RESUMO
The use of pesticides in viticulture may play a crucial role in ensuring the health and quality of grapes. This review analyzes the most common pesticides used, illustrating their classification and toxicity, and their variations throughout the winemaking process. Fungicides are generally harmless or mildly toxic, whereas insecticides are classified as either highly or moderately hazardous. Potential alternatives to synthetic pesticides in wine production are also reviewed, thereby including biopesticides and biological agents. Analytical methods for detecting and quantifying pesticide residues in wine are then described, including liquid chromatography and gas chromatography coupled with mass spectrometry. This review also discusses the impact of the winemaking process on pesticide content. Pesticides with strong hydrophobicity were more likely to accumulate in solid byproducts, whereas hydrophilic pesticides were distributed more in the liquid phase. Grape's skin contains lipids, so hydrophobic pesticides adsorb strongly on grape surfaces and the clarification has been shown to be effective in the reduction of hydrophobic compounds. Therefore, the final wine could have more quantities of hydrophilic pesticides. Alcoholic fermentation has been shown to be crucial in pesticide dissipation. However, pesticide residues in wine have been shown an antagonistic effect on yeasts, affecting the safety and quality of wine products. Therefore, proteomic and genomic analyses of yeast growth are reviewed to understand the effects of pesticides on yeast during fermentation. The last section describes new effective methods used in removing pesticides from grapes and wine, thereby improving product quality and reducing harmful effects.
Assuntos
Fermentação , Praguicidas , Vitis , Vinho , Vinho/análise , Praguicidas/química , Praguicidas/análise , Vitis/química , Resíduos de Praguicidas/análise , Resíduos de Praguicidas/química , Manipulação de Alimentos/métodos , Contaminação de Alimentos/análiseRESUMO
A prognostic scoring system that can differentiate ß-thalassemia patients based on mortality risk is lacking. We analysed data from 3145 ß-thalassemia patients followed through a retrospective cohort design for the outcome of death. An a priori list of prognostic variables was collected. ß Coefficients from a multivariate cox regression model were used from a development dataset (n = 2516) to construct a formula for a Thalassemia International Prognostic Scoring System (TIPSS) which was subsequently applied to a validation dataset (n = 629). The median duration of observation was 10.0 years. The TIPSS score formula was constructed as exp (1.4 × heart disease + 0.9 × liver disease + 0.9 × diabetes + 0.9 × sepsis + 0.6 × alanine aminotransferase ≥42 IU/L + 0.6 × hemoglobin ≤9 g/dL + 0.4 × serum ferritin ≥1850 ng/mL). TIPSS score thresholds of greatest differentiation were assigned as <2.0 (low-risk), 2.0 to <5.0 (intermediate-risk), and ≥5.0 (high-risk). The TIPSS score was a good predictor for the outcome of death in the validation dataset (AUC: 0.722, 95%CI: 0.641-0.804) and survival was significantly different between patients in the three risk categories (P < 0.001). Compared to low-risk patients, the hazard ratio for death was 2.778 (95%CI: 1.335-5.780) in patients with intermediate-risk and 6.431 (95%CI: 3.151-13.128) in patients with high-risk. This study provides a novel tool to support mortality risk categorization for patients with ß-thalassemia that could help management and research decisions.
Assuntos
Derivação Portossistêmica Transjugular Intra-Hepática , Talassemia , Talassemia beta , Humanos , Prognóstico , Estudos Retrospectivos , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Talassemia beta/complicações , Talassemia beta/diagnósticoRESUMO
Within the EU, changes in policy and public sentiment have made it more urgent to consider the adoption of sustainable agricultural practices. Consequently, one of the EU's goals is to reduce pesticide use by 50 per cent by 2030, including in viticulture. One of the proposed approaches is to expand the use of disease resistant hybrid grape-cultivars (DRHGC), such as 'PIWI' grapes (German, Pilzwiderstandsfähige Rebsorten), and to introduce new DRHGCs. However, the characteristics of DRHGCs are different from those of Vitis vinifera, which makes it necessary to take measures and make changes in winemaking technology to maintain high wine quality. This paper examines the chemistry of wines made from DRHGC and discusses their impact on aroma and flavor profiles. It also reviews the main winemaking practices suggested to produce high-quality wines from DRHGCs. The chemistry of DRHGCs is different to wine produced from V. vinifera, which can lead to both challenges during winemaking and unusual flavor profiles. Although newer DRHGCs have been bred to avoid unexpected flavors, many DRHGCs are still rich in proteins and polysaccharides. This can make tannin extraction difficult and produce wines with little astringency. In addition to this, new or alternative winemaking techniques such as thermovinification and the use of alternative yeast strains (non-Saccharomyces) can be used to produce wines from DRHGCs that are acceptable to consumers.
