HEALTH SYSTEM ANALYSIS OF THE BARRIERS TO ACCESS, AVAILABILITY, UTILISATION AND READINESS OF SEXUAL AND REPRODUCTIVE HEALTH SERVICES IN COVID-19 AFFECTED AREAS: DEVELOPMENT AND VALIDATION OF A DATA COLLECTION SYSTEM TO BE APPLIED FOR FUTURE HEALTH PANDEMICS

Background: The Coronavirus Disease 19 (COVID-19) pandemic has severely impacted sexual health service provision with consequences at both individual and public health level. The collection of real-time high-quality data is of utmost importance to monitor the impact on service delivery and disruption in case of future health emergencies. Aims: This is a 3-year study, implemented in the framework of a broader collaboration between World Health Organization (WHO) Department of Sexual and Reproductive Health Research and University of Brighton (UOB) with the University Hospital Verona (UHVR). The overarching study aim was to develop and pilot a secure, standardised, web-based electronic case report form (eCRF), via Research Electronic Data Capture (REDCap) system, for sexually transmitted infection (STIs) and HIV clinical data management. The eCRF constituted the basis for a research infrastructure aimed at conducting multi-centric implementation studies able to answer selected research questions and guide decision making processes. Methods: The eCRF construction required a multidisciplinary approach (9 study experts from UHVR and UOB with different backgrounds) and consisted of a series of distinct steps: i) identification of a minimum set of standardised HIV-STIs core variables required to increase study consistency; ii) design of the eCRF framework according to literature key-principles with particular focus on a structure based on modularity, longitudinal mode, flexibility, intuitive workflow, and compliance with the General Data Protection Regulation; iii) set up of a series of quality checks at different levels to minimise errors and ensure data integrity at time of data entry; iv) eCRF piloting by 12 healthcare providers external to the study, who were asked to assess and provide feedback on key eCRF aspects; v) testing of entry procedure and quality checks efficiency using clinical routine data on HIV-Pre-Exposure Prophylaxis (PrEP) users accessing UHVR Centro MISTRA from January 2108 to September 2022. Mixed manual and automatic entry processes (with import of a pre-existing Excel sheet) were performed for checking feasibility of both tasks. The tool usability was evaluated via an implementation study which tested data entry system (data reconciliation) and data processing through exploratory statistical analyses, which focused on the assessment of COVID-19 impact on PrEP users in pre-pandemic, pandemic, and post-pandemic periods. Results: Four instruments were developed (Demographics, Past Medical History, Standard Visits, Antimicrobial Prescription) hosting 7 modules. The modular approach was used to test the current set of instruments and, in the future, to add further functionalities allowing an interchangeable, dynamic, and independent modules development without impacting the overall eCRF frame. The repeatable Standard Visit instrument (including sexual behaviour, PrEP intake, signs & symptoms, and laboratory assessment modules) is the eCRF core. Given the longitudinal mode, baseline instrument is populated only at enrolment and then can be further filled in at various time points (patient follow-up visits), if needed. The core eCRF feature is the possibility of completing visits based on patients’ needs with little burden for physician or data collector. The reconciliation process uploading already collected data into the eCRF was straightforward with 95% of successful import without need of further review. Exploratory analyses were conducted on 256 PrEP users and 1595 visits. Main findings showed significant decrease in visits number and increase in PrEP discontinuation during pandemic period. Conclusion: The study led to the implementation of an easy-to-use eCRF able to host standardised, real-time, high-quality data. The eCRF suggests a wide range of applicability in both research and clinical areas to be adopted in case of future health emergencies, potentially useful to guide clinical decision-making and support healthcare practice with telehealth implementation

In vivo studies on antibiotic combination for the treatment of carbapenem-resistant Gram-negative bacteria: a systematic review and meta-analysis protocol

ObjectiveThere is poor evidence to determine the superiority of combination regimens versus monotherapy against infections due to carbapenem-resistant (CR) Gram-negative bacteria. In vivo models can simulate the pathophysiology of infections in humans and assess antibiotic efficacy. We aim to investigate in vivo effects of antibiotic combination on mortality and disease burden for infections due to CR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacteriaceae and provide an unbiased overview of existing knowledge. The results of the study can help prioritising future research on the most promising therapies against CR bacteria.Methods and analysisThis protocol was formulated using the Systematic Review Protocol for Animal Intervention Studies (SYRCLE) Checklist. Publications will be collected from PubMed, Scopus, Embase and Web of Science. Quality checklists adapted by Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies and SYRCLE's risk of bias tool will be used. If the meta-analysis seems feasible, the ES and the 95% CI will be analysed. The heterogeneity between studies will be assessed by I2 test. Subgroup meta-analysis will be performed when possible to assess the impact of the studies on efficacy of the treatments. Funnel plotting will be used to evaluate the risk of publication bias.DisseminationThis systematic review and meta-analysis is part of a wider research collaboration project, the COmbination tHErapy to treat sepsis due to carbapenem-Resistant bacteria in adult and paediatric population: EvideNCE and common practice (COHERENCE) study that includes also the analyses of in vitro and human studies. Data will be presented at international conferences and the results will be published in peer-reviewed journals.PROSPERO registration numberCRD42019128104(available at: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019128104)

Systematic review and meta-analysis of in vitro efficacy of antibiotic combination therapy against carbapenem-resistant Gram-negative bacilli.

