Operational complexity versus design efficiency: challenges of implementing a phase IIa multiple parallel cohort targeted treatment platform trial in advanced breast cancer.

BACKGROUND: Platform trial designs are used increasingly in cancer clinical research and are considered an efficient model for evaluating multiple compounds within a single disease or disease subtype. However, these trial designs can be challenging to operationalise. The use of platform trials in oncology clinical research has increased considerably in recent years as advances in molecular biology enable molecularly defined stratification of patient populations and targeted therapy evaluation. Whereas multiple separate trials may be deemed infeasible, platform designs allow efficient, parallel evaluation of multiple targeted therapies in relatively small biologically defined patient sub-populations with the promise of increased molecular screening efficiency and reduced time for drug evaluation. Whilst the theoretical efficiencies are widely reported, the operational challenges associated with these designs (complexity, cost, regulatory, resource) are not always well understood. MAIN: In this commentary, we describe our practical experience of the implementation and delivery of the UK plasmaMATCH trial, a platform trial in advanced breast cancer, comprising an integrated screening component and multiple parallel downstream mutation-directed therapeutic cohorts. plasmaMATCH reported its primary results within 3 years of opening to recruitment. We reflect on the operational challenges encountered and share lessons learnt to inform the successful conduct of future trials. Key to the success of the plasmaMATCH trial was well co-ordinated stakeholder engagement by an experienced clinical trials unit with expert methodology and trial management expertise, a federated model of clinical leadership, a well-written protocol integrating screening and treatment components and including justification for the chosen structure and intentions for future adaptions, and an integrated funding model with streamlined contractual arrangements across multiple partners. Findings based on our practical experience include the importance of early engagement with the regulators and consideration of a flexible resource infrastructure to allow adequate resource allocation to support concurrent trial activities as adaptions are implemented in parallel to the continued management of patient safety and data quality of the ongoing trial cohorts. CONCLUSION: Platform trial designs allow the efficient reporting of multiple treatment cohorts. Operational challenges can be overcome through multidisciplinary engagement, streamlined contracting processes, rationalised protocol and database design and appropriate resourcing.

Optimization of Aircraft Taxiing Strategies to Reduce the Impacts of Landing and Take-Off Cycle at Airports

The increasing attention of opinion towards climate change has prompted public authorities to provide plans for the containment of emissions to reduce the environmental impact of human activities. The transport sector is one of the main ones responsible for greenhouse emissions and is under investigation to counter its burdens. Therefore, it is essential to identify a strategy that allows for reducing the environmental impact produced by aircraft on the landing and take-off cycle and its operating costs. In this study, four different taxiing strategies are implemented in an existing Italian airport. The results show advantageous scenarios through single-engine taxiing, reduced taxi time through improved surface traffic management, and onboard systems. On the other hand, operating towing solutions with internal combustion cause excessive production of pollutants, especially HC, CO, NOX, and particulate matter. Finally, towing with an electrically powered external vehicle provides good results for pollutants and the maximum reduction in fuel consumption, but it implies externalities on taxiing time. Compared to the current conditions, the best solutions ensure significant reductions in pollutants throughout the landing and take-off cycle (−3.2% for NOx and −44.2% for HC) and economic savings (−13.4% of fuel consumption).

Spatio-temporal distribution pattern of COVID-19 in the Northern Italy during the first-wave scenario: The role of the highway network.

Background: The rapid outbreak of Coronavirus disease 2019 (COVID-19) has posed several challenges to the scientific community. The goal of this paper is to investigate the spread of COVID-19 in Northern Italy during the so-called first wave scenario and to provide a qualitative comparison with the local highway net. Methods: Fixed a grid of days from February 27, 2020, the cumulative numbers of infections in each considered province have been compared to sequences of thresholds. As a consequence, a time-evolving classification of the state of danger in terms of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, in view of the smallest threshold overtaken by this comparison, has been obtained for each considered province. The provinces with a significant amount of cases have then been collected into matrices containing only the ones featuring a significant amount of cases. Results: The time evolution of the classification has then been qualitatively compared to the highway network, to identify similarities and thus linking the rapid spreading of COVID-19 and the highway connections. Conclusions: The obtained results demonstrate how the proposed model properly fits with the spread of COVID-19 along with the Italian highway transport network and could be implemented to analyze qualitatively other disease transmissions in different contexts and time periods.

Increased Placental Anti-Oxidant Response in Asymptomatic and Symptomatic COVID-19 Third-Trimester Pregnancies.

Despite Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) -induced Oxidative Stress (OxS) being well documented in different organs, the molecular pathways underlying placental OxS in late-pregnancy women with SARS-CoV-2 infection are poorly understood. Herein, we performed an observational study to determine whether placentae of women testing positive for SARS-CoV-2 during the third trimester of pregnancy showed redox-related alterations involving Catalase (CAT) and Superoxide Dismutase (SOD) antioxidant enzymes as well as placenta morphological anomalies relative to a cohort of healthy pregnant women. Next, we evaluated if placental redox-related alterations and mitochondria pathological changes were correlated with the presence of maternal symptoms. We observed ultrastructural alterations of placental mitochondria accompanied by increased levels of oxidative stress markers Thiobarbituric Acid Reactive Substances (TBARS) and Hypoxia Inducible Factor-1 α (HIF-1α) in SARS-CoV-2 women during the third trimester of pregnancy. Importantly, we found an increase in placental CAT and SOD antioxidant enzymes accompanied by physiological neonatal outcomes. Our findings strongly suggest a placenta-mediated OxS inhibition in response to SARS-CoV-2 infection, thus contrasting the cytotoxic profile caused by Coronavirus Disease 2019 (COVID-19).

Chronicles from the new normal: Urban planning, mobility and land-use management in the face of the COVID-19 crisis.

The world is facing new challenges due to the SARS-CoV-2 (Severe Acute Respiratory Syndrome CoronaVirus 2) virus outbreak identified in Wuhan, China in December 2019. The aim of this paper is to investigate and discuss how cities are being managed in the anti-pandemic "new normal". And this in light of unexpected phenomena such as: the on-going modal shift from public transport to private modes vs the new momentum gained by walking, and social lifestyles dictated by confinement first and now by unregulated behavior, also affecting land use. Add to this unpreparedness of pre-pandemic transport policies and the new emerging opportunities; the fresh directions for research and development, for example in the field of urban mobility management. With the additional goal to contribute to further advance the research, the paper also clearly shows that the crisis can be overcome only by considering different fields of action and by considering our common past.

Airport Landside Sustainable Capacity and Level of Service of Terminal Functional Subsystems

The airport terminal is a complex building composed of many functional subsystems dimensioned to host passenger traffic, considering an appropriate level of service (LoS). The most widely known method to assess the LoS and design the terminal areas is the Airport Development Reference Manual by the International Air Transport Association (IATA). Based on this, a calculation tool in Microsoft Excel®was implemented to assess the capacity and dimension of the facilities for each functional subsystem of the terminal. The tool, composed of nine correlated spreadsheets, is a useful model to design new structures, evaluate the LoS currently offered, plan interventions, and face the new rules of passenger distancing due to the COVID-19 emergency. An international airport terminal with 20 million/year including Schengen and extra-Schengen passengers was studied. The LoS of the terminal subsystems was assessed and the areas needed for each subsystem were calculated. In the analyzed case study, most subsystems (departure hall, check-in, boarding gates, baggage claim, and arrival halls) were over-designed, according to the definition of the IATA LoS. This means that available spaces for queues and holding are sufficiently large to easily face the new rules of social distancing for passengers due to the recent COVID-19 emergency.