Assuntos
Vitis , Vinho , Vinho/análise , Taninos , Antioxidantes/análise , LevedurasRESUMO
In ß-thalassaemia, the severity of inherited ß-globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long-term outcomes remain limited. We analysed data from 2109 ß-thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as ß0 /ß0 , ß0 /ß+ , ß+ /ß+ , ß0 /ß++ , ß+ /ß++ , and ß++ /ß++ . Patients were followed from birth until death or loss to follow-up. The median follow-up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, ß0 and ß+ mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with ß0 /ß0 , ß0 /ß+ , or ß+ /ß+ had a 2·104-increased risk of death [95% confidence interval (CI): 1·176-3·763, P = 0·011] and 2·956-increased odds of multiple morbidity (95% CI: 2·310-3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with ß-thalassaemia and suggests inclusion of both ß+ and ß0 mutations in strata of greatest severity.
Assuntos
Mutação , Globinas beta/genética , Talassemia beta/epidemiologia , Talassemia beta/genética , Adulto , Alelos , Estudos de Coortes , Gerenciamento Clínico , Feminino , Seguimentos , Genótipo , Saúde Global , Humanos , Estimativa de Kaplan-Meier , Masculino , Morbidade , Mortalidade , Razão de Chances , Fenótipo , Vigilância da População , Prognóstico , Modelos de Riscos Proporcionais , Índice de Gravidade de Doença , Adulto Jovem , Talassemia beta/sangue , Talassemia beta/diagnósticoRESUMO
Paediatric drug development faces several barriers. These include fragmentation of stakeholders and inconsistent processes during the conduct of research. This review summarises recent efforts to overcome these barriers in Europe. Two exemplar initiatives are described. The European Paediatric Translational Research Infrastructure facilitates preclinical research and other work that underpins clinical trials. conect4children facilitates the design and implementation of clinical trials. Both these initiatives listen to the voices of children and their advocates. Coordination of research needs specific effort that supplements work on science, resources and the policy context.
Assuntos
Pesquisa Farmacêutica , Criança , Europa (Continente) , Humanos , Pesquisa Translacional BiomédicaRESUMO
The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients' treatment.
Assuntos
Talassemia/diagnóstico , Talassemia/etiologia , Adolescente , Adulto , Transfusão de Sangue , Terapia por Quelação , Feminino , Hemoglobinas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Fatores de Risco , Índice de Gravidade de Doença , Talassemia/sangue , Talassemia/terapia , Adulto JovemRESUMO
BACKGROUND: We describe our experience from a multi-national application of a European Union-funded research-driven paediatric trial (DEEP-2, EudraCT 2012-000353-31; NCT01825512). This paper aims to evaluate the impact of the local and national rules on the trial authorisation process in European and non-European countries. National/local provisions and procedures, number of Ethics Committees and Competent Authorities to be addressed, documentation required, special provisions for the paediatric population, timelines for completing the authorisation process and queries received were collected; compliance with the European provisions were evaluated. Descriptive analysis, Wilcoxon Rank-Sum test and General Linear Model analysis were used to determine factors potentially influencing the timelines. The Cluster Analysis procedure was used to identify homogenous groups of cases. RESULT: The authorisation process was completed in 7.7 to 53.8 months in European countries and in 17.1 to 27.1 months in non-European countries. The main factors influencing these timelines were the requests for changes/clarifications in European countries and the different national legislations in non-European countries. CONCLUSION: This work confirms that the procedures and requirements for the clinical trial application of a paediatric trial are different. In the European Union, the timeframes for submission were generally harmonised but longer. In non-European countries, delays were caused by national dispositions but the entire authorisation process resulted faster with less requests from ECs/CAs. The upcoming application of Regulation (EU) 536/2014 is expected to harmonise practices in Europe and possibly outside. Networks on paediatric research acting at international level will be crucial in this effort.
