Autocatalysis in Eschenmoser Coupling Reactions.

The Eschenmoser coupling reaction (ECR) of thioamides with electrophiles is believed to proceed via thiirane intermediates. However, little is known about converting the intermediates into ECR products. Previous mechanistic studies involved external thiophiles to remove the sulfur atom from the intermediates. In this work, an ECR proceeding without any thiophilic agent or base is studied by electrospray ionization-mass spectrometry. ESI-MS enables the detection of the so-far elusive polysulfide species Sn , with n ranging from 2 to 16 sulfur atoms, proposed to be the key species leading to product formation. Integrating observations from ion mobility spectrometry, ion spectroscopy, and reaction monitoring via flow chemistry coupled with mass spectrometry provides a comprehensive understanding of the reaction mechanism and uncovers the autocatalytic nature of the ECR reaction.

Proximity of alcohol outlets and presentation to hospital by young people after self-harm: A retrospective geospatial study using the integrated data infrastructure.

OBJECTIVES: There is a well-established association between alcohol use, misuse, intoxication and self-harm, the latter of which is associated with suicide. This study aimed to better understand the association between proximity to alcohol outlets and the likelihood of young people presenting to hospital following self-harm. METHODS: This was a nationwide retrospective geospatial study using data from the New Zealand Integrated Data Infrastructure using population-level data for 10-29-year-olds for the 2018 and 2017 calendar years. Presentations to hospital following self-harm were identified using the national minimum data set. Proximity to alcohol outlets was defined in road network distance (in kilometres) and ascertained using Integrated Data Infrastructure geospatial data. Alternative measures of proximity were employed in sensitivity analyses. Complete-case two-level random intercept logistic regression models were used to estimate the relationship between alcohol outlet proximity and hospital presentation for self-harm. Adjusted models included sex, age, ethnicity, area-level deprivation, urbanicity and distance to nearest medical facility. Analyses were also stratified by urbanicity. RESULTS: Of the 1,285,368 individuals (mean [standard deviation] age 20.0 [5.9] years), 7944 (0.6%) were admitted to hospital for self-harm. Overall, the odds of presenting to hospital for self-harm significantly decreased as the distance from the nearest alcohol outlet increased, including in adjusted models (adjusted odds ratio 0.980; 95% confidence interval = [0.969-0.992]); the association was robust to changes in the measure of alcohol proximity. The effect direction was consistent across all categorisations of urbanicity, but only statistically significant in large urban areas and rural areas. CONCLUSIONS: The findings of this study show a clear association between young people's access to alcohol outlets and presentation to hospital for self-harm and may provide a mandate for government policies and universal interventions to reduce young people's access to alcohol outlets. Further research regarding causative mechanisms is needed.

Timepix3: Temperature Influence on Radiation Energy Measurement with Si Sensor.

The Timepix3 readout ASIC chip is a hybrid pixelated radiation detector, designed at CERN, which contains a 256 px × 256 px matrix. Each of the 65,536 radiation-sensitive pixels can record an incoming particle, its energy deposition or time of arrival and measure them simultaneously. Since the detector is suitable for a wide range of applications from particle physics, national security and medicine to space science, it can be used in a wide range of temperatures. Until now, it has to be calibrated every time to the operating point of the application. This paper studies the possibility of energy measurement with Timepix3 equipped with a 500 m thick silicon sensor and MiniPIX readout interface in the temperatures between 10 ∘C and 70 ∘C with only one calibration. The detector has been irradiated by X-ray fluorescence photons in the energy range from 8 keV to 57 keV, and 31 keV to 81 keV photons from the 133Ba radioactive source. A deviation of 5% in apparent energy value may occur for a 10 ∘C change in temperature from the reference point, but, with the next temperature change, it can reach up to -30%. Moreover, Barium photons with an energy of 81 keV appear as deposited energy of only 55 keV at a detector temperature of 70 ∘C. An original compensation method that reduces the relative measurement error from -30% to less than 1% is presented in this paper.

Timepix3: Compensation of Thermal Distortion of Energy Measurement.

