Background: The incidence of postoperative nausea and vomiting (PONV) can be reduced by dexamethasone. Single dose administration may cause elevated blood glucose levels in obese adults. No data are available for children. Objective: The aim was to evaluate perioperative blood glucose changes related to body weight in children who received dexamethasone. Methods: This prospective observational study included 62 children. All patients received total intravenous anesthesia and a single dose of dexamethasone (0.15mg/kg, maximum 8mg). Blood glucose levels were measured up to 6 hours. Standard deviation scores (SDS) were calculated using age- and gender-specific BMI percentiles, p<0.05. Results: 62 children (11.5±2.9years, median SDS 0.43, 29% overweight/obese) were included. Blood glucose level increased from 5.52±0.52 to 6.74±0.84mmol/l 6h after dexamethasone without correlation to the BMI-SDS. Conclusions: This study shows an increase of perioperative blood glucose (normoglycemic ranges) after single dose of dexamethasone but no BMI-dependent effect in children. Therefore, low-dose dexamethasone may be used in obese children for PONV prophylaxis.

Title: Diabetes mellitus in Equistrian Sport in Czech Republic Objectives: The aim of the literature review part of the thesis was to give an introduction to the issue of diabetes mellitus as well as the effect of sport on the decompensation of the disease, to search for available sources on a narrowly focused topic - the impact of horse riding on diabetes mellitus, and to process the findings in a clear form into the first (literature review) part of the work. The goal of the second (research) part was to map, with the use of questionnaires and interviews, the situation of diabetes patients in the Czech Republic who do equestrian sport actively. In the case study their subjective feelings were reviewed. The main aim was to prove the positive impact of horse riding on diabetes mellitus, or more precisely to find out if it is stress or physical exertion that has a greater effect on the blood glucose (BG) level. Furthermore, the thesis focuses on the issue of public awareness of disease management as well as first aid. Methods: The first part of the thesis was carried out in the form of a literature review, for which research articles and other literature sources were found primarily on electronic information portals (mainly Web of Science, etc.) For the second (research) part a questionnaire (on the...

Exposure to environmental chemicals has been shown to affect health status throughout the life course. Quantifying the joint effect of environmental mixtures over time is crucial to determine optimal intervention timing. Establishing causal relationships from environmental mixture data can be challenging due to various factors, including multicollinearity, complex functional form of exposure-response relationships, and residual unmeasured confounding. These issues can lead to biased estimates of treatment effects and pose significant obstacles in accurately identifying the true relationship between the pollutants and outcome variables. Causal interpretation of longitudinal environmental mixture studies encounters challenges. This dissertation explores the use of causal inference in environmental mixture studies, with a particular emphasis on addressing three key challenges. First, there is currently no statistical approach that allows simultaneous consideration of time-varying confounding, flexible modeling, and variable selection when examining the effect of multiple, correlated, and time-varying exposures. Second, the violation of a critical assumption that underpins all causal inference methods - namely, the absence of unmeasured confounding - poses a significant problem, as models that incorporate multiple environmental exposures may exacerbate the degree of bias depending on the nature of unmeasured confounding. Finally, there is a lack of computational resources that facilitate the application of newly developed causal inference methods for analyzing environmental mixtures. In Chapter 2, we introduce a causal inference method, g-BKMR, which enables to estimate nonlinear, non-additive effects of time-varying exposures and time-varying confounders, while also allowing for variable selection. An extensive simulation study shows that g-BKMR outperforms approaches that rely on correct model specification or do not account for time-dependent confounding, especially when correlation across time-varying exposures is high or the exposure-outcome relationship is nonlinear. We apply g-BKMR to quantify the contribution of metal mixtures to blood glucose in the Strong Heart Study, a prospective cohort study of American Indians. Chapter 3, we address the issue of time-varying unmeasured confounding when estimating time-varying effects of exposure to environmental chemicals. We review the Bayesian g-formula under the assumption of no unmeasured confounding, and then introduce a Bayesian probabilistic sensitivity analysis approach that can account for multiple, potentially time-varying, unmeasured confounders and continuous exposures. Through a simulation study, we demonstrate that the proposed algorithm outperforms the naive method, which fails to consider the influence of confounding. Chapter 4, introduces causalbkmr, a novel R package and can be currently be accessed on Github. causalbkmr is designed to support the implementation of g-BKMR, BKMR Causal Mediation Analysis, and Multiple Imputation BKMR, thereby offering a user-friendly and effective platform for executing these state-of-the-art methods in practice in the context of complex mixtures analysis. While the package bkmr is available, the novel package causalbkmr expands upon bkmr by enabling its application specifically to environmental mixture data within a causal inference framework. The implementation of these novel methodologies within causalbkmr allows for the extraction of causal interpretations, thus enhancing the analytical capabilities provided by the package. Chapter 5 concludes with a discussion and outlines potential future directions for investigation.

