 12.
Several studies in mammalian and fish models, both in vitro and in vivo, suggested that pyrimethanil may influence the biosynthesis of sexual hormones and/or interact with sexual hormone receptor thus acting as EDC10, 33. Given the fact that EDCs are responsible of many adverse reproductive outcomes in developing amphibians, we first evaluated gonads histology in order to identify putative effects on sex ratio and gonadal differentiation. EDCs may also act through broader mechanisms/pathways than firstly recognized, exerting different effects in a tissue specific manner14, therefore we also analysed morphological alterations in two organs highly susceptible to xenobiotic toxicity.
The kidney is an important site of injury after chemical exposure, due to their involvement in a number of interrelated functions (i.e. maintenance of internal water, ion, and acid-base balance, selective reabsorption and secretion, and excretion of nitrogenous and other waste products of metabolism)34, 35. The liver has long been considered the major target organ for most chemicals, including EDCs, in consequence of its essential functional features (i.e. maintaining of the metabolic homeostasis including protein synthesis, storage metabolites, detoxification)14, 34, 35.
By using a morphological approach we evaluated the differential response of three important target organs thus furnishing a comprehensive overview of pyrimethanil effects and toxicity. The individual recognition of animals exposed to the fungicide allowed us to analyse the results also in the light of our previous finding on development and deformity.
Histological examinations revealed, in liver of animals exposed to pyrimethanil, considerable morphological changes (Fig. 6). In samples from the low concentration group, the liver appeared highly vascularized and the numerous blood vessels appeared often occluded (Fig. 6a). The large amount of blood resulted in sinusoidal congestion and dilation giving to the liver a loose appearance (Fig. 6a). In addition, the liver parenchyma dyschromia, due to degenerative phenomena, was evident at higher magnification (Fig. 6b). In some areas, hepatocytes showed a clear, foamy cytoplasm whereas in other cases the cytoplasm appeared highly hypereosinophilic (Fig. 6c). In the portal area, also cuboidal cells forming interlobular bile ducts displayed signs of degeneration (Fig. 6d). Signs of inflammation (e.g. infiltration of mononuclear cells) in sinusoids and among hepatocytes were frequently detected (Fig. 6e). In addition, a large amount of apoptotic bodies could be seen (Fig. 6f).
Our results were successful in demonstrating that the anilinopyrimidine fungicide pyrimethanil has the potential to induce histological alterations in tissues of the Italian tree frog H. intermedia. We revealed that a long term exposure (78 days) to environmentally realistic concentrations of this fungicide caused severe histopathologic damages in gonads, liver and kidney. To the best of our knowledge, this is the first report describing the effects of pyrimethanil on the morphology of these organs in amphibian. The findings of this study are consistent with our previous results showing the reduced survival rate, the alteration in development and metamorphic traits and the incidence of severe malformations induced by this fungicide in the same species. Moreover, we described for the first time the histological features of H. intermedia gonads, liver and kidney, under basal condition.
Anuran gonads are most susceptible to malformation during the period of sexual differentiation and the time in which this takes place has been demonstrated to differ among species11, 36, 39, 40. After exposure to pyrimethanil, we detected an unmodified phenotypic sex ratio in both experimental groups; also morphological analysis revealed no sex reversal or abnormal gonadal intersex at metamorphosis thus supporting the hypothesis that this fungicide is not able to induce feminization or masculinization in H. intermedia. Numerous studies in amphibians indicate the incidence of intersex as the main gonadal abnormality induced by exposure to EDCs9, 11, 12, 41. According to previous results on the effects induced by EDCs on amphibian sexual development, the susceptibility and the incidence of sex reversals are a species-specific response42 and references therein. Our results emphasize the importance of studies on non-model species when evaluating the effects of EDCs and other pollutants, since an extrapolation of single-species data to other may be misleading41. 589ccfa754
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