Radiotherapy in a FLASH : Towards clinical translation of ultra-high dose rate electron therapy

FLASH radiotherapy (FLASH-RT) is a promising new approach to radiotherapy that has the potential to transform the field. By administering radiation at ultra-high dose rates (UHDR) on a millisecond timescale, FLASH-RT may increase normal tissue tolerance compared to conventional radiotherapy while maintaining the anti-tumoral effect. However, the short treatment times present unique physical and technical challenges that must be resolved to ensure safe clinical implementation. The overall aim of this thesis was to address some of these challenges and promote the clinical translation of electron FLASH-RT. Specifically, the studies included in this thesis aimed to develop, establish, and evaluate tools and procedures to measure, plan, and deliver the UHDR electron beam of a modified clinical linear accelerator.In conventional radiotherapy, transmission chambers are used for beam monitoring during treatment delivery. In the first part of this thesis, we showed that the charge collection efficiency of the accelerator’s built-in transmission chamber decreases substantially as the dose-per-pulse (DPP) increases. However, we also demonstrated that this issue could be overcome and that the operating range of the chamber could be extended up to the ultra-high DPP regime by adjusting its position, design, and operation. Our results suggest that a transmission chamber-based monitoring approach might also be employed in UHDR electron beams, which would make the procedure for FLASH-RT delivery similar to conventional delivery.In the second part of this thesis, we established and evaluated dosimetric procedures for preclinical and clinical UHDR irradiations. Accurate delivery of the desired dose is critical to enable robust radiobiological studies that can help identify the biological mechanisms underlying the sparing effect of FLASH-RT and provide guidance in selecting beam parameters to test in clinical studies. We also demonstrated the feasibility of FLASH-RT in a clinical setting by initiating treatments of veterinary patients and conducting a dose-escalation trial in canine patients with spontaneously developed tumours. Finally, we also investigated a passive intensity-modulation technique with the aim of reducing the risk of radiation-induced side effects resulting from heterogeneous dose distributions in upcoming clinical trials. Our findings indicate that this technique, which is compatible with FLASH-RT delivery, can enhance the homogeneity of the dose distribution compared to utilizing an open electron beam. In the work included in this thesis, we established and evaluated tools and procedures to enable accurate UHDR delivery in a preclinical and clinical setting, which is crucial for a safe path towards clinical translation of FLASH-RT

Added values in groceries : a case study of a market leader

Konkurrensen på den svenska dagligvarumarknaden är stor. I dagens matbutiker möts konsumenten av ett ofantligt utbud av produkter. Varje vara finns i olika märken, i olika prisklasser och i olika produktutformningar med olika egenskaper. Detta gör att det är svårt för producenter att få in en ny produkt på marknaden och dessutom allt svårare att hålla kvar den där. Därmed kan mervärdesaspekten bli allt viktigare för producenterna eftersom den ger en möjlighet till att differentiera sig från konkurrenterna genom att skapa mervärden som konsumenten efterfrågar. Mervärden ses som värdeökningar för en produkt eller tjänst som uppkommer på grund av till exempel en speciell egenskap, aktivitet, funktion eller nytta. Denna studie syftar till att förklara några av de grunder som finns för att använda mervärden i marknadsföringen av livsmedel. Studien förklarar också vad Lindahls mejeriprodukter anser är differentieringsgrunder för deras produkt turkisk yoghurt. För att ge den empiriska studien ett djup och kontext har en kombination av flera källor använts. En litteraturstudie har gjorts för att skapa en teoretisk kunskapsbas med hjälp av tidigare forskning och därefter har en fallstudie genomförts på produkten turkisk yoghurt från företaget Lindahls mejeriprodukter. Den teoretiska kunskapsbasen har varit en grund för insamlingen och tolkningen av empiriskt data. Några centrala begrepp inom den teoretiska kunskapsbasen är marknadsföringsmixen, varumärkesteori, köpbeslutskategorisering och mervärden. Det som framkommit under studien är att differentieringsgrunder för Lindahls mejeriprodukter är att de var först in på marknaden, att de har ett starkt varumärke, en bra grundprodukt, en god kundkontakt samt är och har alltid varit marknadsledare i produktsegmentet matlagningsyoghurt. Vidare visar studien att de grunder för mervärdesskapande som anses mest betydelsefulla är hälsoaspekten, miljö- och hållbarhetsaspekten, identitetsskapande samt design.The competition in the Swedish grocery market is well developed. In grocery stores the consumers meet a vast range of products. Each product is available in different brands, price ranges and characteristics. This makes it difficult for producers to get their new products into the market and even more difficult to keep them there. Therefore it is possible that the aspect of added value becomes increasingly important for the producers as it provides a means to differentiate them from the competition and enables a creation of added value that the consumers demand. Added value is seen as an increase of value for a product or service that comes from special characteristics, activities, functions or benefits that is seen as additional to the expected standard. The aim of this study is to explain grounds used in marketing a food product with added values. The study also explains what the company Lindahls dairy products believe are the grounds for differentiation for their Turkish-style-yoghurt. A combination of sources has been used as a means to give the paper a greater understanding. A literature study has been done on previous research to create a theoretical knowledge-base and a case study has been done on the product Turkish-style-yoghurt from Lindahls dairy products. The theoretical knowledge-base functioned as a ground for the collecting of empirical data. Some of the key conceptions from the theoretical knowledge-base are the marketing mix, branding, buying behavior and added values. The study demonstrates that the grounds for differentiation for Lindahls dairy products are the following: they were first in the market, they have a strong brand, their product has a good standard, they have a well-established contact with their customers and they have always been the market leader in the segment of their products. Furthermore the study shows that the grounds considered the most important for creating added value are health concerns, environmental sustainability, identity creation and design

