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Recommendations on the clinical application and future potential of α-particle therapy
No full textThis review comprehensively assesses the clinical applications and future potential of alpha-emitting radionuclides available for targeted alpha-particle therapy (TAT) in cancer treatment. The approval of radium-223 therapy in 2013 marked a significant advancement in alpha-emitting therapeutic radiopharmaceuticals, which are primarily used in treatment of prostate cancer. The EU SECURE project was introduced as a major initiative to enhance the sustainability and safety of medical alpha-emitting radionuclides production in Europe. This literature review was conducted by a multidisciplinary team on selected radionuclides, including actinium-225, bismuth-213, astatine-211, lead-212, terbium-149, radium-223 and thorium-227. These were selected based on their clinical significance, as identified in the EU PRISMAP project and subsequent literature searches. The review process involved searching major databases using specific keywords related to alpha-emitter therapy and was limited to articles in English. For each selected radionuclide, the physical characteristics, the radiochemistry, and the pre-clinical and clinical studies are explored. Actinium-225 is the most widely studied alpha emitter, with several preclinical and clinical studies on prostate cancer and neuroendocrine tumours. Other types of tumours (such as glioblastoma) still require preclinical and clinical development. Bismuth-213 bound to antibodies, peptides and nanobodies has shown optimal results in preclinical and clinical studies, with increased median survival and no significant toxicity. Astatine-211 differs from most other α-emitters relevant to TAT, since it yields one α-particle per decay. This offers certain translational advantages, including the simplification of radiation dosimetry calculations and quality control (QC). Lead-212 has the advantage of being an in situ generator with likely widespread availability. Although clinical data are limited, the findings are promising at this stage. The unconventional production of Terbium-149 is the primary reason it has not yet progressed to clinical trials. Overcoming this production obstacle would allow more detailed preclinical investigations. Optimal results with Thorium-227-labelled agents have been observed in preclinical studies, including delays in cellular growth, multiple double-strand breaks and complete regression. Intermediate phase I trial results have also been reported, demonstrating safety and tolerability, as well as an objective response rate of 25%.: The results highlight the advantages of alpha particles in targeting cancer cells with minimal radiation to normal tissue, emphasising the need for high specificity and stability in delivery mechanisms, as well as suggesting that the full clinical potential of alpha particle therapy remains unexplored. Theranostic approach and dosimetric evaluations still represent relevant challenges
Effect of tool geometry and LCO2 cooling on cutting forces and delamination when drilling CFRP composites using PCD tools
No full textLightweight materials like Carbon Fiber Reinforced Polymers (CFRPs) present certain challenges, mainly regarding the resultant surface integrity of the holes. Different techniques such as optimized tool geometries, machining techniques and cooling/lubricating techniques have been tested for improving surface integrity on CFRPs. Unfortunately using coolants presents certain challenges when machining CFRPs, as the moisture absorption can degrade the mechanical properties of the composite, on top of the environmental and health hazards created by water and oil based metalworking fluids. Therefore, this study aims to evaluate the influence of environmentally friendly liquid carbon dioxide (LCO2) based cooling/lubricating conditions and Polycrystalline Diamond (PCD) drill bit geometries (point angle) on the delamination when drilling CFRP composites. The results showed significant influence of the tool geometry and cooling condition on the surface integrity of CFRPs, especially in the case of the former
Comparison of ASP.NET web technologies: MVC and Blazor
No full textDiplomsko delo primerja ogrodji ASP.NET Core MVC in ASP.NET Core Blazor z namenom ovrednotenja njunih prednosti in omejitev pri razvoju sodobnih spletnih aplikacij. V ta namen sta bili razviti dve funkcionalno primerljivi aplikaciji z enakim zalednim delom in vizualno identičnim uporabniškim vmesnikom, pri čemer je bila ena implementirana v tehnologiji MVC, druga pa v Blazor. Razviti aplikaciji sta bili primerjani, pri čemer smo se osredotočili na tri vidike: programerskega, performančnega in uporabniškega.
