The Women4Health cohort: a unique cohort to study women-specific mechanisms of cardio-metabolic regulation.

Aims: Epidemiological research has shown relevant differences between sexes in clinical manifestations, severity, and progression of cardiovascular and metabolic disorders. To date, the mechanisms underlying these differences remain unknown. Given the rising incidence of such diseases, gender-specific research on established and emerging risk factors, such as dysfunction of glycaemic and/or lipid metabolism, of sex hormones and of gut microbiome, is of paramount importance. The relationships between sex hormones, gut microbiome, and host glycaemic and/or lipid metabolism are largely unknown even in the homoeostasis status. Yet this knowledge gap would be pivotal to pinpoint to key mechanisms that are likely to be disrupted in disease context. Methods and results: Here we present the Women4Health (W4H) cohort, a unique cohort comprising up to 300 healthy women followed up during a natural menstrual cycle, set up with the primary goal to investigate the combined role of sex hormones and gut microbiota variations in regulating host lipid and glucose metabolism during homoeostasis, using a multi-omics strategy. Additionally, the W4H cohort will take into consideration another ecosystem that is unique to women, the vaginal microbiome, investigating its interaction with gut microbiome and exploring-for the first time-its role in cardiometabolic disorders. Conclusion: The W4H cohort study lays a foundation for improving current knowledge of women-specific mechanisms in cardiometabolic regulation. It aspires to transform insights on host-microbiota interactions into prevention and therapeutic approaches for personalized health care.

Cost-Utility Analysis of Pharmacogenetic Testing Based on CYP2C19 or CYP2D6 in Major Depressive Disorder: Assessing the Drivers of Different Cost-Effectiveness Levels from an Italian Societal Perspective.

BACKGROUND AND OBJECTIVES: Major depressive disorder (MDD) is a common and severe psychiatric disorder that has enormous economical and societal costs. As pharmacogenetics is one of the key tools of precision psychiatry, we analyze the cost-utility of test screening of CYP2C19 and CYP2D6 for patients suffering from major depressive disorder (MDD) and try to understand the main drivers that influence the cost-utility. METHODS: We developed two pharmacoeconomic nonhomogeneous Markov models to test the cost-utility, from an Italian societal perspective, of pharmacogenetic testing genetic to characterize the metabolizing profiles of cytochrome P450 (CYP) 2C19 and CYP2D6 in a hypothetical case study of patients suffering from major depressive disorder (MDD). The model considers different scenarios of adjustment of antidepressant treatment according to the patient's metabolizing profile or treatment over a period of 18 weeks. The uncertainty of model parameters is tested through both a probabilistic sensitivity analysis and a one-way deterministic sensitivity analysis, and these results are used in a post-hoc analysis to understand the main drivers of three alternative cost-effectiveness levels ("poor," "standard," and "high"). These drivers are first evaluated from an exploratory multidimensional perspective and next from a predictive perspective as the probability that a patient belongs to a specific cost-effectiveness level is estimated on the basis of a restricted set of parameters used in the original pharmacoeconomic model. RESULTS: The models for CYP2C19 and CYP2D6 indicate that screening has an incremental cost-effectiveness ratio of 60,000€ and 47,000€ per quality-adjusted life year (QALY), respectively. The probabilistic sensitivity analysis shows that the treatments are cost-effective for a 75,000€ willingness to pay (WTP) threshold in 58% and 63% of the Monte Carlo replications, respectively. The post-hoc analysis highlights the factors that allow us to clearly discriminates poor cost-effectiveness from high cost-effectiveness scenarios and demonstrates that it is possible to predict with reasonable accuracy the cost-effectiveness of a genetic test and the associated therapeutic pattern. CONCLUSIONS: Our findings suggest that screenings for both CYP2C19 and CYP2D6 enzymes for patients with MDD are cost-effective for a WTP threshold of 75,000€ per QALY, and provide relevant suggestions about the most important aspects to be further explored in clinical studies aimed at addressing the cost-effectiveness of genetic testing for patients diagnosed with MDD.

Cost utility analysis of Remdesivir and Dexamethasone treatment for hospitalised COVID-19 patients - a hypothetical study.

