La greffe de cellules souches hématopoïétiques (CSH) constitue une avancée thérapeutique considérable dans le traitement de maladies hématologiques et non hématologiques. Toutefois, malgré qu’elle sauve des vies, elle n’est pas sans risque. Le syndrome lymphoprolifératif post-transplantation (SLPT) est l’une des complications qui peut survenir après ce type de greffe avec un risque de mortalité pouvant atteindre 80% en l’absence de traitement. Par ailleurs, les traitements disponibles pour limiter le développement de ce syndrome ne sont pas sans effets néfastes. Le SLPT est surtout une conséquence d’une primo-infection ou d’une réactivation non-contrôlée du virus d’Epstein-Barr (VEB). Au moins 90% des adultes sont porteurs du VEB alors que ce pourcentage est d’environ 50-70% chez les enfants. Il est important de bien comprendre les facteurs de risque de l’infection active du VEB et du SLPT pour une meilleure gestion des greffés. Cette thèse a pour objectif de contribuer aux connaissances quant aux déterminants du VEB et du SLPT chez les greffés pédiatriques de CSH. Dans un premier temps, une revue systématique combinée à une méta-analyse a été réalisée pour élaborer un portrait exhaustif des facteurs de risque connus du VEB et du SLPT chez les greffés adultes et pédiatriques de CSH. Ensuite, à l’aide d’une étude de cohorte prospective multicentrique canadienne qui a enrôlé 156 patients pédiatriques greffés de CSH, le lien entre la transfusion de produits sanguins et l’infection VEB post-greffe a été analysé. Finalement, l’étude de cohorte multicentrique a aussi permis d’explorer des nouveaux facteurs de risque des évènements liés au VEB allant de l’ADNémie VEB à la suspicion du SLPT. Les résultats de la revue systématique et de la méta-analyse ont montré que l’utilisation de la globuline antithymocyte (ATG) pour prévenir la maladie du greffon contre l’hôte est le principal facteur impliqué dans la survenue post-greffe des infections actives du VEB et du SLPT. La forte hétérogénéité entre les études a limité la comparaison des résultats et très peu d’études portaient exclusivement sur les patients pédiatriques. D’autre part, l’analyse statistique au sein de la cohorte multicentrique n’a pas révélé une augmentation statistiquement significative du risque d’infection du VEB post-greffe associé à la transfusion. Toutefois, une analyse de génotypage du virus a indiqué que la transfusion serait très probablement liée à la primo-infection VEB d’un patient séronégatif, et ce malgré la leucoréduction (qui élimine virtuellement la présence des virus associés aux composantes cellulaires des produits sanguins). Par ailleurs, nos analyses dans la cohorte multicentrique ont corroboré l’association entre l’ATG et les évènements liés au VEB post-greffe et mis en relief deux nouvelles associations. Le mycophénolate mofétil, un médicament utilisé pour prévenir la maladie du greffon contre l’hôte, limiterait le risque des évènements liés au VEB par son action antiproliférative des lymphocytes T et B (incluant ceux infectés par le VEB), tandis que les filles seraient plus à risque des formes relativement sévères de l’infection du VEB post-greffe que les garçons. Le rationnel autour de cette dernière association n’est pas connu. Des nouvelles recherches permettront d’apprécier la reproductibilité de ces résultats. / Hematopoietic stem cell transplantation (HSC) constitutes a notable therapeutic advance in the treatment of hematological and non-hematological diseases. However, despite saving lives, it is not without risk. Post-transplant lymphoproliferative disease (PTLD) is one of the complications that can occur after this type of transplant with a mortality risk of up to 80% if left untreated. Moreover, the treatments available to limit the development of this disease are not without harmful effects on transplant recipients. PTLD is predominantly a consequence of primary infection or uncontrolled reactivation of Epstein-Barr virus (EBV). At least 90% of adults are carriers of EBV, compared to around 50-70% in the pediatric population. It is important to understand the risk factors for active EBV infection and PLTD in order to better manage transplant recipients. This thesis aims to contribute to knowledge on the determinants of active EBV infection and PTLD in pediatric HSC transplant recipients. A systematic review combined with a meta-analysis was carried out to develop a comprehensive portrait of the known risk factors for EBV and PTLD in adult and pediatric HSC transplant recipients. Then, using a Canadian multicenter prospective cohort study that enrolled 156 pediatric HSC transplant patients, the link between blood product transfusion and post-transplant EBV infection was analyzed. Finally, the multicenter cohort study also explored new risk factors for EBV-related events ranging from EBV DNAemia to suspicion of PTLD. The results of the systematic review and the meta-analysis revealed that the use of anti-thymocyte globulin (ATG) to prevent graft-versus-host disease is the main factor implicated in the post-transplant occurrence of active EBV infection and PTLD. The high heterogeneity between studies limited the comparison of results and very few studies focused exclusively on pediatric patients. On the other hand, statistical analysis within the multicenter cohort did not reveal a significant increase in the risk of post-transplant EBV infection associated with transfusion. However, genotyping analysis of viral strains from blood donors of an EBV-negative patient who received an EBV-negative graft indicated that one of the blood donors was the source of the primary EBV infection in the patient, despite leukoreduction (which virtually eliminates the presence of cell-associated viruses in blood products). Furthermore, our analyses in the multicenter cohort corroborated the association between ATG and post-transplant EBV-related events, and highlighted two new associations. First, mycophenolate mofetil, a drug used to prevent graft-versus-host disease, is believed to reduce the risk of EBV-related events through its antiproliferative action on T and B lymphocytes (including EBV-infected B cells). Second, girls are more at risk of relatively severe forms of post-transplant EBV infection than boys. The rationale behind this latter association is unknown. New research will make it possible to assess the reproducibility of these results.

