Creating a hyperpolarised pseudo singlet state through polarisation transfer from parahydrogen under SABRE

The creation of magnetic states that have long lifetimes has been the subject of intense investigation, in part because of their potential to survive the time taken to travel from the point of injection in a patient to the point where a clinically diagnostic MRI trace is collected. We show here that it is possible to harness the Signal Amplification By Reversible Exchange (SABRE) process to create such states in a hyperpolarised form that improves their detectability in seconds without the need for any chemical change by reference to the model substrate 2-aminothiazole. We achieve this by transferring Zeeman derived polarisation that is 1500 times larger than that normally available at 400 MHz with greater than 90 % efficiency into the new state, which in this case has a 27 second lifetime

Predicting the next pandemic: VACCELERATE ranking of the World Health Organization's Blueprint for Action to Prevent Epidemics

Introduction: The World Health Organization (WHO)'s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of triggering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. Methods: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. Results: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS-CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. Conclusion: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks

Dynamic NMR of nano- and microstructured materials

The fast technological advancement which took place over the past few decades sustained the development of various categories of advanced polymeric, composite and porous materials, with complex physical and chemical properties determined by their structure and dynamics at nano- and micrometer levels. This brought forth the necessity of combining different methods of analysis, which cover multiple length scales, in order to allow for a comprehensive characterization and a valid prediction of a material's macroscopic behaviour. The purpose of this work was to characterize the structure and dynamics of various types of nano- and micro structured systems, such as silane crosslinked poly(ethylene), cement-in-polymer dispersion with different compositions or model and natural porous media, using a combination of nuclear magnetic resonance (NMR) methods that provide relevant information on different length scales of interest. Data processing and interpretation was facilitated by self-made computational procedures and mathematical models. The different subjects approached in this work are briefly presented in Chapter 1 (Introduction) and discussed in detail further on in an order according to the length scale of the motion probed. In Chapter 2 proton NMR wideline spectroscopy is used to obtain information on the phase composition, molecular mobility and domain sizes of crosslinked poly(ethylene) (PE), a polymer commonly used in a broad range of applications, from day-to-day life basic commodities like water and sewage pipes, to insulating coatings for medium and high voltage wires. Due to its industrial importance, this type of PE has been previously characterized using a variety of methods. The novelty brought by this study is the quantitative analysis of the spin diffusion (SD) coefficients and domain sizes of different phases by a dedicated software developed for solving the spin diffusion equations for a lamellar morphology, using as input data extracted from NMR double quantum filtered SD experiments and including a series of bonds for and minimizing uncertainties in the estimation of essential parameters. Recently developed cement-in-polymer dispersions (c/p) with different compositions and cement to polymer ratios are investigated in Chapters 3 and 4, by a vast array of NMR techniques, that probe, on different length scales, the structure of the investigated specimens, as well as the dynamics of water transport inside the materials. Chapter 3 presents the results obtained using multinuclear solid state magic angle spinning NMR to probe, at nanometer level, the structure of cement-in-polymer dispersions . The hydration effects and crystallization of the inorganic matrix are probed by 29Si NMR while the chemical reactions of the organic phase are quantified by 13C cross-polarization; the results are correlated with data offered by other analysis techniques. The study of hydrated c/p is continued in Chapter 4, where proton NMR imaging is employed to obtain information about the microstructural changes which take place upon exposure to water at different temperatures. The water transport in the c/p matrix is monitored on line and the hydration phenomenon, together with information about the physical suffered by the samples are discussed with regard to polymer type, amount and curing conditions. A simple mathematical model of diffusion in a cylindrical system, involving time dependent diffusion coefficients and variable surface concentrations, is used to predict the manner in which the water amount inside the organic/cementitious pastes evolves in time. Further on, the effects of diffusive and advective transport in model and natural porous media are systematically investigated in Chapters 5 and 6. NMR exchange relaxometry is known as a very powerful tool for probing the structure and dynamics of fully or partially hydrated porous systems, but, until know, no information existed on how the effects of slow advective transport - a phenomenon of considerable interest for different branches of science and industry - are reflected in the NMR results. In this work, exchange relaxometry data were obtained from experiments performed on soda lime glass bead packs and quartz sand exposed to unidirectional flow. The complex results were analyzed in terms of an application-oriented mathematical model, yielding insight into the origin of the observed diffusion and flow signatures and opening up the possibility of using inexpensive and portable low field instruments for on site fluid velocity measurements. The thesis is concluded with a set of general remarks which summarize the results, showing that irrespective of the complex material under study, either a daily use plastic, a building material, or a soil specimen, various NMR techniques are readily available to elucidate dynamic phenomena on a wide variety of length scales