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Bakgrund: Parodontit är en vanligt och multifaktoriell inflammatorisk sjukdom som skadar de mjuka vävnaderna kring tänderna. Diabetes mellitus typ 2 är en kronisk sjukdom som beror på bristfällig insulinproduktion i kroppen och höga sockernivåer i blodet.  Syfte:  Syftet med denna studie var att kartlägga sambandet mellan parodontit och diabetes typ 2 hos vuxna individer. Metod: Litteraturstudie. Resultat: Ett signifikant samband mellan parodontit och diabetes typ 2 kan påvisas. Diabetiker med dålig glykemisk kontroll har en högre svårighetsgrad av parodontit än de som har god glykemisk kontroll. Nio av tio granskade studier visar att icke-kirurgisk parodontitbehandling har en god effekt på minskning av blodglukosnivån. Dessutom tyder resultaten att personer med diabetes typ 2 och dålig glykemisk kontroll har färre kvarvarande tänder än icke-diabetiker.  Slutsats: diabetes typ 2 är en stark riskfaktor för förekomsten och utvecklingen av parodontit.  Diabetiker med dålig kontroll av blodglukosnivån har färre tänder än de som har god glykemisk kontroll. Icke-kirurgisk parodontitterapi har en god effekt på minskning av blodglukosnivå hos individer med typ 2 diabetes. / Background: Periodontitis is a multifactorial inflammatory and common disease among the population that destroys the soft tissues around the teeth. Diabetes mellitus type 2 is a chronic metabolic disorder which depends on inadequate insulin production in the body and  high sugar levels in the blood. Aim: The aim of the study was to evaluate the association between periodontal disease and diabetes mellitus type 2 in the adult population. Method: A literature review. Results: The results of the study showed a significant association between diabetes mellitus type 2 and periodontal disease. Diabetics with poor glycemic control had a higher severity of periodontal disease than those with good glycemic control. Almost all of the reviewed articles showed that a non-surgical periodontitis therapy reduced the hyperglycemic level. In addition, the results of the study showed that diabetics with poor glycemic control had fewer remaining teeth than those who had good glycemic control or non-diabetics. Conclusion: Diabetes mellitus type 2 is a significant risk factor for the incidence and progression of periodontal disease. Diabetics with good glycemic control had more teeth than non-diabetics. Non-surgical periodontitis treatment had a good effect on decreasing blood glucose level in patients with type 2 diabetes mellitus.

[EN] Type 1 diabetes mellitus is a chronic and incurable disease that affects millions of people all around the world. Its main characteristic is the destruction (totally or partially) of the beta cells of the pancreas. These cells are in charge of producing insulin, main hormone implied in the control of blood glucose. Keeping high levels of blood glucose for a long time has negative health effects, causing different kinds of complications. For that reason patients with type 1 diabetes mellitus need to receive insulin in an exogenous way. Since 1921 when insulin was first isolated to be used in humans and first glucose monitoring techniques were developed, many advances have been done in clinical treatment with insulin. Currently 2 main research lines focused on improving the quality of life of diabetic patients are opened. The first one is concentrated on the research of stem cells to replace damaged beta cells and the second one has a more technological orientation. This second line focuses on the development of new insulin analogs to allow emulating with higher fidelity the endogenous pancreas secretion, the development of new noninvasive continuous glucose monitoring systems and insulin pumps capable of administering different insulin profiles and the use of decision-support tools and telemedicine. The most important challenge the scientific community has to overcome is the development of an artificial pancreas, that is, to develop algorithms that allow an automatic control of blood glucose. The main difficulty avoiding a tight glucose control is the high variability found in glucose metabolism. This fact is especially important during meal compensation. This variability, together with the delay in subcutaneous insulin absorption and action causes controller overcorrection that leads to late hypoglycemia (the most important acute complication of insulin treatment). The proposals of this work pay special attention to overcome these difficulties. In that way interval models are used to represent the patient physiology and to be able to take into account parametric uncertainty. This type of strategy has been used in both the open loop proposal for insulin dosage and the closed loop algorithm. Moreover the idea behind