The Timepix3 is a hybrid pixellated radiation detector consisting of a 256 px × 256 px radiation-sensitive matrix. Research has shown that it is susceptible to energy spectrum distortion due to temperature variations. This can lead to a relative measurement error of up to 35% in the tested temperature range of 10 °C to 70 °C. To overcome this issue, this study proposes a complex compensation method to reduce the error to less than 1%. The compensation method was tested with different radiation sources, focusing on energy peaks up to 100 keV. The results of the study showed that a general model for temperature distortion compensation could be established, where the error in the X-ray fluorescence spectrum of Lead (74.97 keV) was reduced from 22% to less than 2% for 60 °C after the correction was applied. The validity of the model was also verified at temperatures below 0 °C, where the relative measurement error for the Tin peak (25.27 keV) was reduced from 11.4% to 2.1% at -40 °C. The results of this study demonstrate the effectiveness of the proposed compensation method and models in significantly improving the accuracy of energy measurements. This has implications for various fields of research and industry that require accurate radiation energy measurements and cannot afford to use power for cooling or temperature stabilisation of the detector.

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

Reactions of thiobenzamide or thioacetamide with 4-bromo-1,1-dimethyl-1,4-dihydroisoquinoline-3(2H)-one, 4-bromoisoquinoline-1,3(2H,4H)-dione and two α-bromo(phenyl)acetamides were examined under various conditions (base, solvent, thiophile, temperature) and structure/medium features that influence product distribution (Eschenmoser coupling reaction, Hantzsch thiazole synthesis and elimination to nitriles) were identified. The key factor that enables the successful Eschenmoser coupling reaction involves the optimum balance in acidity of nitrogen and carbon atoms of the intermediary α-thioiminium salts.

Synthesis and Characterization of New Boron Compounds Using Reaction of Diazonium Tetraphenylborate with Enaminoamides.

A family of oxazaborines, diazaborinones, triazaborines, and triazaborinones was prepared by reaction of polarized ethylenes, such as ß-enaminoamides, with 4-methylbenzenediazonium tetraphenylborates. The reaction conditions (stirring in CH2Cl2 at room temperature (Method A) or stirring with CH3COONa in CH2Cl2 at room temperature (Method B) or refluxing in the CH2Cl2/toluene mixture (Method C)) controlled the formation and relative content of these compounds in the reaction mixtures from one to three products. Substituted oxazaborines gradually rearranged into diazaborinones at 250 °C. The prepared compounds were characterized by 1H NMR, 13C NMR, IR, and UV-Vis spectroscopy, HRMS, or microanalysis. The structure of individual compounds was confirmed by 11B NMR, 15N NMR, 1D NOESY, and X-ray analysis. The mechanism of reaction of enaminoamides with 4-methylbenzenediazonium tetraphenylborate was proposed.

Synthesis of the Kinase Inhibitors Nintedanib, Hesperadin, and Their Analogues Using the Eschenmoser Coupling Reaction.

A novel synthetic approach involving an Eschenmoser coupling reaction of substituted 3-bromooxindoles (H, 6-Cl, 6-COOMe, 5-NO2) with two substituted thiobenzanilides in dimethylformamide or acetonitrile was used for the synthesis of eight kinase inhibitors including Nintedanib and Hesperadin in yields exceeding 76%. Starting compounds for the synthesis are also easily available in good yields. 3-Bromooxindoles were prepared either from corresponding isatins using a three-step synthesis in an average overall yield of 65% or by direct bromination of oxindoles (yield of 65-86%). Starting N-(4-piperidin-1-ylmethyl-phenyl)-thiobenzamide was prepared by thionation of the corresponding benzanilide in an 86% yield and N-methyl-N-(4-thiobenzoylaminophenyl)-2-(4-methylpiperazin-1-yl)acetamide was prepared by thioacylation of the corresponding aniline with methyl dithiobenzoate in an 86% yield.

The good, the bad, and the environment: developing an area-based measure of access to health-promoting and health-constraining environments in New Zealand.