Dynamic NMR of nano- and microstructured materials

The fast technological advancement which took place over the past few decades sustained the development of various categories of advanced polymeric, composite and porous materials, with complex physical and chemical properties determined by their structure and dynamics at nano- and micrometer levels. This brought forth the necessity of combining different methods of analysis, which cover multiple length scales, in order to allow for a comprehensive characterization and a valid prediction of a material's macroscopic behaviour. The purpose of this work was to characterize the structure and dynamics of various types of nano- and micro structured systems, such as silane crosslinked poly(ethylene), cement-in-polymer dispersion with different compositions or model and natural porous media, using a combination of nuclear magnetic resonance (NMR) methods that provide relevant information on different length scales of interest. Data processing and interpretation was facilitated by self-made computational procedures and mathematical models. The different subjects approached in this work are briefly presented in Chapter 1 (Introduction) and discussed in detail further on in an order according to the length scale of the motion probed. In Chapter 2 proton NMR wideline spectroscopy is used to obtain information on the phase composition, molecular mobility and domain sizes of crosslinked poly(ethylene) (PE), a polymer commonly used in a broad range of applications, from day-to-day life basic commodities like water and sewage pipes, to insulating coatings for medium and high voltage wires. Due to its industrial importance, this type of PE has been previously characterized using a variety of methods. The novelty brought by this study is the quantitative analysis of the spin diffusion (SD) coefficients and domain sizes of different phases by a dedicated software developed for solving the spin diffusion equations for a lamellar morphology, using as input data extracted from NMR double quantum filtered SD experiments and including a series of bonds for and minimizing uncertainties in the estimation of essential parameters. Recently developed cement-in-polymer dispersions (c/p) with different compositions and cement to polymer ratios are investigated in Chapters 3 and 4, by a vast array of NMR techniques, that probe, on different length scales, the structure of the investigated specimens, as well as the dynamics of water transport inside the materials. Chapter 3 presents the results obtained using multinuclear solid state magic angle spinning NMR to probe, at nanometer level, the structure of cement-in-polymer dispersions . The hydration effects and crystallization of the inorganic matrix are probed by 29Si NMR while the chemical reactions of the organic phase are quantified by 13C cross-polarization; the results are correlated with data offered by other analysis techniques. The study of hydrated c/p is continued in Chapter 4, where proton NMR imaging is employed to obtain information about the microstructural changes which take place upon exposure to water at different temperatures. The water transport in the c/p matrix is monitored on line and the hydration phenomenon, together with information about the physical suffered by the samples are discussed with regard to polymer type, amount and curing conditions. A simple mathematical model of diffusion in a cylindrical system, involving time dependent diffusion coefficients and variable surface concentrations, is used to predict the manner in which the water amount inside the organic/cementitious pastes evolves in time. Further on, the effects of diffusive and advective transport in model and natural porous media are systematically investigated in Chapters 5 and 6. NMR exchange relaxometry is known as a very powerful tool for probing the structure and dynamics of fully or partially hydrated porous systems, but, until know, no information existed on how the effects of slow advective transport - a phenomenon of considerable interest for different branches of science and industry - are reflected in the NMR results. In this work, exchange relaxometry data were obtained from experiments performed on soda lime glass bead packs and quartz sand exposed to unidirectional flow. The complex results were analyzed in terms of an application-oriented mathematical model, yielding insight into the origin of the observed diffusion and flow signatures and opening up the possibility of using inexpensive and portable low field instruments for on site fluid velocity measurements. The thesis is concluded with a set of general remarks which summarize the results, showing that irrespective of the complex material under study, either a daily use plastic, a building material, or a soil specimen, various NMR techniques are readily available to elucidate dynamic phenomena on a wide variety of length scales

The Importance of Dose Intensity When Administering Cytotoxic Chemotherapy in NSCLC—A Matter as Actual Now as in the Past