El di(2-etilhexil) ftalat (DEHP) és un plastificant que s’afegeix als productes de clorur de polivinil (PVC) per a dotar-los de més flexibilitat. El material mèdic fet de PVC, i en particular els dispositius i bosses que s’utilitzen en les transfusions de sang, conté el DEHP com additiu. Així, el receptor d’una transfusió està altament exposat a aquest compost. L’objectiu de la tesi va ser estudiar els metabòlits del DEHP en orina com a possibles marcadors de la pràctica d’una transfusió de sang en l’esport. Es va desenvolupar i validar un mètode d’anàlisi per cromatografia líquida acoblada a espectrometria de masses en tàndem per a la quantificació dels principals metabòlits del DEHP en orina humana: mono-(2-etilhexil) ftalat (MEHP), mono-(2-etil-5-hidroxihexil) ftalat (MEHHP), mono-(2-etil-5-oxohexil) ftalat (MEOHP), mono-(2-carboximetilhexil) ftalat (2cx-MMHP) i mono-(2-etil-5-carboxipentil) ftalat (5cx-MEPP). El mètode es va aplicar a mostres procedents de voluntaris sans (grup control), de pacients hospitalitzats que havien rebut una transfusió de sang i de pacients hospitalitzats sotmesos a tractaments mèdics amb materials de PVC i no a transfusions. Es van obtenir diferències significatives en les concentracions dels tres metabòlits estudiats (MEHP, MEHHP, MEOHP) entre les mostres dels pacients transfosos respecte els altres dos grups de població. El mètode també es va aplicar a mostres d’orina de vint-i-cinc voluntaris sans que s’havien sotmès a un procediment d’autotransfusió. Els resultats van indicar concentracions elevades dels cinc metabòlits del DEHP en orina fins a les 48 hores després d’haver rebut la sang. Finalment, es van determinar les concentracions dels cinc metabòlits de DEHP en una població d’esportistes i es van calcular límits de referència que permetessin sospitar d’una transfusió. Així doncs, els resultats indiquen que la mesura dels metabòlits de DEHP en orina pot ser usada com una eina pel cribatge de l’ús de transfusions en l’esport. / The plasticizer di(2-ethylhexyl)phthalate (DEHP) is used in polyvinyl chloride products (PVC) to increase its flexibility. Medical devices made of PVC, especially blood bags used in blood transfusions, contain DEHP as additive. Therefore, subjects submitted to blood transfusion are widely exposed to this compound. The aim of the project was to evaluate DEHP metabolites in urine as possible markers of the use of a blood transfusion in sports. An analytical method was developed and validated to quantify the main DEHP metabolites mono-(2-ethylhexyl)phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl)phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl)phthalate (MEOHP), mono-(2-carboxymethylhexyl)phthalate (2cx-MMHP) and mono-(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP), in human urine by liquid chromatography tandem mass spectrometry. The methodology was applied to samples belonging to healthy volunteers (control group), hospitalized patients subjected to blood transfusions and hospitalized patients subjected to medical treatments involving plastic material different to blood transfusions. Significant differences were obtained in the concentrations of the three metabolites studied (MEHP, MEHHP, MEOHP) between transfused patients samples’ and the other two population groups. The method was also applied to urine samples from twenty-five healthy volunteers who were subjected to an autologous blood transfusion. The results indicated high concentrations of the five DEHP metabolites in urine up to 48 hours after the blood transfusion. Finally, the concentration of the five DEHP metabolites were evaluated in a sportsmen population and reference limits to allow suspicion of blood transfusion were calculated. Thus, the results indicate that the DEHP metabolites could be used as markers of blood transfusions in sports.