Ugotovili smo, da nobena izmed tehnologij ni boljša v vseh vidikih. Blazor je boljši v programerskem vidiku, v performančnem vidiku ni enoznačne prednosti, saj so rezultati odvisni od samega poteka uporabe. S strani vidika uporabniške izkušnje pa sta aplikaciji dosegli podoben rezultat. Na podlagi celotne primerjave se je v okviru obravnavanega primera Blazor izkazal kot ugodnejša izbira.This thesis compares the ASP.NET Core MVC and ASP.NET Core Blazor frameworks with the aim of evaluating their advantages and limitations in the development of modern web applications. For this purpose, two functionally comparable applications with the same backend and visually identical user interface were developed, one implemented in MVC technology and the other in Blazor. The comparison covers three aspects: programming, performance, and user experience.
We found that neither technology is superior in all aspects. Blazor is superior from a programming perspective, while there is no clear advantage in terms of performance, as the results depend on the course of use. From a user experience perspective, both applications achieved similar results. Based on the overall comparison, Blazor proved to be the more favorable choice in the scope of the case under consideration
Non-viral genome editing in Jurkat T-cell line for targeted knockout of TRAC gene and insertion of the green fluorescent protein gene with CRISPR/Cas9
No full textImunoterapija predstavlja enega obetavnejših pristopov v sodobnem zdravljenju raka, saj temelji na preusmerjanju in krepitvi bolnikovega lastnega imunskega sistema za specifično prepoznavanje in uničevanje rakavih celic. Pomembno strategijo na tem področju predstavlja genetsko inženirstvo celic T, kjer tehnologije, kot je CRISPR/Cas, omogočajo natančno in učinkovito spreminjanje imunskih celic za terapevtsko uporabo. V tem magistrskem delu smo razvili in optimizirali nevirusno metodologijo za urejanje genoma v celični liniji Jurkat, ki predstavlja model za celice T. Z uporabo ribonukleoproteinskih (RNP) kompleksov, sestavljenih iz Cas9 in enojne usmerjevalne RNA (sgRNA), smo uspešno izvedli izbitje tarčnega gena TRAC, ki kodira komponento T-celičnega receptorja (TCR). Nadalje smo s posredovanjem popravljanja na osnovi homologije (HDR) v isti genomski lokus uspešno vstavili zapis za reporterski protein GFP. Učinkovitost in stabilnost genetskih sprememb smo spremljali s pretočno citometrijo. Rezultati potrjujejo, da predstavljena metodologija omogoča tako učinkovito izbitje genov kot tudi tarčno integracijo želenega konstrukta, kar predstavlja pomemben korak k razvoju nevirusnih strategij za genetsko inženirstvo celic T v okviru celične imunoterapije raka.Immunotherapy presents one of the promising approaches in modern cancer treatment, as it relies on redirecting and enhancing the patient’s own immune system to specifically recognize and eliminate malignant cells. A key strategy within this field is the genetic engineering of T cells, where technologies such as CRISPR/Cas enable precise and efficient reprogramming of immune cells for therapeutic use. In this master’s thesis, we developed and optimized a non-viral genome editing methodology in the Jurkat T-cell line. Using ribonucleoprotein (RNP) complexes composed of Cas9 and single guide RNA (sgRNA), we achieved efficient knockout of the target gene TRAC, which encodes a component of the T-cell receptor (TCR). Subsequently, through homology-directed repair (HDR), we introduced a sequence for the reporter protein GFP into the same genomic locus. The efficiency and stability of the modifications were monitored by flow cytometry. Our results confirm that the presented methodology enables both efficient gene knockout and targeted insertion of desired genetic constructs, representing an important step toward the development of non-viral strategies for T-cell genetic engineering in the context of cellular cancer immunotherapy
Preparation of a histidine analogue and its recombinant incorporation into selected proteins
No full textZeleni fluorescentni protein (GFP) je globularni protein, ki ima strukturo β-sodčka, znotraj katerega se spontano tvori kromofor. Gradijo ga aminokislinski ostanki Ser65-Tyr66-Gly67, ki v notranjosti spontano ciklizirajo, takšen kromofor pa je vir močne fluorescence. V modrem fluorescentnem proteinu (BFP) je aminokislinski ostanek Tyr66 zamenjan s histidinskim, kar vpliva na fotokemijske lastnosti proteina. Histidin je esencialna aminokislina z imidazolno stransko verigo, ki omogoča funkcije, ki drugim aminokislinam niso na voljo, saj lahko preklaplja med nevtralnim in pozitivno nabitim stanjem pri fizioloških pogojih, kar mu omogoča vrsto različnih interakcij. S pomočjo z bakrom-katalizirane reakcije vodikovega azida in L-propargil glicina lahko pripravimo