Amperometric Self-Referencing Ceramic Based Microelectrode Arrays for D-Serine Detection

D-serine is the major D-amino acid in the mammalian central nervous system. As the dominant co-agonist of the endogenous synaptic NMDA receptor, D-serine plays a role in synaptic plasticity, learning, and memory. Alterations in D-serine are linked to neuropsychiatric disorders including schizophrenia. Thus, it is of increasing interest to monitor the concentration of D-serine in vivo as a relevant player in dynamic neuron-glia network activity. Here we present a procedure for amperometric detection of D-serine with self-referencing ceramic-based microelectrode arrays (MEAs) coated with D-amino acid oxidase from the yeast Rhodotorula gracilis (RgDAAO). We demonstrate in vitro D-serine recordings with a mean sensitivity of 8.61 ± 0.83 pA/µM to D-serine, a limit of detection (LOD) of 0.17 ± 0.01 µM, and a selectivity ratio of 80:1 or greater for D-serine over ascorbic acid (mean ± SEM; n = 12) that can be used for freely moving studies

Crystallographic characterization of the geometry changes upon electron loss from 2-tert-butyl-3-aryl-2,3-diazabicyclo 2.2.2 octanes

Crystal structures of 2-tert-butyl-3-(2,3,5,6-tetramethylphenyl)-2,3-diazabicyclo[2.2.2]-octane radical cation nitrate (HyDU+NO_3-) [Hy = (2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl]; 2-tert-butyl-3-(1-naphthyl)-2,3-diazabicyclo[2.2.2]octane radical cation hexafluoroantiminate (Hy^1NA+SbF_6-); 2-tert-butyl-3-(2-naphthyl)-2,3-diazabicyclo-[2.2.2]octane radical cation hexafluoroantiminate (Hy^2NA+SbF_6-); 1,5-bis(2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl)naphthalene dication bis(tetraphenylborate) (Hy_2^(15)NA^(2+)(Ph_4B^-)_2); and 2,7-bis(2-tert-butyl-2,3-diazabicyclo[2.2.2]oct-3-yl)naphthalene dication bis(hexafluoroantiminate) (Hy_2^(27)NA^(2+)(SbF_6^-)_2·CH_3CN) are reported, and the geometries about the oxidized Hy units compared with literature data for neutral Hy-substituted analogues and the geometry changes upon electron loss for these compounds, which have a lone pair, lone pair twist angle in the neutral form (θ(0)) in the range 122−130°, are compared with those for tetraalkylhydrazines that have θ(0) values near 180, 90, and 0°

Implants and all-ceramic restorations in a patient treated for aggressive periodontitis: a case report