The superiority of combination therapy for carbapenem-resistant Gram-negative bacilli (CR-GNB) infections remains controversial. In vitro models may predict the efficacy of antibiotic regimens against CR-GNB. A systematic review and meta-analysis was performed including pharmacokinetic/pharmacodynamic (PK/PD) and time-kill (TK) studies examining the in vitro efficacy of antibiotic combinations against CR-GNB [PROSPERO registration no. CRD42019128104]. The primary outcome was in vitro synergy based on the effect size (ES): high, ES ≥ 0.75, moderate, 0.35ES0.75; low, ES ≤ 0.35; and absent, ES = 0). A network meta-analysis assessed the bactericidal effect and re-growth rate (secondary outcomes). An adapted version of the ToxRTool was used for risk-of-bias assessment. Over 180 combination regimens from 136 studies were included. The most frequently analysed classes were polymyxins and carbapenems. Limited data were available for ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. High or moderate synergism was shown for polymyxin/rifampicin against Acinetobacter baumannii [ES = 0.91, 95% confidence interval (CI) 0.44-1.00], polymyxin/fosfomycin against Klebsiella pneumoniae (ES = 1.00, 95% CI 0.66-1.00) and imipenem/amikacin against Pseudomonas aeruginosa (ES = 1.00, 95% CI 0.21-1.00). Compared with monotherapy, increased bactericidal activity and lower re-growth rates were reported for colistin/fosfomycin and polymyxin/rifampicin in K. pneumoniae and for imipenem/amikacin or imipenem/tobramycin against P. aeruginosa. High quality was documented for 65% and 53% of PK/PD and TK studies, respectively. Well-designed in vitro studies should be encouraged to guide the selection of combination therapies in clinical trials and to improve the armamentarium against carbapenem-resistant bacteria

Clinical Impact of Monoclonal Antibodies in the Treatment of High-Risk Patients with SARS-CoV-2 Breakthrough Infections:The ORCHESTRA Prospective Cohort Study

The clinical impact of anti-spike monoclonal antibodies (mAb) in Coronavirus Disease 2019 (COVID-19) breakthrough infections is unclear. We present the results of an observational prospective cohort study assessing and comparing COVID-19 progression in high-risk outpatients receiving mAb according to primary or breakthrough infection. Clinical, serological and virological predictors associated with 28-day COVID-19-related hospitalization were identified using multivariate logistic regression and summarized with odds ratio (aOR) and 95% confidence interval (CI). A total of 847 COVID-19 outpatients were included: 414 with primary and 433 with breakthrough infection. Hospitalization was observed in 42/414 (10.1%) patients with primary and 8/433 (1.8%) patients with breakthrough infection (p &lt; 0.001). aOR for hospitalization was significantly lower for breakthrough infection (aOR 0.12, 95%CI: 0.05–0.27, p &lt; 0.001) and higher for immunocompromised status (aOR:2.35, 95%CI:1.08–5.08, p = 0.003), advanced age (aOR:1.06, 95%CI: 1.03–1.08, p &lt; 0.001), and male gender (aOR:1.97, 95%CI: 1.04–3.73, p = 0.037). Among the breakthrough infection group, the median SARS-CoV-2 anti-spike IgGs was lower (p &lt; 0.001) in immunocompromised and elderly patients &gt;75 years compared with that in the immunocompetent patients. Our findings suggest that, among mAb patients, those with breakthrough infection have significantly lower hospitalization risk compared with patients with primary infection. Prognostic algorithms combining clinical and immune-virological characteristics are needed to ensure appropriate and up-to-date clinical protocols targeting high-risk categories.</p

Clinical management of severe infections caused by carbapenem-resistant Gram-negative bacteria: a worldwide cross-sectional survey addressing the use of antibiotic combinations.

OBJECTIVES: Optimal treatment of carbapenem-resistant Gram-negative (CR-GNB) infections is uncertain due to the lack of good-quality evidence and the limited effectiveness of available antibiotics. The aim of this survey was to investigate clinicians' prescribing strategies for treating CR-GNB infections worldwide. METHODS: A 36-items-questionnaire was developed addressing the following aspects of antibiotic prescribing: respondent's background, diagnostic and therapeutic availability, preferred antibiotic strategies and rationale for selecting combination therapy. Prescribers were recruited following the snowball-sampling approach, and a post-stratification correction with inverse proportional weights was used to adjust the sample's representativeness. RESULTS: 1012 respondents from 95 countries participated in the survey. Overall, 298 (30%) of respondents had local guidelines for treating CR-GNB at their facility and 702 (71%) had access to Infectious Diseases consultation, with significant discrepancies according to country economic status: 85% (390/502) in High-Income-Countries vs 59% (194/283) in Upper-Medium-Income-Countries and 30% (118/196) in Lower-Middle-Income-Countries/Lower-Income-Countries). Targeted regimens varied widely, ranging from 40 regimens for CR-Acinetobacter spp. to more than 100 regimens for CR-Enterobacteriaceae. Although the majority of respondents acknowledged the lack of evidence behind this choice, dual combination was the preferred treatment scheme and carbapenem-polymyxin was the most prescribed regimen, irrespective of pathogen and infection source. Respondents noticeably disagreed around the meaning of 'combination therapy' with 20% (150/783) indicating the simple addition of multiple compounds, 42% (321/783) requiring the presence of in vitro activity and 38% (290/783) of in vitro-synergism. CONCLUSIONS: Management of CR-GNB infections is far from being standardized. Strategic public health focussed randomised controlled trials are urgently required to inform evidence-based treatment guidelines