BACKGROUND: Sars-Cov-2 is a novel corona virus associated with significant morbidity and mortality. Remdesivir and Dexamethasone are two treatments that have shown to be effective against the Sars-Cov-2 associated disease. However, a cost-effectiveness analysis of the two treatments is still lacking. OBJECTIVE: The cost-utility of Remdesivir, Dexamethasone and a simultaneous use of the two drugs with respect to standard of care for treatment Covid-19 hospitalized patients is evaluated, together with the effect of Remdesivir compared to the base model but based on alernative assumptions. METHODS: A decision tree for an hypothetical cohort of Covid-19 hospitalized patients, from an health care perspective and a one year horizon is specified. Efficacy data are retrieved from a literature review of clinical trials, whilst costs and utility are obtained from other published studies. RESULTS: Remdesivir, if health care costs are related to the days of hospitalization, is a cost saving strategy. Dexamethasone is cost effective with an ICER of 5208/QALY, and the concurrent use of Remdesivir and Dexamethasone is the most favorable strategy for higher level of willingness to pay thresholds. Moreover, if Remdesivir has a positive effect on mortality the utility is three times higher respect to base case. Whereas, if health care costs are not related to the length of patient hospitalization Remdesivir has an ICER respect to standard of care of 384412.8/QALY gained, which is not cost effective. We also find that Dexaamethasone is cost effective respect to standard care if we compute the cost for live saved with an ICER of 313.79 for life saved. The uncertainty of the model parameters is also tested through both a one-way deterministic sensitivity analysis and a probabilistic sensitivity analysis. CONCLUSION: We find that the use of Remdesivir and/or Dexamethasone is effective from an economic standpoint.

Protocol for a pharmacogenetic study of antidepressants: characterization of drug-metabolizing profiles of cytochromes CYP2D6 and CYP2C19 in a Sardinian population of patients with major depressive disorder.

The effectiveness of antidepressants shows high interindividual variability ranging from full symptomatologic remission to treatment-resistant depression. Many factors can determine the variation in the clinical response, but a fundamental role is played by genetic variation within the genes encoding for the enzymes most involved in the metabolism of antidepressant drugs: the CYP2D6 and CYP2C19 isoforms of the cytochrome P450 system. This study is poised to clarify whether the different metabolizing phenotypes related to CYP2D6 and CYP2C19 could have an impact on the clinical efficacy of antidepressants and whether the frequency of these phenotypes of metabolization shows differences in the population of Sardinian patients compared to other Caucasian populations. The sample is being recruited from patients followed-up and treated at the Psychiatric Unit of the Department of Medical Science and Public Health, University of Cagliari and the University Hospital Agency of Cagliari (Italy). The study design includes three approaches: (1) a pharmacogenetic analysis of 80 patients diagnosed with MDD resistant to antidepressant treatment compared to 80 clinically responsive or remitted patients; (2) a prospective arm (N = 30) of the study where we will test the impact of genetic variation within the CYP2D6 and CYP2C19 genes on clinical response to antidepressants and on their serum levels and (3) the assessment of the socio-economic impact of antidepressant therapies, and estimation of the cost-effectiveness of the pharmacogenetic test based on CYP genes.

On the Use of Markov Models in Pharmacoeconomics: Pros and Cons and Implications for Policy Makers.

We present an overview of the main methodological features and the goals of pharmacoeconomic models that are classified in three major categories: regression models, decision trees, and Markov models. In particular, we focus on Markov models and define a semi-Markov model on the cost utility of a vaccine for Dengue fever discussing the key components of the model and the interpretation of its results. Next, we identify some criticalities of the decision rule arising from a possible incorrect interpretation of the model outcomes. Specifically, we focus on the difference between median and mean ICER and on handling the willingness-to-pay thresholds. We also show that the life span of the model and an incorrect hypothesis specification can lead to very different outcomes. Finally, we analyse the limit of Markov model when a large number of states is considered and focus on the implementation of tools that can bypass the lack of memory condition of Markov models. We conclude that decision makers should interpret the results of these models with extreme caution before deciding to fund any health care policy and give some recommendations about the appropriate use of these models.

Social-emotional functioning in planned lesbian families: does biological versus non-biological mother status matter? An Italian pilot study.

To date, few studies have investigated the social-emotional functioning of planned lesbian families, wherein only one parent is the biological mother of the child. We examined if being a biological versus non-biological mother plays a role in planned lesbian couple functioning and mother-infant play interactions. The present study analyzes the attachment state of mind, couple alliance, parenting stress, and emotional availability in a sample of 40 mothers (20 biological and 20 non-biological). The results showed that mothers' life-long attachment experiences and related mental states of mind, rather than biological relatedness between the parent and child, matter in a mother and child's emotional involvement in parent-child interaction. Furthermore, the results confirmed the different impact of the perceived quality of the couple alliance on biological and non-biological mothers. The findings obtained elucidated what counts in this new family typology, and constitute a heuristic solicitation for future studies to better understand the key factors and mechanisms implied in social-emotional functioning.