Assuntos
Princípios Morais , Pesquisadores , Criança , Europa (Continente) , União Europeia , HumanosRESUMO
AIM: The European Network of Excellence for Paediatric Clinical Research, known as the TEDDY Network, carried out a survey to determine the capacity and competence of paediatric centres to perform research studies. METHODS: A cross-sectional, web-based pilot survey was conducted from October 2016 to April 2017 with paediatric clinical research centres in 11 countries: Albania, Austria, Belgium, Denmark, Iceland, Ireland, Italy, Norway, Spain, Switzerland and the United Kingdom. All were registered with the TEDDY Network database. RESULTS: We approached 107 centres and 63 provided data on their experiences and expertise in paediatric clinical trials. Four groups of performance indicators were identified, referring to scientific experience, trial readiness, trial competence, regulatory issues, ethics and patients. Most centres were actively involved in paediatric clinical research: 53 centres (84.1%) had received funds for more than five paediatric studies in the last 5 years, and 42 (66.7%) had a specific clinical trial unit and dedicated study coordinators. We concluded that the European centres we studied had the capability and capacity to conduct paediatric trials, but there was still room for improvement, including enhanced collaboration. CONCLUSION: This pilot survey demonstrated that there is potential for performing paediatric trials across Europe, but improvements are possible.
Assuntos
Estudos Transversais , Áustria , Bélgica , Criança , Europa (Continente) , Humanos , Islândia , Irlanda , Itália , Noruega , Espanha , Suíça , Reino UnidoRESUMO
The use of machine learning (ML) in medicine is becoming increasingly fundamental to analyse complex problems by discovering associations among different types of information and to generate knowledge for medical decision support. Many regulatory and ethical issues should be considered. Some relevant EU provisions, such as the General Data Protection Regulation, are applicable. However, the regulatory framework for developing and marketing a new health technology implementing ML may be quite complex. Other issues include the legal liability and the attribution of negligence in case of errors. Some of the above-mentioned concerns could be, at least partially, resolved in case the ML software is classified as a 'medical device', a category covered by EU/national provisions. Concluding, the challenge is to understand how sustainable is the regulatory system in relation to the ML innovation and how legal procedures should be revised in order to adapt them to the current regulatory framework.
Assuntos
Aprendizado de Máquina/ética , Aprendizado de Máquina/legislação & jurisprudência , Aprendizado de Máquina/normas , Informática Médica , Software , Viés , Confidencialidade/legislação & jurisprudência , Tomada de Decisões/ética , Desenvolvimento de Medicamentos , Descoberta de Drogas , Humanos , Imperícia , Legislação de Dispositivos Médicos , Medicina de Precisão , Gestão de Riscos , Segurança/legislação & jurisprudência , ConfiançaRESUMO
The lack of paediatric medicines, including innovative and advanced ones, is a long-lasting and well-known problem at European and international levels. Despite the existing legal frameworks and incentives, children remain deprived of many kinds of therapy because of challenges faced in appropriately study and tailoring medicinal and other products for them. In this context, the necessity to foster paediatric research addressing unsolved and uncovered issues within a 'translational approach' has appeared. This article, after having clarified the concept of translational research in the perspective of the establishment of a European paediatric research infrastructure (RI), will identify and point out ethical, legal and regulatory issues particularly relevant in a children's rights perspective. It concludes asking for the setting up of an adequate model of governance within a future RI, including adequate and independent ethical oversight and a pluridisciplinary common service dealing with ethical, legal and societal issues relevant for children.