A 23-year-old female with aggressive periodontitis was treated using dental implants and LAVA system. The severely compromised teeth were extracted irrespective of initial conservative periodontal treatment. An implant-supported overdenture with 4 implants was fabricated for the maxilla and all-ceramic restorations for the mandible. Esthetic and functional goals were achieved with team approach involving periodontists and prosthodontists. This case report describes a treatment procedure for a generalized aggressive periodontitis patient with severe bone resorption

Оптимизация преподавания темы "Диагностика и лечение атеросклероза" на факультете повышения квалификации врачей

ФАКУЛЬТЕТЫ ПОВЫШЕНИЯ КВАЛИФИКАЦИИПОВЫШЕНИЕ КВАЛИФИКАЦИИОБРАЗОВАНИЕ МЕДИЦИНСКОЕ, ПОВЫШЕНИЕ КВАЛИФИКАЦИИПРЕПОДАВАНИЕМЕТОДИКА ПРЕПОДАВАНИЯОБРАЗОВАТЕЛЬНЫЕ ТЕХНОЛОГИ

Развитие исследовательской деятельности учащихся при изучении естественнонаучных дисциплин

ЕСТЕСТВЕННОНАУЧНЫЕ ДИСЦИПЛИНЫИССЛЕДОВАТЕЛЬСКАЯ ДЕЯТЕЛЬНОСТЬУЧЕБНЫЕ ПОСОБИЯВ пособии приведен анализ развития понятия "исследовательская деятельность", определена структура и уровни развития исследовательской деятельности учащихся, представлена модель развития исследовательской деятельности в процессе изучения естественнонаучных дисциплин и педагогические условия ее реализации

Beam control system and output fine-tuning for safe and precise delivery of FLASH radiotherapy at a clinical linear accelerator

IntroductionWe have previously adapted a clinical linear accelerator (Elekta Precise, Elekta AB) for ultra-high dose rate (UHDR) electron delivery. To enhance reliability in future clinical FLASH radiotherapy trials, the aim of this study was to introduce and evaluate an upgraded beam control system and beam tuning process for safe and precise UHDR delivery.Materials and MethodsThe beam control system is designed to interrupt the beam based on 1) a preset number of monitor units (MUs) measured by a monitor detector, 2) a preset number of pulses measured by a pulse-counting diode, or 3) a preset delivery time. For UHDR delivery, an optocoupler facilitates external control of the accelerator’s thyratron trigger pulses. A beam tuning process was established to maximize the output. We assessed the stability of the delivery, and the independent interruption capabilities of the three systems (monitor detector, pulse counter, and timer). Additionally, we explored a novel approach to enhance dosimetric precision in the delivery by synchronizing the trigger pulse with the charging cycle of the pulse forming network (PFN).ResultsImproved beam tuning of gun current and magnetron frequency resulted in average dose rates at the dose maximum at isocenter distance of >160 Gy/s or >200 Gy/s, with or without an external monitor chamber in the beam path, respectively. The delivery showed a good repeatability (standard deviation (SD) in total film dose of 2.2%) and reproducibility (SD in film dose of 2.6%). The estimated variation in DPP resulted in an SD of 1.7%. The output in the initial pulse depended on the PFN delay time. Over the course of 50 measurements employing PFN synchronization, the absolute percentage error between the delivered number of MUs calculated by the monitor detector and the preset MUs was 0.8 ± 0.6% (mean ± SD).ConclusionWe present an upgraded beam control system and beam tuning process for safe and stable UHDR electron delivery of hundreds of Gy/s at isocenter distance at a clinical linac. The system can interrupt the beam based on monitor units and utilize PFN synchronization for improved dosimetric precision in the dose delivery, representing an important advancement toward reliable clinical FLASH trials

The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders

Understanding the neurochemical basis for cognitive function is one of the major goals of neuroscience, with a potential impact on the diagnosis, prevention and treatment of a range of psychiatric and neurological disorders. In this review, the focus will be on a biochemical pathway that remains under-recognised in its implications for brain function, even though it can be responsible for moderating the activity of two neurotransmitters fundamentally involved in cognition – glutamate and acetylcholine. Since this pathway – the kynurenine pathway of tryptophan metabolism - is induced by immunological activation and stress it also stands in an unique position to mediate the effects of environmental factors on cognition and behaviour. Targetting the pathway for new drug development could, therefore, be of value not only for the treatment of existing psychiatric conditions, but also for preventing the development of cognitive disorders in response to environmental pressures