the design of this last proposal is to avoid controller overcorrection to minimize hypoglycemia while adding robustness against glucose sensor failures and over/under- estimation of meal carbohydrates. The algorithms proposed have been validated both in simulation and in clinical trials. / [ES] La diabetes mellitus tipo 1 es una enfermedad crónica e incurable que afecta a millones de personas en todo el mundo. Se caracteriza por una destrucción total o parcial de las células beta del páncreas. Estas células son las encargadas de producir la insulina, hormona principal en el control de glucosa en sangre. Valores altos de glucosa en la sangre mantenidos en el tiempo afectan negativamente a la salud, provocando complicaciones de diversa índole. Es por eso que los pacientes con diabetes mellitus tipo 1 necesitan recibir insulina de forma exógena. Desde que se consiguiera en 1921 aislar la insulina para poder utilizarla en clínica humana, y se empezaran a desarrollar las primeras técnicas de monitorización de glucemia, se han producido grandes avances en el tratamiento con insulina. Actualmente, las líneas de investigación que se están siguiendo en relación a la mejora de la calidad de vida de los pacientes diabéticos, tienen fundamentalmente 2 vertientes: una primera que se centra en la investigación en células madre para la reposición de las células beta y una segunda vertiente de carácter más tecnológico. Dentro de esta segunda vertiente, están abiertas varias líneas de investigación, entre las que se encuentran el desarrollo de nuevos análogos de insulina que permitan emular más fielmente la secreción endógena del páncreas, el desarrollo de monitores continuos de glucosa no invasivos, bombas de insulina capaces de administrar distintos perfiles de insulina y la inclusión de sistemas de ayuda a la decisión y telemedicina. El mayor reto al que se enfrentan los investigadores es el de conseguir desarrollar un páncreas artificial, es decir, desarrollar algoritmos que permitan disponer de un control automático de la glucosa. La principal barrera que se encuentra para conseguir un control riguroso de la glucosa es la alta variabilidad que presenta su metabolismo. Esto es especialmente significativo durante la compensación de las comidas. Esta variabilidad junto con el retraso en la absorción y actuación de la insulina administrada de forma subcutánea favorece la aparición de hipoglucemias tardías (complicación aguda más importante del tratamiento con insulina) a consecuencia de la sobreactuación del controlador. Las propuestas presentadas en este trabajo hacen especial hincapié en sobrellevar estas dificultades. Así, se utilizan modelos intervalares para representar la fisiología del paciente, y poder tener en cuenta la incertidumbre en sus parámetros. Este tipo de estrategia se ha utilizado tanto en la propuesta de dosificación automática en lazo abierto como en el algoritmo en lazo cerrado. Además la principal idea de diseño de esta última propuesta es evitar la sobreactuación del controlador evitando hipoglucemias y añadiendo robustez ante fallos en el sensor de glucosa y en la estimación de las comidas. Los algoritmos propuestos han sido validados en simulación y en clínica. / [CA] La diabetis mellitus tipus 1 és una malaltia crònica i incurable que afecta milions de persones en tot el món. Es caracteritza per una destrucció total o parcial de les cèl.lules beta del pàncrees. Aquestes cèl.lules són les encarregades de produir la insulina, hormona principal en el control de glucosa en sang. Valors alts de glucosa en la sang mantinguts en el temps afecten negativament la salut, provocant complicacions de diversa índole. És per això que els pacients amb diabetis mellitus tipus 1 necessiten rebre insulina de forma exògena. Des que s'aconseguís en 1921 aïllar la insulina per a poder utilitzar-la en clínica humana, i es començaren a desenrotllar les primeres tècniques de monitorització de glucèmia, s'han produït grans avanços en el tractament amb insulina. Actualment, les línies d'investigació que s'estan seguint en relació a la millora de la qualitat de vida dels pacients diabètics, tenen fonamentalment 2 vessants: un primer que es centra en la investigació de cèl.lules mare per a la reposició de les cèl.lules beta i un segon vessant de caràcter més tecnològic. Dins d' aquest segon vessant, estan obertes diverses línies d'investigació, entre les que es troben el desenrotllament de nous anàlegs d'insulina que permeten emular més fidelment la secreció del pàncrees, el desenrotllament de monitors continus de glucosa no invasius, bombes d'insulina capaces d'administrar distints perfils d'insulina i la inclusió de sistemes d'ajuda a la decisió i telemedicina. El major repte al què s'enfronten els investigadors és el d'aconseguir desenrotllar un pàncrees