njegov analog azahistidin. Tega lahko selektivno vgradimo v izbrane proteine namesto histidina. V sklopu diplomske naloge smo z molekulskim kloniranjem pripravili ekspresijska vektorja z zapisoma za tako imenovana superfolder GFP (sfGFP) in superfolder BFP (sfBFP), sintetizirali azahistidin in ga s pomočjo avksotrofnih bakterijskih sevov vgradili v oba proteina, pripravili pa smo tudi njuni nemodificirani verziji. Fluorescentnim proteinom s histidinskimi ali z azahistidinskimi ostanki smo pomerili fluorescenco pri različnih pH vrednostih. Pri sfGFP-ju s histidinom smo dobili vzbujevalni vrh pri ~480 nm in emisijski vrh pri ~510 nm. Intenzivnost fluorescence je z naraščujočim pH naraščala do pH 9, nato pa je ta nekoliko upadla. Z zamenjavo histidinskih ostankov z azahistidinskimi se je pojavil dodatni ekscitacijski vrh pri ~390 nm. Nastanek tega je posledica prehoda tirozinskega ostanka v kromoforju iz deprotonirane v nevtralno obliko. Zamenjava histidinskih aminokislinskih ostankov v azahistidinske je vplivala na spekter kljub temu, da sfGFP ne vsebuje histidinskega aminokislinskega ostanka v samem kromoforju. His148 se nahaja neposredni bližini kromoforja in zamenjava tega je najverjetneje povzročila nastanek nekoliko bolj kislega okolja, kar je vplivalo na fluorescenco. Pri sfBFP-ju s histidinskimi ostanki sta se vrhova pojavila pri ~380 in 450 nm. Intenzivnost fluorescence je bila najvišja pri pH 8. Z zamenjavo histidinskih ostankov z azahistidinskimi pa se je fluorescenca močno zmanjšala oz. izničila, saj smo tokrat zamenjali aminokislinski ostanek v samem kromoforju.The green fluorescent protein (GFP) is a globular protein with a β-barrel structure, within which a chromophore forms spontaneously. It is built from the amino acid residues Ser56-Tyr66-Gly67, which cyclize spontaneously inside the barrel, and this chromophore is the source of strong fluorescence. In the blue fluorescent protein (BFP), the Tyr66 residue is replaced by histidine, which affects the photochemical properties of the protein. Histidine is an essential amino acid with an imidazole side chain, enabling functions unavailable to other amino acids, since it can switch between neutral and positively charged states under physiological conditions, allowing a variety of interactions. Using the copper-catalyzed reaction of hydrogen azide and L-propargylglicine, its analogue azahistidine can be prepared. This can be selectively incorporated into proteins in place of histidine. In the course of this thesis, we generated expression vectors containing the sequences for superfolder GFP (sfGFP) and superfolder BFP (sfBFP) using molecular cloning, synthesized azahistidine, and incorporated it into both proteins with the help of auxotrophic bacterial strains, while also preparing their natural variants. The fluorescence of proteins containing histidine or azahistidine residues was measured at different pH values. For sfGFP with histidine, we obtained an excitation peak at ~480 nm and an emission peak at ~510 nm. Fluorescence intensity increased with rising pH up to pH 9, after which it slightly decreased. Upon replacement of histidine residues with azahistidine, an additional excitation peak appeared at ~390 nm. This arose from the transition of the tyrosine residue in the chromophore from its deprotonated to its neutral form. Substitution of histidine residues with azahistidine influenced the spectrum despite sfGFP not containing histidine directly in the chromophore. His148 is located in close proximity to the chromophore, and its replacement most likely created a slightly more acidic environment, which affected fluorescence. For sfBFP with histidine residues, the peaks appeared at ~380 and 450 nm, with maximum fluorescence intensity at pH 8. However, replacing histidine residues with azahistidine drastically reduced or abolished fluorescence, since this time the substitution occurred in the chromophore itself
Synthesis of fragments for preparing [1,2,4]triazolo[4,3-a]pyridinone butyrylcholine esterase inhibitors
No full textAlzheimerjeva bolezen (AB) je najpogostejša oblika demence in predstavlja velik zdravstveni izziv sodobne družbe. Zanjo so značilni kognitivni, funkcionalni in vedenjski simptomi, katerih pojav je povezan z odlaganjem amiloidnih plakov in tvorbo nevrofibrilarnih pentelj zaradi hiperfosforilacije proteina tau. Ker natančen mehanizem nastanka bolezni še ni pojasnjen, so bile razvite različne hipoteze, kot so amiloidna hipoteza, hipoteza proteina tau, holinergična in nevrovnetna hipoteza ter druge. Trenutna zdravila za AB omogočajo predvsem lajšanje simptomov, ne pa tudi zaustavitve patoloških procesov. Pri sodobnih raziskavah se za zdravljenje AB vedno bolj uveljavlja pristop večtarčnih ligandov, ki omogočajo hkratno delovanje na več ključnih tarč.