BACKGROUND: Accounting for the co-occurrence of multiple environmental influences is a more accurate reflection of population exposure than considering isolated influences, aiding in understanding the complex interactions between environments, behaviour and health. This study examines how environmental 'goods' such as green spaces and environmental 'bads' such as alcohol outlets co-occur to develop a nationwide area-level healthy location index (HLI) for New Zealand. METHODS: Nationwide data were collected, processed, and geocoded on a comprehensive range of environmental exposures. Health-constraining 'bads' were represented by: (i) fast-food outlets, (ii) takeaway outlets, (iii) dairy outlets and convenience stores, (iv) alcohol outlets, (v) and gaming venues. Health-promoting 'goods' were represented by: (i) green spaces, (ii) blue spaces, (iii) physical activity facilities, (iv) fruit and vegetable outlets, and (v) supermarkets. The HLI was developed based on ranked access to environmental domains. The HLI was then used to investigate socio-spatial patterning by area-level deprivation and rural/urban classification. RESULTS: Results showed environmental 'goods' and 'bads' co-occurred together and were patterned by area-level deprivation. The novel HLI shows that the most deprived areas of New Zealand often have the most environmental 'bads' and less access to environmental 'goods'. CONCLUSIONS: The index, that is now publicly available, is able to capture both inter-regional and local variations in accessibility to health-promoting and health-constraining environments and their combination. Results in this study further reinforce the need to embrace the multidimensional nature of neighbourhood and place not only when designing health-promoting places, but also when studying the effect of existing built environments on population health.

Spatial-temporal patterns of childhood immunization in New Zealand (2006-2017): an improving pattern but not for all?

BACKGROUND: Declining childhood immunization represents a serious public health problem globally and in New Zealand. To guide efforts to increase immunization coverage, this study monitors nationwide change in immunization coverage since the introduction of the National Immunisation Register (NIR) in 2005 and spatiotemporal patterns of immunization coverage from 2006 to 2017. METHODS: The study population consisted of 4 482 499 individual immunization records that were obtained from the NIR (2005-2017). Data on yearly and average immunization coverage in census area units (CAUs) in New Zealand were calculated by milestone age (6/8/12/18/24/60/144 months). Data for 2005 were excluded due to missing records in the introductory period of the NIR. We analyzed spatial and spatiotemporal patterns using Gi* and SaTScan methods. RESULTS: Immunization coverage improved since the introduction of the NIR in 2005, reaching a peak in 2014 and 2015 with a slight decrease in 2016 and 2017. Well and insufficiently immunized areas were identified with spatial autocorrelation analyses highlighting several hot- and cold-spots. Comparison of CAUs with neighbouring CAUs allowed for the identification of places where immunization coverage was significantly higher or lower than expected, over both time and space. CONCLUSION: We provide the first spatiotemporal analysis of childhood immunization in New Zealand that utilizes a large sample of over 4.4 million individual immunization records. Our spatial analyses enable policymakers to understand the development of childhood immunization coverage and make more effective prevention strategies in New Zealand.

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction.

A highly modular method for the synthesis of (Z)-3-[amino(phenyl/methyl)methylidene]-1,3-dihydro-2H-indol-2-ones starting from easily available 3-bromooxindoles or (2-oxoindolin-3-yl)triflate and thioacetamides or thiobenzamides is described. A series of 49 compounds, several of which have previously been shown to possess significant tyrosin kinase inhibiting activity, was prepared in yields varying mostly from 70 to 97% and always surpassing those obtained by other published methods. The method includes an Eschenmoser coupling reaction, which is very feasible (even without using a thiophile except tertiary amides) and scalable. The (Z)-configuration of all products was confirmed by NMR techniques.

The Crisis Map of the Czech Republic: the nationwide deployment of an Ushahidi application for disasters.

Crisis mapping is a legitimate component of both crisis informatics and disaster risk management. It has become an effective tool for humanitarian workers, especially after the earthquake in Haiti in 2010. Ushahidi is among the many mapping platforms on offer in the growing field of crisis mapping, and involves the application of crowdsourcing to create online and interactive maps of areas in turmoil. This paper presents the Crisis Map of the Czech Republic, which is the first such instrument to be deployed nationwide in Central Europe. It describes the methodologies used in the preparatory work phase and details some practices identified during the creation and actual employment of the map. In addition, the paper assesses its structure and technological architecture, as well as its potential possible development in the future. Lastly, it evaluates the utilisation of the Crisis Map during the floods in the Czech Republic in 2013.