artificial, és a dir, desenrotllar algoritmes que permeten disposar d'un control automàtic de la glucosa. La principal barrera que es troba per a aconseguir un control rigorós de la glucosa és l'alta variabilitat que presenta el seu metabolisme. Açò és especialment significatiu durant la compensació dels menjars. Aquesta variabilitat junt amb el retard en l'absorció i actuació de la insulina administrada de forma subcutània afavorix l'aparició d'hipoglucèmies tardanes (complicació aguda més important del tractament amb insulina) a conseqüència de la sobreactuació del controlador. Les propostes presentades en aquest treball fan especial insistència en suportar aquestes dificultats. Així, s'utilitzen models intervalares per a representar la fisiologia del pacient, i poder tindre en compte la incertesa en els seus paràmetres. Aquest tipus d'estratègia s'ha utilitzat tant en la proposta de dosificació automàtica en llaç obert com en l' algoritme en llaç tancat. A més, la principal idea de disseny d'aquesta última proposta és evitar la sobreactuació del controlador evitant hipoglucèmies i afegint robustesa. / Revert Tomás, A. (2015). Robust strategies for glucose control in type 1 diabetes [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/56001

Blood glucose (BG) spikes increase chronic disease risk in those with and without diabetes. The fiber and phytonutrient content of fruit, such as raspberries has the potential to attenuate the BG spike of a high glycemic load (HGL) meal. We examined the effect of red raspberries (RRs) on the BG spike when added to a HGL meal. In this randomized cross-over trial, 16 university students were given breakfast cereal and almond milk (control), the control breakfast with 140g added RRs, and the control breakfast with sugar equivalent to the sugar content of the RRs (50% sugar increase from control). Meals given on 3 separate test days, being separated by a 1-week washout period. BG was measured at: fasting then 15 min, 30 min, 60 min, 90 min, and 120 min postprandial. Repeated measures ANOVA was performed to investigate differences in peak minus baseline BG (spike) and glucose incremental area under the curve (IAUC). The added RR meal had a lower BG spike compared to the added sugar meal (-12.8 mg/dL, CI: -22.8 to -2.79, p = 0.0083). Additionally, a lower BG was seen comparing the added RR meal to the control meal (-10.9 mg/dL, CI: -20.9 to -0.83, p = 0.0318). There were no significant differences for IAUC and the timing of peak BG among the meals. RR effect is likely attributed to high fiber-to-sugar ratio, polyphenol content, and greater amount of beneficial micronutrients. Based on obtained results from this pilot study, the practice of adding RRs to HGL meals such as breakfast, seems to reduce risk for T2DM in health populations through BG spike attenuation.

Brown adipose tissue (BAT) serves as a crucial thermogenic organ, extracting glucose and lipids from circulation to generate heat. Enhancing BAT activity holds potential as a therapy for treating metabolic diseases, such as obesity and diabetes. The sympathetic nervous system (SNS) is the main regulator of BAT activity by increasing extraction and oxidation of substrates. However, the SNS role in metabolic disorders is complex. In obesity, there is increased sympathetic tone, yet reduced BAT responsiveness. Furthermore, increasing systemic sympathetic tone in individuals already at heightened cardiovascular risk leads to adverse complications, as demonstrated by recent clinical trials. As a result, BAT’s impact on overall health in humans has been challenged in recent years, largely due to the lack of methods to selectively activate BAT without affecting other organs. Here, I used chemogenetics and retrograde viral injections in the interscapular BAT (iBAT) of mice to selectively activate only the neurons projecting to this tissue. Targeted activation of BAT did increase thermogenesis and improved glucose homeostasis. Leveraging on the single-cell RNA sequencing from our laboratory, we identified two sympathetic populations innervating iBAT: one primarily targets the small arterioles, while the other innervates the parenchyma. These populations mediate non-overlapping sympathetic-functions in iBAT: activating only the vascular projecting neurons lowers blood glucose without affecting thermogenesis, while activating the other population results in increased energy expenditure, local thermogenesis, and blood flow, with no effect on glycemia. The findings from this work could pave the way to the development of targeted strategies against metabolic disorders characterized by hyperglycemia, highlighting the potential of selectively activating specific SNS components to normalize blood glucose levels.

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal.