Namen magistrske naloge je bil sinteza spojin, ki bi sočasno zavirale butirilholin esterazo (BChE) in z mitogenom aktivirano protein kinazo p38α (p38α MAPK). BChE ima namreč pomembno vlogo v pozni fazi AB, saj postane glavni encim za razgradnjo acetilholina, medtem ko p38α MAPK sodeluje pri nevrovnetnih procesih, povezanih s toksičnim učinkom Aβ in hiperfosforilacijo tau proteina. Njuno hkratno zaviranje predstavlja potencialno strategijo za izboljšanje kognitivnih funkcij in vplivanje na patofiziološki potek bolezni.
Eksperimentalno delo je temeljilo na razvoju spojin, pri čemer nam je kot izhodiščna molekula služila spojina 41, ki je znan zaviralec p38α MAPK. V sklopu sintez so bile izvedene reakcije ciklizacije, aromatske nukleofilne substitucije, redukcije in diazotiranja. Med postopki so se pokazali številni izzivi, med drugim nestabilnost produktov, težave s selektivnostjo reakcij, stranski produkti in praktične omejitve pri delu z žveplovimi spojinami. Kljub temu je uspela priprava več vmesnih produktov, ki predstavljajo obetavne fragmente za nadaljnji razvoj.
Čeprav nam ni uspelo sintetizirati končnih spojin z dvojnim zaviralnim učinkom, rezultati nakazujejo smiselnost nadaljnjega raziskovanja. Pridobljeni fragmenti lahko služijo kot osnova za optimizacijo in pripravo učinkovitih večtarčnih ligandov, ki bi v prihodnje prispevali k celovitejšemu zdravljenju Alzheimerjeve bolezni.Alzheimer\u27s disease is the most common form of dementia and represents a major public health challenge in modern society. It is characterized by cognitive, functional and behavioral symptoms which are associated with the deposition of amyloid plaques and the formation of the neurofibrillary tangles caused by tau protein hyperphosphorylation. Since the exact mechanism underlying the disease remains unclear, several hypotheses have been proposed, including the amyloid hypothesis, hypothesis protein tau, cholinergic hypothesis, neuroinflammatory and others. Current therapies primarily alleviate symptoms but do not halt the pathological processes. In recent research, the concept of multitarget ligands has gained increasing importance, as it allows simultaneous action on multiple key targets.
The aim of master’s thesis was the synthesis of compounds capable of simultaneously inhibiting butyrylcholine esterase (BChE) and p38α mitogen-activated protein kinase (p38α MAPK). BChE plays an important role in the later stages of Alzheimer’s disease, as it becomes the main enzyme responsible for acetylcholine degradation, while p38α MAPK is involved in neuroinflammatory processes associated with the toxic effects of Aβ and tau protein hyperphosphorylation. Their concurrent inhibition represents a potential strategy to improve cognitive functions and influence the pathophysiological progression of the disease.
The experimental work was based on the development of compounds, using compound 41, a known p38α MAPK inhibitor, as the starting molecule. The synthesis included cyclization, aromatic nucleophilic substitution, reduction and diazotization reactions. Several challenges emerged during these procedures, such as instability of products, limited reaction selectivity, the formation of side products and practical difficulties associated with sulfur-containing compounds. Nevertheless, several intermediates were successfully synthesized, representing promising fragments for further development.