Author's name: Bc. Irena Malá School: Charles university, Prague 1st Faculty of Medicine Institut of Theory and Practice of Nursing Vídeňská 800, 140 59 Prague 4 - Krč Program: Health Care Administration Title: Early postoperative care of the patient with the left ventricular assist device HeartMate II Diploma thesis supervisor: PhDr. Hocková Jana, PhD. Number of pages: 170 Number of attachments: 41 Year: 2013 Key words: early postoperative care, hypotermia, blood transfusion, fluid resuscitation, perioperative cardiovascular dysfunction, pharmacologic support, ventricular assist device HeartMateII, monitoration, device, cardiac arrhythmias, ventilation management, postoperative anticoagulation, glycemic kontrol, renal insufficiency, nutrition, nursing, complications, physiotherapy, psychological aspects The occurrence of the heart failure is similar to an epidemic with high mortality. This fact, together with stagnate or even decreasing number of suitable donors, led to a need of replacing the heart pump activity with an artificial one. Mechanical cardiac support systems are sophisticated devices that are able to support a certain period of time or completely replace the function of the heart as a pump. The indications implantation of mechanical cardiac support is significant symptomatic heart...

Newborn screening programs measure analyte levels in neonatal blood spots to identify individuals at high risk of disease. Carnitine and acylcarnitine levels are primary markers used in the detection of fatty acid oxidation disorders. These analytes may be influenced by certain pre/perinatal or newborn screening related factors. The primary objective of this study was to explore the association between these characteristics and levels of blood carnitines and acylcarnitines in the newborn population. The study was composed of two parts: a systematic review and a clinical database analysis of existing newborn screening data. The systematic review results suggested considerable variability across studies in the presence and directionality of associations between analyte levels and birth weight, gestational age, age at time of blood spot collection, type of sample, and storage time. Sex was not significantly associated with carnitine or acylcarnitine levels in neonatal blood. We identified a need to more fully investigate a potential interaction between gestational age and birth weight in regard to analyte levels. The secondary data analyses indicated a statistically significant relationship between analyte levels and all perinatal / infant and newborn screening related factors of interest, but effect sizes were generally small. The interaction between gestational age and birth weight was significant in all models; when further explored through graphical analysis with conditional means, extremely premature neonates stood out as having distinct analyte patterns in relation to birth weight. Variation in the ratio of total acylcarnitine to free carnitine was better accounted for by the perinatal and newborn factors than was variation in any individual carnitine or acylcarnitine, indicating that proportions of carnitine and acylcarnitines may be more important in understanding an individual’s metabolic functioning than individual analyte levels. A low proportion of variation was explained in all multivariate models, supporting the use of universal algorithms in newborn screening and suggesting the need for further large scale empirical research targeted at previously unaccounted for perinatal factors such as birth stress.

Newborn screening programs measure analyte levels in neonatal blood spots to identify individuals at high risk of disease. Carnitine and acylcarnitine levels are primary markers used in the detection of fatty acid oxidation disorders. These analytes may be influenced by certain pre/perinatal or newborn screening related factors. The primary objective of this study was to explore the association between these characteristics and levels of blood carnitines and acylcarnitines in the newborn population. The study was composed of two parts: a systematic review and a clinical database analysis of existing newborn screening data. The systematic review results suggested considerable variability across studies in the presence and directionality of associations between analyte levels and birth weight, gestational age, age at time of blood spot collection, type of sample, and storage time. Sex was not significantly associated with carnitine or acylcarnitine levels in neonatal blood. We identified a need to more fully investigate a potential interaction between gestational age and birth weight in regard to analyte levels. The secondary data analyses indicated a statistically significant relationship between analyte levels and all perinatal / infant and newborn screening related factors of interest, but effect sizes were generally small. The interaction between gestational age and birth weight was significant in all models; when further explored through graphical analysis with conditional means, extremely premature neonates stood out as having distinct analyte patterns in relation to birth weight. Variation in the ratio of total acylcarnitine to free carnitine was better accounted for by the perinatal and newborn factors than was variation in any individual carnitine or acylcarnitine, indicating that proportions of carnitine and acylcarnitines may be more important in understanding an individual’s metabolic functioning than individual analyte levels. A low proportion of variation was explained in all multivariate models, supporting the use of universal algorithms in newborn screening and suggesting the need for further large scale empirical research targeted at previously unaccounted for perinatal factors such as birth stress.