Clinical efficacy of different monoclonal antibody regimens among non-hospitalised patients with mild to moderate COVID-19 at high risk for disease progression: a prospective cohort study

This study aimed to compare the clinical progression of COVID-19 in high-risk outpatients treated with the monoclonal antibodies (mAb) bamlanivimab, bamlanivimab-etesevimab and casirivimab-imdevimab. This is an observational, multi-centre, prospective study conducted from 18 March to 15 July 2021 in eight Italian tertiary-care hospitals including mild-to-moderate COVID-19 outpatients receiving bamlanivimab (700&nbsp;mg), bamlanivimab-etesevimab (700-1400&nbsp;mg) or casirivimab-imdevimab (1200-1200&nbsp;mg). All patients were at high risk of COVID-19 progression according to Italian Medicines Agency definitions. In a patient subgroup, SARS-CoV-2 variant and anti-SARS-CoV-2 serology were analysed at baseline. Factors associated with 28-day all-cause hospitalisation were identified using multivariable multilevel logistic regression (MMLR) and summarised with adjusted odds ratio (aOR) and 95% confidence interval (CI). A total of 635 outpatients received mAb: 161 (25.4%) bamlanivimab, 396 (62.4%) bamlanivimab-etesevimab and 78 (12.2%) casirivimab-imdevimab. Ninety-five (15%) patients received full or partial SARS-CoV-2 vaccination. The B.1.1.7 (Alpha) variant was detected in 99% of patients. Baseline serology showed no significant differences among the three mAb regimen groups. Twenty-eight-day all-cause hospitalisation was 11.3%, with a significantly higher proportion (p 0.001) in the bamlanivimab group (18.6%), compared to the bamlanivimab-etesevimab (10.1%) and casirivimab-imdevimab (2.6%) groups. On MMLR, aORs for 28-day all-cause hospitalisation were significantly lower in patients receiving bamlanivimab-etesevimab (aOR 0.51, 95% CI 0.30-0.88 p 0.015) and casirivimab-imdevimab (aOR 0.14, 95% CI 0.03-0.61, p 0.009) compared to those receiving bamlanivimab. No patients with a history of vaccination were hospitalised. The study suggests differences in clinical outcomes among the first available mAb regimens for treating high-risk COVID-19 outpatients. Randomised trials are needed to compare efficacy of mAb combination regimens in high-risk populations and according to circulating variants

Competiton and regulation in the railway industry

The railway industry has foregone important changes in the last years, due to the European reform aimed at its liberalization. A number of studies analyze the qualitative differences across countries, because each Member State has some degree of discretion as the European directives provide only for the main principles (Seabright, 2003; Newbery, 1999; Gomez-Ibanez, 2003; Gomez-Ibanez e De Rus, 2007). But as for the effect of the reform, the analysis are still limited (Friebel, 2008; Quinet, 2006; Schmutzler and Lalive, 2008) and also from a theoretical point of view, only few papers consider the railway industry (De Villemeur et al. 2003). Therefore, the aim of the thesis is to investigate some interesting and important aspects of the railway sector. In particular, I first focus on the role of private or public ownership to incentive investments in rolling stock and second on the issue of public service obligations. The thesis is organized as follows: the introduction illustrates main provisions of the European reform and highlights the characteristics of the sector. The first chapter reviews the literature on public-private partnerships with reference to the issue of bundling or unbundling of different phases of a project. The interest for this kind of arrangement is related to the question of how to solve the problem of scarcity of rolling stock that appears to affect the competitive selection of the service provider. In the second chapter I present a model to study what the effect of the ownership of the rolling stock is on the incentive of the provider of the service to invest also in the case of asymmetric information over the cost. In this latter case a trade off emerges between the effect of the investment and the rent from asymmetric information In the second part of the thesis I analyze the issue of public service obligation. In chapter three I present a review of the literature about the universal service, a concept close to public service obligation but formally applied only in the telecommunications and in the postal sector. In the forth chapter, I consider the effect of PSO on total welfare according to different market structures and in particular when a PSO fund is set up. I analyze welfare effect both under complete information and under asymmetric information over demand. It appears that the set up of a PSO fund grants welfare gains also under asymmetric information

L'intervento pubblico nel trasporto ferroviario. Prospettive di liberalizzazione e esigenze di servizio pubblico.

none3C. Cambini; G. Catalano; A. SavoldiC., Cambini; Catalano, GIUSEPPE PASQUALE ROBERTO; A., Savold