Using geovisual analytics in Google Earth to understand disease distribution: a case study of campylobacteriosis in the Czech Republic (2008-2012).

BACKGROUND: Visual analytics aims to connect the processing power of information technologies and the user's ability of logical thinking and reasoning through the complex visual interaction. Moreover, the most of the data contain the spatial component. Therefore, the need for geovisual tools and methods arises. Either one can develop own system but the dissemination of findings and its usability might be problematic or the widespread and well-known platform can be utilized. The aim of this paper is to prove the applicability of Google Earth™ software as a tool for geovisual analytics that helps to understand the spatio-temporal patterns of the disease distribution. METHODS: We combined the complex joint spatio-temporal analysis with comprehensive visualisation. We analysed the spatio-temporal distribution of the campylobacteriosis in the Czech Republic between 2008 and 2012. We applied three main approaches in the study: (1) the geovisual analytics of the surveillance data that were visualised in the form of bubble chart; (2) the geovisual analytics of the disease's weekly incidence surfaces computed by spatio-temporal kriging and (3) the spatio-temporal scan statistics that was employed in order to identify high or low rates clusters of affected municipalities. The final data are stored in Keyhole Markup Language files and visualised in Google Earth™ in order to apply geovisual analytics. RESULTS: Using geovisual analytics we were able to display and retrieve information from complex dataset efficiently. Instead of searching for patterns in a series of static maps or using numerical statistics, we created the set of interactive visualisations in order to explore and communicate results of analyses to the wider audience. The results of the geovisual analytics identified periodical patterns in the behaviour of the disease as well as fourteen spatio-temporal clusters of increased relative risk. CONCLUSIONS: We prove that Google Earth™ software is a usable tool for the geovisual analysis of the disease distribution. Google Earth™ has many indisputable advantages (widespread, freely available, intuitive interface, space-time visualisation capabilities and animations, communication of results), nevertheless it is still needed to combine it with pre-processing tools that prepare the data into a form suitable for the geovisual analytics itself.

Long-term health conditions among household families in Aotearoa New Zealand: cross-sectional analysis of integrated Census and administrative data.

AIM: Little is known about the extent to which families in Aotearoa New Zealand are affected by long-term health conditions (HCs). This study aimed to explore the rates of nine selected HCs among New Zealand family members within the same household. METHOD: Linked population and administrative health data were obtained for families living in the same household according to the 2013 New Zealand Census (N=1,043,172). Health data (2008-2013) were used to ascertain whether people in these families (N=3,137,517) received treatment or services for nine selected HCs: cancer, chronic obstructive pulmonary disease, heart disease, diabetes, dementia, gout, stroke, traumatic brain injury (TBI), or mental health/behaviour conditions (MHBCs). RESULTS: Over 60% of families included at least one person with a HC, and this rate was higher among multi-generation families (73.9%). The most common HCs were MHBCs (39.4% of families), diabetes (16.0%) and TBI (13.9%). At the highest level of socio-economic deprivation, 57.6% of children aged under 18 years lived with a family member who had a HC. CONCLUSION: Three in five New Zealand household families included someone with at least one of nine selected HCs, with differences in the proportion affected according to family composition, socio-economic status and an individual's ethnicity. This suggests that there are a substantial number of people at risk of the poor outcomes associated with the experience of HCs within their family.

Particle tracking, recognition and LET evaluation of out-of-field proton therapy delivered to a phantom with implants.