Newborn screening programs measure analyte levels in neonatal blood spots to identify individuals at high risk of disease. Carnitine and acylcarnitine levels are primary markers used in the detection of fatty acid oxidation disorders. These analytes may be influenced by certain pre/perinatal or newborn screening related factors. The primary objective of this study was to explore the association between these characteristics and levels of blood carnitines and acylcarnitines in the newborn population. The study was composed of two parts: a systematic review and a clinical database analysis of existing newborn screening data. The systematic review results suggested considerable variability across studies in the presence and directionality of associations between analyte levels and birth weight, gestational age, age at time of blood spot collection, type of sample, and storage time. Sex was not significantly associated with carnitine or acylcarnitine levels in neonatal blood. We identified a need to more fully investigate a potential interaction between gestational age and birth weight in regard to analyte levels. The secondary data analyses indicated a statistically significant relationship between analyte levels and all perinatal / infant and newborn screening related factors of interest, but effect sizes were generally small. The interaction between gestational age and birth weight was significant in all models; when further explored through graphical analysis with conditional means, extremely premature neonates stood out as having distinct analyte patterns in relation to birth weight. Variation in the ratio of total acylcarnitine to free carnitine was better accounted for by the perinatal and newborn factors than was variation in any individual carnitine or acylcarnitine, indicating that proportions of carnitine and acylcarnitines may be more important in understanding an individual’s metabolic functioning than individual analyte levels. A low proportion of variation was explained in all multivariate models, supporting the use of universal algorithms in newborn screening and suggesting the need for further large scale empirical research targeted at previously unaccounted for perinatal factors such as birth stress.

Vid blodgivning donerar blodgivare blod frivilligt. Blodet kan sedan användas inom sjukvården för exempelvis blodtransfusion, vilket kräver blodprodukter kompatibla med patienten. Förekomst av leukocyter i blodprodukter medför en ökad risk för febrila transfusionsreaktioner hos transfunderade patienter. Därför krävs det att vid framställning leukocytreducera blodprodukter och utföra kvalitetskontroll. Med analysen B-leukocytpartikelkoncentration (LPK) kan totalantalet leukocyter i helblod beräknas. Flödescytometri är en metod som kan analysera optiska och fluorescerande egenskaper hos exempelvis celler i en suspension, vilket kan användas för att kvantifiera cellantal. BD Leucocount™-Kit (BD Biosciences) är avsett för flödescytometrisk analys av antalet kvarvarande leukocyter i leukocytreducerade blodprodukter. Vid framställning av blodprodukter ska helblodspåsen vila vid rumstemperatur i minst 3 timmar efter blodgivning. I Falun används antingen ett dagsprogram där produktion sker samma dag som blodgivningen, eller ett övernattningsprogram där produktion sker dagen därpå. Prover från 505 kontrollerade erytrocytenheter, samlade i Falun, har påvisat en skillnad i leukocytkoncentration beroende på vilket program som använts. Anledningen till att erytrocytenheternas leukocytinnehåll skiljer sig är inte känt. Syftet med denna studie är därav att undersöka om vilotiden har någon effekt på leukocytkoncentrationen i helblodspåsar. LPK varierade mellan helblodspåsarna. Ett ökande leukocytantal observerades över tid i majoriteten av helblodspåsar, inklusive medelvärde. Däremot kunde inte hypotesprövning påvisa statistisk signifikans. Hypotesen om att leukocytantalet ökar över tid går emot grundläggande hematologi. Utifrån resultaten i denna studie kan inte hypotesen bevisas. Vidare studier bör genomföras. / During blood donation, blood donors donate blood voluntarily. The blood can then be used in healthcare for, for example, blood transfusions, which requires blood products compatible with the patient. The presence of leukocytes in blood products increases the risk of febrile transfusion reactions in transfused patients. Therefore, leukocyte-reduction in blood products is necessary during production. Each blood center must perform quality control on produced blood products. With the analysis B-leukocyte particle concentration (LPK), the total number of leukocytes in whole blood can be