Além das alterações autonômicas, a síndrome metabólica (SMet) causa disfunção vascular relacionada a eventos cardiovasculares e morte. Considerando que a resistência à insulina é associada à hiperativação simpática, testamos a hipótese de que a presença da glicemia de jejum alterada (GLI) é a principal causa das alterações estruturais e funcionais em grandes e pequenos vasos, via aumento do tônus simpático nesses pacientes. Foram avaliados pacientes com SMet recém diagnosticados (ATP-III) e não medicados, divididos em: glicemia de jejum alterada >=100mg/dL (SMet+GLI, n=35; 50±1 anos) e glicemia normal < 100mg/dL (SMet-GLI, n=24, 46 ± 1). Um grupo de indivíduos saudáveis foi estudado como controle (CS, n=17, 50±1 anos). Foram medidas rigidez arterial (velocidade de onda de pulso, VOP), atividade nervosa simpática muscular (ANSM, microneurografia) fluxo sanguíneo muscular (FSM, pletismografia), pressão arterial média (PAM, oscilométrico), resistência vascular periférica (RVP=PAM/FSM) e dimetilarginina assimétrica (ADMA). SMet+GLI apresentou maior VOP que SMet-GLI e CS (8,0[7,2-8,6], 7,3[6,9-7,9] e 6,9[6,6-7,2]m/s, respectivamente, P=0,001), não havendo diferença entre SMet-GLI e CS. Além disso, SMet+GLI foi similar ao SMet-GLI mas teve maior RVP que CS (P=0,008), não havendo diferença entre SMet-GLI e CS. Adicionalmente, SMet+GLI teve maior ANSM que SMet-GLI e CS; enquanto SMet-GLI teve maior ANSM que CS (31+-1; 26+-1; 19+-1 disparos /min, P < 0,001). ADMA foi similar entre os grupos (0,62 [0,56-0,71], 0,67 [0,59-0,92] e 0,60 [0,54-1,43] umol/L). Dentre os fatores de risco da SMet, GLI foi preditor do aumento da ANSM. ANSM foi associada à VOP (R=0.39; P=0,002) e à RVP (R=0,30, P=0,034). Em conclusão, a hiperativação simpática, que está aumentada na presença da glicemia alterada, é o mecanismo básico que pode explicar, pelo menos em parte, o aumento na VOP e na RVP. GLI parece ser o principal fator de risco no prejuízo da função e estrutura vascular nos pacientes com SMet / Besides autonomic alterations, metabolic syndrome (MetS) causes vascular dysfunction related to cardiovascular events and death. Since insulin resistance is associated with sympathetic hyperactivation, we tested the hypothesis that the presence of impaired fasting glucose (IFG) is the main cause of structural and functional changes of large and small vessels via elevated sympathetic tonus in these patients. We evaluated never treated, newly diagnosed MetS (ATP-III) patients divided into: impaired fasting glucose >100mg/dL (MetS+IFG, n=35; 50±1 y) and normal fasting glucose <100mg/dL (MetS-IFG, n=24, 46±1 y). A healthy control group was also studied (C, n=17, 50±1 y). We measured the arterial stiffness (pulse wave velocity, PWV), muscle sympathetic nerve activity (MSNA, microneurography), forearm blood flow (FBF, plethysmography), mean blood pressure (MBP, oscillometric), peripheral vascular resistance (PVR=MBP/FBF) and asymmetric dimethylarginine (ADMA). MetS+IFG had higher PWV than MetS-IFG and C (8.0[7.2-8.6], 7.3[6.9-7.9] and 6.9[6.6-7.2]m/s, respectively, P=0.001), whereas SMet-GLI was similar to CS. Moreover, MetS+IFG was similar to MetS-IFG, but had higher PVR than C (P=0.008) and SMet-GLI was similar to CS. In addition, MetS+IFG had higher MSNA than MetS-IFG and C; whereas MetS-IFG had higher MSNA than C (31 +- 1; 26+- 1; 19+-1 bursts/min, P < 0.001). ADMA were similar among groups (0.62 [0.56-0.71] vs 0.67 [0.59-0.92] and 0.60 [0.54-1.43] umol/L). Among MetS risk factors, IFG was predictor of increased MSNA. Further, MSNA was associated with PWV (R=0.39; P=0.002) and PVR (R=0.30, P=0.034). In conclusion, sympathetic hyperactivation, which is enhanced in the presence of high blood glucose, is the basic mechanism that could explain, at least in part, the increase in PWV and PVR. IFG appears to be the main risk factor in the vascular function and structure damage in MetS patients