Lung cancer, as the leading cause of death in oncology is one of the most challenging diseases nowadays. Even after the implementation of checkpoint inhibitors and targeted therapy as a standard of therapy for metastatic disease, the chemotherapy backbone remains essential in the treatment of these patients. This study aimed to evaluate how administration particularities in chemotherapy and toxicity management can influence the outcome. We conducted a retrospective single-institution study, at Elias University Emergency Hospital, Bucharest, Romania, between 2014 and 2018, in a heterogeneous patient population with metastatic non-small cell lung cancer that received combination chemotherapy. The inclusion criteria for this trial were—histological proof of non-small cell lung cancer (NSCLC), stage IV disease, ECOG (Eastern Cooperative Oncology Group) performance status of a maximum of two, treatment with cytotoxic chemotherapy for at least four courses (patients with fewer courses were excluded). All patients received combination chemotherapy. The main focus was on the effect of dose reduction and treatment delay on overall survival and progression-free survival. A total of 129 patients were enrolled. The response rate in the studied population was 69% and 62.8% had no toxicity greater than grade 2. Chemotherapy regimens used had the following distribution—paclitaxel + carboplatin 41.9%, paclitaxel + carboplatin + bevacizumab 12.4%, pemetrexed + carboplatin 12.4%, gemcitabine + carboplatin 26.4% and other regimens 7%. Mean PFS (Progression Free Survival) was 9.1 months and the mean OS (Overall Survival) was 14 months. OS was not significantly different in the treatment delay group versus the no delay one, p < 0.25 but dose- reduction significantly impacted OS, p < 0.03. Administration particularities, like febrile neutropenia prophylaxis, treatment of chemotherapy-related anemia, respecting the details of chemostability and preparation rules and emesis prophylaxis, were considered reasons for the good outcome. Details regarding cytotoxic chemotherapy administration remain of paramount importance for a good outcome and the benefit for survival they convey is crucial. Sometimes the benefit the patient derives from these details is comparable to the one newer therapies convey

Predicting the next pandemic: VACCELERATE ranking of the World Health Organization's Blueprint for Action to Prevent Epidemics

Introduction: The World Health Organization (WHO)'s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of triggering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. Methods: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. Results: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS-CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. Conclusion: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31â127 anaesthetic procedures in 30â874 children with a mean age of 6·35 years (SD 4·50) were included. The incidence of perioperative severe critical events was 5·2% (95% CI 5·0â5·5) with an incidence of respiratory critical events of 3·1% (2·9â3·3). Cardiovascular instability occurred in 1·9% (1·7â2·1), with an immediate poor outcome in 5·4% (3·7â7·5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10â000. This was independent of type of anaesthesia. Age (relative risk 0·88, 95% CI 0·86â0·90; p<0·0001), medical history, and physical condition (1·60, 1·40â1·82; p<0·0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0·99, 0·981â0·997; p<0·0048 for respiratory critical events, and 0·98, 0·97â0·99; p=0·0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia. Funding European Society of Anaesthesiology

Incidence of severe critical events in paediatric anaesthesia (APRICOT): a prospective multicentre observational study in 261 hospitals in Europe

Background Little is known about the incidence of severe critical events in children undergoing general anaesthesia in Europe. We aimed to identify the incidence, nature, and outcome of severe critical events in children undergoing anaesthesia, and the associated potential risk factors. Methods The APRICOT study was a prospective observational multicentre cohort study of children from birth to 15 years of age undergoing elective or urgent anaesthesia for diagnostic or surgical procedures. Children were eligible for inclusion during a 2-week period determined prospectively by each centre. There were 261 participating centres across 33 European countries. The primary endpoint was the occurence of perioperative severe critical events requiring immediate intervention. A severe critical event was defined as the occurrence of respiratory, cardiac, allergic, or neurological complications requiring immediate intervention and that led (or could have led) to major disability or death. This study is registered with ClinicalTrials.gov, number NCT01878760. Findings Between April 1, 2014, and Jan 31, 2015, 31 127 anaesthetic procedures in 30 874 children with a mean age of 6.35 years (SD 4.50) were included. The incidence of perioperative severe critical events was 5.2% (95% CI 5.0-5.5) with an incidence of respiratory critical events of 3.1% (2.9-3.3). Cardiovascular instability occurred in 1.9% (1.7-2.1), with an immediate poor outcome in 5.4% (3.7-7.5) of these cases. The all-cause 30-day in-hospital mortality rate was 10 in 10 000. This was independent of type of anaesthesia. Age (relative risk 0.88, 95% CI 0.86-0.90; p<0.0001), medical history, and physical condition (1.60, 1.40-1.82; p<0.0001) were the major risk factors for a serious critical event. Multivariate analysis revealed evidence for the beneficial effect of years of experience of the most senior anaesthesia team member (0.99, 0.981-0.997; p<0.0048 for respiratory critical events, and 0.98, 0.97-0.99; p=0.0039 for cardiovascular critical events), rather than the type of health institution or providers. Interpretation This study highlights a relatively high rate of severe critical events during the anaesthesia management of children for surgical or diagnostic procedures in Europe, and a large variability in the practice of paediatric anaesthesia. These findings are substantial enough to warrant attention from national, regional, and specialist societies to target education of anaesthesiologists and their teams and implement strategies for quality improvement in paediatric anaesthesia