Assuntos
Menores de Idade , Direitos do Paciente , Pediatria , Terapias em Estudo/normas , Pesquisa Translacional Biomédica/ética , Pesquisa Translacional Biomédica/legislação & jurisprudência , Criança , Confidencialidade/ética , Confidencialidade/legislação & jurisprudência , Europa (Continente) , Edição de Genes/ética , Edição de Genes/legislação & jurisprudência , Humanos , Direito à Saúde , Pesquisa Translacional Biomédica/organização & administraçãoRESUMO
AIMS: Despite long clinical experience with deferiprone, there is limited information on its pharmacokinetics in children aged <6 years. Here we assess the impact of developmental growth on the pharmacokinetics of deferiprone in this population using a population approach. Based on pharmacokinetic bridging concepts, we also evaluate whether the recommended doses yield appropriate systemic exposure in this group of patients. METHODS: Data from a study in which 18 paediatric patients were enrolled were available for the purposes of this analysis. Patients were randomised to three deferiprone dose levels (8.3, 16.7 and 33.3 mg kg-1 ). Blood samples were collected according to an optimised sampling scheme in which each patient contributed to a maximum of five samples. A population pharmacokinetic model was developed using NONMEM v.7.2. Model selection criteria were based on graphical and statistical summaries. RESULTS: A one-compartment model with first-order absorption and first-order elimination best described the pharmacokinetics of deferiprone. Drug disposition parameters were affected by body weight, with both clearance and volume increasing allometrically with size. Simulation scenarios show that comparable systemic exposure (AUC) is achieved in children and adults after similar dose levels in mg kg-1 , with median (5-95th quantiles) AUC values, respectively, of 340.6 (223.2-520.0) µmol l-1 h and 318.5 (200.4-499.0) µmol l-1 h at 75 mg kg-1 day-1 , and 453.7 (297.3-693.0) µmol l-1 h and 424.2 (266.9-664.0) µmol l-1 h at 100 mg kg-1 day-1 given as three times daily (t.i.d.) doses. CONCLUSIONS: Based on the current findings, a dosing regimen of 25 mg kg-1 t.i.d. is recommended in children aged <6 years, with the possibility of titration up to 33.3 mg kg-1 t.i.d.
Assuntos
Piridonas/administração & dosagem , Piridonas/farmacocinética , Pré-Escolar , Simulação por Computador , Deferiprona , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Lactente , Quelantes de Ferro/farmacocinética , Masculino , Modelos Biológicos , Piridonas/sangue , Método Simples-CegoAssuntos
Anemia/complicações , Sobrecarga de Ferro/complicações , Talassemia beta/complicações , Adulto , Anemia/mortalidade , Anemia/terapia , Transfusão de Sangue , Feminino , Humanos , Sobrecarga de Ferro/mortalidade , Estimativa de Kaplan-Meier , Masculino , Mortalidade , Risco , Adulto Jovem , Talassemia beta/mortalidade , Talassemia beta/terapiaRESUMO
The need for performing clinical trials to develop well-studied and appropriate medicines for inherited neurometabolic disease patients faces ethical concerns mainly raising from four aspects: the diseases are rare; include young and very young patients; the neurological impairment may compromise the capability to provide 'consent'; and the genetic nature of the disease leads to further ethical implications. This work is intended to identify the ethical provisions applicable to clinical research involving these patients and to evaluate if these cover the ethical issues. Three searches have been performed on the European regulatory/legal framework, the literature and European Union-funded projects. The European legal framework offers a number of ethical provisions ruling the clinical research on paediatric, rare, inherited diseases with neurological symptoms. In the literature, relevant publications deal with informed consent, newborn genetic screenings, gene therapy and rights/interests of research participants. Additional information raised from European projects on sharing patients' data from different countries, the need to fill the gap of the regulatory framework and to improve information to stakeholders and patients/families. CONCLUSION: Several recommendations and guidelines on ethical aspects are applicable to the inherited neurometabolic disease research in Europe, even though they suffer from the lack of a common ethical approach. What is Known: ⢠When planning and conducting clinical trials, sponsors and researchers know that clinical trials are to be performed according to well-established ethical rules, and patients should be aware about their rights. ⢠In the cases of paediatric patients, vulnerable patients unable to provide consent, genetic diseases' further rules apply. What is New: ⢠This work discusses which ethical rules apply to ensure protection of patient's rights if all the above-mentioned features coexist. ⢠This work shows available data and information on how these rules have been applied.