Objective.This study aims to assess the composition of scattered particles generated in proton therapy for tumors situated proximal to some titanium (Ti) dental implants. The investigation involves decomposing the mixed field and recording Linear Energy Transfer (LET) spectra to quantify the influence of metallic dental inserts located behind the tumor.Approach.A therapeutic conformal proton beam was used to deliver the treatment plan to an anthropomorphic head phantom with two types of implants inserted in the target volume (made of Ti and plastic, respectively). The scattered radiation resulted during the irradiation was detected by a hybrid semiconductor pixel detector MiniPIX Timepix3 that was placed distal to the Spread-out Bragg peak. Visualization and field decomposition of stray radiation were generated using algorithms trained in particle recognition based on artificial intelligence neural networks (AI NN). Spectral sensitive aspects of the scattered radiation were collected using two angular positions of the detector relative to the beam direction: 0° and 60°.Results.Using AI NN, 3 classes of particles were identified: protons, electrons & photons, and ions & fast neutrons. Placing a Ti implant in the beam's path resulted in predominantly electrons and photons, contributing 52.2% of the total number of detected particles, whereas for plastic implants, the contribution was 65.4%. Scattered protons comprised 45.5% and 31.9% with and without metal inserts, respectively. The LET spectra were derived for each group of particles identified, with values ranging from 0.01 to 7.5 keVµm-1for Ti implants/plastic implants. The low-LET component was primarily composed of electrons and photons, while the high-LET component corresponded to protons and ions.Significance.This method, complemented by directional maps, holds the potential for evaluating and validating treatment plans involving stray radiation near organs at risk, offering precise discrimination of the mixed field, and enhancing in this way the LET calculation.

An in-vivo treatment monitoring system for ion-beam radiotherapy based on 28 Timepix3 detectors.

Ion-beam radiotherapy is an advanced cancer treatment modality offering steep dose gradients and a high biological effectiveness. These gradients make the therapy vulnerable to patient-setup and anatomical changes between treatment fractions, which may go unnoticed. Charged fragments from nuclear interactions of the ion beam with the patient tissue may carry information about the treatment quality. Currently, the fragments escape the patient undetected. Inter-fractional in-vivo treatment monitoring based on these charged nuclear fragments could make ion-beam therapy safer and more efficient. We developed an ion-beam monitoring system based on 28 hybrid silicon pixel detectors (Timepix3) to measure the distribution of fragment origins in three dimensions. The system design choices as well as the ion-beam monitoring performance measurements are presented in this manuscript. A spatial resolution of 4 mm along the beam axis was achieved for the measurement of individual fragment origins. Beam-range shifts of 1.5 mm were identified in a clinically realistic treatment scenario with an anthropomorphic head phantom. The monitoring system is currently being used in a prospective clinical trial at the Heidelberg Ion Beam Therapy Centre for head-and-neck as well as central nervous system cancer patients.

Switchable cyclopalladation of substrates containing two directing groups: on the way to non-symmetrical [2.2]-dipalladaparacyclophanes.

Simple switching of the site-selectivity of C-H activation reactions of substrates containing multiple directing groups is particularly important for the so-called late stage functionalization synthetic approach. In this work, we verified the possibility of achieving this by adding acids of different strengths. Using a substrate containing two differently strong (and basic) directing groups, the influence of the addition of acids on the regioselectivity of the C-H activation step of the reaction with palladium acetate was thoroughly studied. The addition of no or weak acids results in cyclopalladation being controlled by a stronger directing group. However, the addition of a strong acid causes protonation of this group and the reaction is then controlled by a weaker directing group. Finally, this approach enables double C-H activation leading to a unique class of compounds: "non-symmetrical" [2.2]-dipalladaparacyclophanes.

Single proton LET characterization with the Timepix detector and artificial intelligence for advanced proton therapy treatment planning.