Although the final compounds with dual inhibitory activity were not successfully synthesized, the results indicate the relevance of further research. The synthesized fragments can serve as a foundation for optimization and the design of effective multitarget ligands, which may in the future contribute to more comprehensive treatment strategies for Alzheimer’s disease
Vpliv različic razporeditve lovilnih petelj na raztezne lastnosti levo-desnih votkovnih pletiv iz mešanice volna/PAN
No full textThis study examines the stretch properties of nine variants of single-tuck weft-knitted fabrics made from 31 tex ×2 wool/PAN yarn and compares them with a plain fabric. The research emphasizes how variations in the arrangement and percentage of tuck loops within the stitch repeat affect the fabrics\u27 stretch characteristics. Results show that the presence and percentage of tuck loops at the width repeat significantly influence stretch properties. The plain fabric displayed apparent anisotropy, with widthwise deformation roughly four times greater than lengthwise deformation. This behaviour was largely dominated by the elastic component, indicating strong immediate recovery and dimensional stability. In contrast, tuck stitch variants showed more balanced deformation between directions, reflecting the moderating influence of tuck loops on fabric anisotropy. Increasing the percentage of tuck loops improved lengthwise extensibility while decreasing widthwise recovery, thereby altering elastic and residual deformation behaviour. The analysis of deformation components revealed that tuck loops decrease the elastic deformation ratio and increase delayed and residual deformation, suggesting greater stress relaxation and a higher permanent set. These results highlight the sensitive interplay between the presence and combination of knit and tuck loops and their effects on loop configuration and fabric mechanics. The results thus confirm that the controlled use of tuck stitches provides a practical approach to optimizing fabric performance in terms of stretch, recovery and stability, thereby offering valuable insights for designing functional and high-performance knitted textiles.V raziskavi so bile proučene raztezne lastnosti devetih različic levo-desnih lovilnih votkovnih pletiv in primerjane z lastnostmi enostavnega levo-desnega pletiva. Pletiva so bila izdelana iz preje z dolžinsko maso 31 tex × 2, iz mešanice volna/PAN. V raziskavi se je ugotavljal vpliv različic razporeditve in deleža lovilnih petelj (Tn) v sosledju na raztezne lastnosti pletiv. Enostavna pletena struktura kaže izrazito anizotropijodeformacija v prečni smeri je približno štirikrat večja kot v vzdolžni smeri. Pri takšnem obnašanju pletiva pretežno prevladuje elastična komponenta deformacije (E1), kar kaže na visoko takojšnjo elastično povratnost in dobro dimenzijsko stabilnost. Nasprotno pa strukture z različno razporejenimi lovilnimi petljami kažejo bolj uravnoteženo deformacijo v obeh smereh, kar pomeni zmeren vpliv lovilnih petelj na anizotropijo pletiva. Z naraščajočim deležem lovilnih petelj se povečuje razteznost v vzdolžni smeri, hkrati pa se zmanjšuje elastična povratnost v prečni smeri, kar vpliva na spremembo razmerja med elastično in trajno deformacijo. Analiza komponent deformacije je pokazala, da lovilne petlje zmanjšujejo delež elastične deformacije (E1/E) ter povečujejo delež zakasnele (E2/E) in trajne deformacije (E3/E), kar kaže na večjo sprostitev napetosti in večjo trajno deformacijo pletiv. Rezultati poudarjajo ključen vzajemni učinek zank in lovilnih petelj ter njihov vpliv na konfiguracijo zančne strukture in mehanske lastnosti pletiv. Rezultati raziskave potrjujejo, da je nadzorovana uporaba lovilnih petelj učinkovit pristop k optimizaciji uporabnih lastnosti pletiv, kot so razteznost, povratnost in dimenzijska stabilnost, ki so pomembne za razvoj funkcionalnih in visokozmogljivih pletenih tekstilij
Industrija 5.0 - revolucija v zagotavljanju etične mode
No full textThe global fashion industry faces numerous ethical concerns. The Global South, in particular, suffers from unethical practices in the fashion industry due to the complexity of the supply chain and the lack of regulations governing workers’ welfare. Additionally, the rapid growth of the fashion industry has also caused a negative impact on the environment. Ethical fashion prioritizes transparency, accountability and the well-being of workers, while ensuring environmental and social sustainability. This study suggests Industry 5.0 as a suitable approach to ensure ethical fashion due to its focus on human centricity. Industry 5.0 values human well-being with a synergy of technologies such as artificial