Assuntos
Pesquisa Biomédica/ética , Ensaios Clínicos como Assunto/ética , Consentimento Livre e Esclarecido/legislação & jurisprudência , Doenças Metabólicas , Doenças do Sistema Nervoso , Doenças Raras , Criança , Europa (Continente) , União Europeia , HumanosRESUMO
The European framework surrounding clinical trials on medicinal products for human use is going to change as demonstrated by the large debate at European institutional level. One of the major challenges is to overcome the lack of harmonisation of clinical trial procedures among countries. This aspect is gaining more and more importance, considering the increasing number of multicentre and multinational studies. In this work, the actual European rules governing the Clinical Trial Application have been analysed throughout the different steps including the registration of the trial in the European database; the preparation of documents to be submitted and their contents; the preparation of documents related to the information and consent process; the submission to competent bodies. Specific issues related to paediatric research and trials involving non EU/EEA countries have been addressed as well. Results reveal that the European legislation offers a well defined set of European rules covering different aspects of a Clinical Trial Application. However, these are not suitable to meet the challenges from multicentre and multinational clinical studies. A stronger set of rules, such as is available in a composite European Regulation has been adopted and is expected to harmonise practices and enable sponsors to carry out well conducted trials. But will the new regulation overcome the existing criticisms of Directive 2001/20/EC?
Assuntos
Pesquisa Biomédica/legislação & jurisprudência , Ensaios Clínicos como Assunto/legislação & jurisprudência , Cooperação Internacional/legislação & jurisprudência , Pesquisa Biomédica/ética , Tecnologia Biomédica , Criança , Ética em Pesquisa , Europa (Continente) , União Europeia , HumanosRESUMO
Personalized medicine is defined as a medical model using the characterization of individuals' phenotypes and genotypes (e [...].
RESUMO
Introduction: The European Medicines Agency (EMA) offers scientific advice to support the qualification procedure of novel methodologies, such as preclinical and in vitro models, biomarkers, and pharmacometric methods, thereby endorsing their acceptability in medicine research and development (R&D). This aspect is particularly relevant to overcome the scarcity of data and the lack of validated endpoints and biomarkers in research fields characterized by small samples, such as pediatrics. Aim: This study aimed to analyze the potential pediatric interest in methodologies qualified as "novel methodologies for medicine development" by the EMA. Methods: The positive qualification opinions of novel methodologies for medicine development published on the EMA website between 2008 and 2023 were identified. Multi-level analyses were conducted to investigate data with a hierarchical structure and the effects of cluster-level variables and cluster-level variances and to evaluate their potential pediatric interest, defined as the possibility of using the novel methodology in pediatric R&D and the availability of pediatric data. The duration of the procedure, the type of methodology, the specific disease or disease area addressed, the type of applicant, and the availability of pediatric data at the time of the opinion release were also investigated. Results: Most of the 27 qualifications for novel methodologies issued by the EMA (70%) were potentially of interest to pediatric patients, but only six of them reported pediatric data. The overall duration of qualification procedures with pediatric interest was longer than that of procedures without any pediatric interest (median time: 7 months vs. 3.5 months, respectively; p = 0.082). In parallel, qualification procedures that included pediatric data lasted for a longer period (median time: 8 months vs. 6 months, respectively; p = 0.150). Nephrology and neurology represented the main disease areas (21% and 16%, respectively), while endpoints, biomarkers, and registries represented the main types of innovative methodologies (32%, 26%, and 16%, respectively). Discussion: Our results underscore the importance of implementing innovative methodologies in regulatory-compliant pediatric research activities. Pediatric-dedicated research infrastructures providing regulatory support and strategic advice during research activities could be crucial to the design of ad hoc pediatric methodologies or to extend and validate them for pediatrics.