Objective.Protons have advantageous dose distributions and are increasingly used in cancer therapy. At the depth of the Bragg peak range, protons produce a mixed radiation field consisting of low- and high-linear energy transfer (LET) components, the latter of which is characterized by an increased ionization density on the microscopic scale associated with increased biological effectiveness. Prediction of the yield and LET of primary and secondary charged particles at a certain depth in the patient is performed by Monte Carlo simulations but is difficult to verify experimentally.Approach.Here, the results of measurements performed with Timepix detector in the mixed radiation field produced by a therapeutic proton beam in water are presented and compared to Monte Carlo simulations. The unique capability of the detector to perform high-resolution single particle tracking and identification enhanced by artificial intelligence allowed to resolve the particle type and measure the deposited energy of each particle comprising the mixed radiation field. Based on the collected data, biologically important physics parameters, the LET of single protons and dose-averaged LET, were computed.Main results.An accuracy over 95% was achieved for proton recognition with a developed neural network model. For recognized protons, the measured LET spectra generally agree with the results of Monte Carlo simulations. The mean difference between dose-averaged LET values obtained from measurements and simulations is 17%. We observed a broad spectrum of LET values ranging from a fraction of keVµm-1to about 10 keVµm-1for most of the measurements performed in the mixed radiation fields.Significance.It has been demonstrated that the introduced measurement method provides experimental data for validation of LETDor LET spectra in any treatment planning system. The simplicity and accessibility of the presented methodology make it easy to be translated into a clinical routine in any proton therapy facility.

Out-of-field measurements and simulations of a proton pencil beam in a wide range of dose rates using a Timepix3 detector: Dose rate, flux and LET.

Stray radiation produced by ultra-high dose-rates (UHDR) proton pencil beams is characterized using ASIC-chip semiconductor pixel detectors. A proton pencil beam with an energy of 220 MeV was utilized to deliver dose rates (DR) ranging from conventional radiotherapy DRs up to 270 Gy/s. A MiniPIX Timepix3 detector equipped with a silicon sensor and integrated readout electronics was used. The chip-sensor assembly and chipboard on water-equivalent backing were detached and immersed in the water-phantom. The deposited energy, particle flux, DR, and the linear energy transfer (LET(Si)) spectra were measured in the silicon sensor at different positions both laterally, at different depths, and behind the Bragg peak. At low-intensity beams, the detector is operated in the event-by-event data-driven mode for high-resolution spectral tracking of individual particles. This technique provides precise energy loss response and LET(Si) spectra with radiation field composition resolving power. At higher beam intensities a rescaling of LET(Si) can be performed as the distribution of the LET(Si) spectra exhibits the same characteristics regardless of the delivered DR. The integrated deposited energy and the absorbed dose can be thus measured in a wide range. A linear response of measured absorbed dose was obtained by gradually increasing the delivered DR to reach UHDR beams. Particle tracking of scattered radiation in data-driven mode could be performed at DRs up to 0.27 Gy/s. In integrated mode, the saturation limits were not reached at the measured out-of-field locations up to the delivered DR of over 270 Gy/s. A good agreement was found between measured and simulated absorbed doses.

Thermal neutron detection and track recognition method in reference and out-of-field radiotherapy FLASH electron fields using Timepix3 detectors.

Objective.This work presents a method for enhanced detection, imaging, and measurement of the thermal neutron flux.Approach. Measurements were performed in a water tank, while the detector is positioned out-of-field of a 20 MeV ultra-high pulse dose rate electron beam. A semiconductor pixel detector Timepix3 with a silicon sensor partially covered by a6LiF neutron converter was used to measure the flux, spatial, and time characteristics of the neutron field. To provide absolute measurements of thermal neutron flux, the detection efficiency calibration of the detectors was performed in a reference thermal neutron field. Neutron signals are recognized and discriminated against other particles such as gamma rays and x-rays. This is achieved by the resolving power of the pixel detector using machine learning algorithms and high-resolution pattern recognition analysis of the high-energy tracks created by thermal neutron interactions in the converter.Main results. The resulting thermal neutrons equivalent dose was obtained using conversion factor (2.13(10) pSv·cm2) from thermal neutron fluence to thermal neutron equivalent dose obtained by Monte Carlo simulations. The calibrated detectors were used to characterize scattered radiation created by electron beams. The results at 12.0 cm depth in the beam axis inside of the water for a delivered dose per pulse of 1.85 Gy (pulse length of 2.4µs) at the reference depth, showed a contribution of flux of 4.07(8) × 103particles·cm-2·s-1and equivalent dose of 1.73(3) nSv per pulse, which is lower by ∼9 orders of magnitude than the delivered dose.Significance. The presented methodology for in-water measurements and identification of characteristic thermal neutrons tracks serves for the selective quantification of equivalent dose made by thermal neutrons in out-of-field particle therapy.