intelligence, blockchain, digital twin and energy-efficient automation. The proper implementation of Industry 5.0 in the fashion industry can promote ethical fashion practices by ensuring fair labour practices, transparency and accountability, by and minimizing environmental impacts. Through an in-depth review of literature regarding Industry 4.0, Industry 5.0 and ethical fashion, this study develops a framework for ethical fashion. A logical, human-centred framework for Industry 5.0 in the context of ethical fashion is produced by searching peer-reviewed literature for specific keywords, applying inclusion criteria and thematically analysing the content to extract significant concepts, technologies and ethical issues. This study also highlights the challenges of integrating Industry 5.0 with ethical fashion, such as building the skills of labourers, the consideration of socio-centricity and policy changes due to the emergence of Industry 5.0.Globalna modna industrija se sooča s številnimi etičnimi izzivi. Globalni jug je zaradi kompleksnosti dobavnih verig in pomanjkljivega urejanja na področju varstva delavcev še posebno izpostavljen neetičnim praksam v modni industriji. Hitra rast modne industrije ima poleg tega izrazite negativne vplive na okolje. Etična moda poudarja preglednost in odgovornost ter dobrobit delavcev ob sočasnem zagotavljanju okoljskih in družbenih vidikov trajnosti. Raziskava opredeljuje industrijo 5.0 kot primeren pristop k zagotavljanju etične mode, saj temelji na človeku usmerjenem pristopu. Industrija 5.0 poudarja blaginjo človeka v sozvočju s tehnologijami, kot so umetna inteligenca, veriženje blokov, digitalni dvojček in energetsko učinkovita avtomatizacija. Ustrezna uvedba industrije 5.0 v modni industriji lahko prispeva k spodbujanju etičnih praks v modi, saj omogoča zagotavljanje pravičnih delovnih razmer, preglednosti in odgovornosti ter zmanjševanje okoljskih vplivov. Na podlagi poglobljenega pregleda literature o industriji 4.0, industriji 5.0 in etični modi raziskava oblikuje pojmovni okvir etične mode. Smiseln in človeku usmerjen okvir industrije 5.0 v kontekstu etične mode je razvit s sistematičnim pregledom recenzirane literature, ki vključuje iskanje po ključnih besedah, uporabo vključitvenih kriterijev ter tematsko analizo vsebin za določitev ključnih konceptov, tehnologij in etičnih vprašanj. Raziskava dodatno opozarja na izzive združevanja industrije 5.0 in etične mode, med katerimi so razvoj kompetenc delavcev, upoštevanje sociocentričnega pristopa ter potreba po spremembah načel zaradi vzpona industrije 5.0
Assumptions and limitations of Bland Altman analysis
No full textUporaba najosnovnejše analize Bland-Altman zahteva upoštevanje nekaterih predpostavk, ki v praksi pogosto niso izpolnjene. Poleg tega smiselna uporaba analize Bland-Altman vključuje uporabo ponovljenih meritev z isto metodo pri istem posamezniku, kar v osnovnem primeru analize ni upoštevano. Da bi omogočili ustrezno analizo ponovljenih podatkov, ter analizo v primeru kršenih predpostavk, avtorja predlagata nekatere popravke, ki pa v medicinski literaturi običajno niso uporabljeni. Prav tako ti popravki pogosto niso na voljo v programski opremi, npr. v R knjižnicah za analizo Bland-Altman. Posledica neuporabe popravkov je napačna ocena standardnega odklona razlik med metodama in zato napačna ocena mej ujemanja med metodama. Takšna napaka lahko pripelje do uporabe neustreznih metod (v primeru preozkih mej ujemanja) ter do neupravičenega zavračanja ustreznih metod (v primeru preširokih mej ujemanja). Cilj tega dela je oceniti posledice opustitve uporabe teh popravkov na zanesljivost pridobljenih rezultatov.The use of the simplest version of Bland-Altman analysis requires some assumptions that are often not met in clinical practice. Furthermore, a complete Bland Altman analysis requires the use of repeated measurements with the same method, which is not possible with the simplest approach. To allow an appropriate analysis of repeated measurements, and to address unmet assumptions, the authors suggest a series of simple corrections. However, these are commonly not used in existing literature, nor are they available in commonly used software, such as R packages. When these corrections are not used, the estimate of the standard deviation of differences between methods is wrong, leading to a wrong estimate of the limits of agreement. This error can lead to the acceptance of inadequate methods (when the limits of agreement are too narrow) or the rejection of adequate methods (when the limits of agreement are too wide). The aim of this thesis is to estimate how the reliability of Bland Altman results is affected by the omission of the proposed corrections