Assuntos
Deferiprona/uso terapêutico , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Talassemia beta/complicações , Fatores Etários , Criança , Deferiprona/administração & dosagem , Deferiprona/efeitos adversos , Humanos , Quelantes de Ferro/administração & dosagem , Quelantes de Ferro/efeitos adversos , Sobrecarga de Ferro/diagnóstico , Região do Mediterrâneo , Resultado do Tratamento , Talassemia beta/diagnóstico , Talassemia beta/terapiaRESUMO
Despite off-label use, the efficacy and safety of gabapentin and tramadol in pediatric patients (3 months to <18 years old) diagnosed with chronic pain has not been characterized. However, generating evidence based on randomized clinical trials in this population has been extremely challenging. The current investigation illustrates the use of clinical trial simulations (CTSs) as a tool for optimizing doses and protocol design for a prospective investigation in pediatric patients with chronic pain. Pharmacokinetic (PK) modeling and CTSs were used to describe the PKs of gabapentin and tramadol in the target population. In the absence of biomarkers of analgesia, systemic exposure (AUC, Css) was used to guide dose selection under the assumption of a comparable exposure-response (PKPD) relationship for either compound between adults and children. Two weight bands were identified for gabapentin, with doses titrated from 5 to 63 mg/kg. This yields gabapentin exposures (AUC0-8 ) of approximately 35 mg/L*h (1200 mg/day adult dose equivalent). For tramadol, median steady state concentrations between 200 and 300 ng/mL were achieved after doses of 2-5 mg/kg, but concentrations showed high interindividual variability. Simulation scenarios showed that titration steps are required to explore therapeutically relevant dose ranges taking into account the safety profile of both drugs. Gabapentin can be used t.i.d. at doses between 7-63 and 5-45 mg/kg for patients receiving gabapentin weighing <15 and ≥15 kg, respectively, whereas a t.i.d. regimen with doses between 1 and 5 mg/kg can be used for tramadol in patients who are not fast metabolisers.
Assuntos
Analgesia , Dor Crônica , Tramadol , Adulto , Humanos , Criança , Lactente , Gabapentina/uso terapêutico , Tramadol/efeitos adversos , Dor Crônica/tratamento farmacológico , Estudos ProspectivosRESUMO
The effects of a) pre-fermentative freezing of the grapes (- 20 °C for two weeks); b) inoculation of the grape must with Saccharomycescerevisiae yeast, or co-inoculation with Saccharomyces cerevisiae yeast and Oenococcus oenibacteria; c) vinification with or without fermentative maceration, and d) cold stabilization with or without bentonite treatment, were studied on the profile of oligomeric condensed tannins (proanthocyanidins, PAC) with non-cyclic or macrocyclic structures in wines made from Schiava cv., a red grape variety. The samples were evaluated just before inoculation and at the bottling of the wine. Commercial Schiava wines from two different producers stored at six and eighteen months were also studied for the effect of artificially introduced dissolved oxygen, and half of these bottles were subjected to periodic mechanical stress for one year, to see the effects on the PAC profile. Freezing of the grapes increased the extraction of all non-cyclic PAC in the must, whereas tetrameric, pentameric, and hexameric cyclic procyanidins (m/z 1153, m/z 1441, m/z 1729, respectively) were not affected; only a tetrameric cyclic prodelphinidin ( m/z 1169) showed a more similar trend to the non-cyclic PAC. In wines at bottling, cyclic procyanidins were higher in wines obtained by fermentative maceration (as well as most non-cyclic congeners); however, the significance of these differences depended on specific interactions between the factors. In contrast, no effect was found on the cyclic tetrameric prodelphinidin (m/z 1169). Bentonite treatment showed no significant effect on either oligomeric non-cyclic or cyclic PAC profiles. The addition of dissolved oxygen led to a significant decrease in non-cyclic trimeric and tetrameric PAC in the samples with respect to the control ones; however, the addition of dissolved oxygen did not influence the profile of the cyclic PAC. This study sheds new light on the substantial differences in the behaviour of the cyclic and non-cyclic oligomeric PAC in red wine in relation to the vinification process and in the bottle. Cyclic oligomeric PAC were more stable and less influenced by applied factors than linear PAC, again proving to be potential markers for the grape variety of wine.