calculated. Flow cytometry is a method that can analyze the optical and fluorescent properties of, for example, cells in a suspension, which can be used to quantify cell numbers. The BD Leucocount™-Kit (BD Biosciences) is intended for flow cytometric analysis of the number of leukocytes remaining in leukocyte-reduced blood products. When producing blood products, the whole blood bag should rest at room temperature for at least three hours after the donation. In Falun, either a day program is used where production takes place on the same day as the blood was donated, or an overnight program where production takes place the next day. Samples from 505 controlled erythrocyte units, collected in Falun, have shown a difference in leukocyte concentration depending on the program used. The reason why the leukocyte content of erythrocyte units differs is not known. The purpose of this study is therefore to investigate whether the resting period has any effect on the leukocyte concentration in whole blood bags. The LPK varied between the whole blood bags. An increasing leukocyte count was observed over time in most of the whole blood bags. However, hypothesis testing did not show statistical significance. The hypothesis that leukocyte counts increase goes against basic hematology. Based on the results of this study, the hypothesis cannot be proven. Further studies should be conducted. / <p>Vårdförbundet tilldelade Leo Svahn stipendium 2021 för <em>bästa kandidatuppsats inom biomedicinsk laboratorievetenskap</em>.</p>

Objetivos: Estimar a concordância entre as práticas e as evidências disponíveis em uma unidade de terapia intensiva pediátrica. Métodos: Estudo retrospectivo de todos os pacientes internados durante 2001. As práticas foram classificadas em adequadas ou não-adequadas de acordo com recomendações. Esperava-se para as práticas recomendadas 90% de concordância, para as contra-indicadas, discordância de até 10% e para aquelas onde havia incertezas, 50%. Resultados: Foram selecionadas 114 publicações e avaliadas 253/275 internações (92%). O uso foi considerado apropriado para albumina em 47,6% (IC 95% 39% – 55%); dopamina <3mg/kg/min 87,9% (83% – 92%); sedação e analgesia 88,6% (87% – 90%); transfusões de concentrado de hemácias 95,2% (92% – 97%); profiliaxia de úlcera de estresse 89,7% (88% – 91%). / Objectives: Estimate the concordance between the practices and the evidence available in a pediatric intensive care unit. Methods: Retrospective study of all admitted patients during 2001. The practices were classified as adequate or non-adequate according to recommendations. It was expected 90% concordance for the recommended practices, while for non-adequate practices, discordance until 10% and for those where there was doubt, 50%. Results: 114 publications were selected and 253/275 admissions (92%) were evaluated. Use was considered appropriate for albumin in 47.6% (IC 95% 39% – 55%); dopamine <3mg/kg/min 87.9% (83% – 92%); sedation and analgesia 88.6% (87% – 90%); red blood cell transfusions 95.2% (92% – 97%); stress ulcer prophylaxis 89.7% (88% – 91%).

Objetivos: Estimar a concordância entre as práticas e as evidências disponíveis em uma unidade de terapia intensiva pediátrica. Métodos: Estudo retrospectivo de todos os pacientes internados durante 2001. As práticas foram classificadas em adequadas ou não-adequadas de acordo com recomendações. Esperava-se para as práticas recomendadas 90% de concordância, para as contra-indicadas, discordância de até 10% e para aquelas onde havia incertezas, 50%. Resultados: Foram selecionadas 114 publicações e avaliadas 253/275 internações (92%). O uso foi considerado apropriado para albumina em 47,6% (IC 95% 39% – 55%); dopamina <3mg/kg/min 87,9% (83% – 92%); sedação e analgesia 88,6% (87% – 90%); transfusões de concentrado de hemácias 95,2% (92% – 97%); profiliaxia de úlcera de estresse 89,7% (88% – 91%). / Objectives: Estimate the concordance between the practices and the evidence available in a pediatric intensive care unit. Methods: Retrospective study of all admitted patients during 2001. The practices were classified as adequate or non-adequate according to recommendations. It was expected 90% concordance for the recommended practices, while for non-adequate practices, discordance until 10% and for those where there was doubt, 50%. Results: 114 publications were selected and 253/275 admissions (92%) were evaluated. Use was considered appropriate for albumin in 47.6% (IC 95% 39% – 55%); dopamine <3mg/kg/min 87.9% (83% – 92%); sedation and analgesia 88.6% (87% – 90%); red blood cell transfusions 95.2% (92% – 97%); stress ulcer prophylaxis 89.7% (88% – 91%).