Bioinformaatika meetodid personaalses farmakoteraapias

Väitekirja elektrooniline versioon ei sisalda publikatsiooneKogutavate terviseandmete hulk kasvab kiiresti. Tänu neile andmetele on meditsiinilise ravi pakkumisel võimalik senisest enam arvesse võtta individuaalseid bioloogilisi andmeid. See doktoritöö käsitleb mitmeid personaalses meditsiinis esinevaid probleeme ja näitab, et ravi individualiseerimiseks kasutatavad andmed tulevad väga erinevatest allikatest. Inimestevahelised erinevused teevad ravimite metabolismi ennustamise keerukaks, siiski on ravi käigus kogutavad kontsentratsioonimõõtmised ravimiefekti hindamisel heaks allikaks. Me arendasime välja täppisdoseerimise tööriista, mis võimaldab vankomütsiini ravil vastsündinutele määrata ravi tõhustavat personaalseid doose kasutades selleks nende endi ravi käigus kogutud kontsentratsioone. Suurema osa ravimiteraapiate puhul ei ole võimalik pidevalt ravimi kontsentratsioone koguda. Nende ülejäänud ravimite puhul on heaks informatsiooniallikaks geneetika. Paljude ravimimetabolismiga seotud geneetiliste variantide mõju on piisav, et tingida muutuseid ravi läbiviimisel. Me uurisime geneetika ja ravimite kõrvalmõjude omavahelisi seoseid kasutades rahvastikupõhist lähenemist. See toetus Eesti Geenivaramu geeniandmetele ja teistele laiapõhjalistele terviseandmete registritele. Me leidsime ja valideerisime seose, et CTNNA3 geenis olev geenivariant tõstab oksikaamide ravil olevate inimeste jaoks kõrvalmõjude sagedust. Arvutuslik geneetika toetub kvantitatiivsetele meetoditele, millest kõige levinum on ülegenoomne assotsiatsiooni analüüs (GWAS). Sagedasti kasutatav GWASi järelsamm on aega nõudev GWASist ilmnenud p-väärtuste visuaalne hindamine teiste samas genoomi piirkonnas olevate geneetiliste variantide kontekstis. Selle sammu automatiseerimiseks arendasime me kaks tööriista, Manhattan Harvester ja Cropper, mis võimaldavad automaatselt huvipakkuvaid piirkondi tuvastada ja nende headust hinnata.The amount of collected health data is growing fast. Insights from these data allow using biological patient specifics to improve therapy management with further individualization. This thesis addresses problems in multiple sub-fields of personalised medicine and aims to illustrate that data for precision medicine emerges from different sources. Drug metabolism is difficult to predict because individual biological differences. Fortunately, drug concentrations are a good proxy for drug effect. To address the growing need for tools that allow on-line therapy adjustment based on individual concentrations we have developed and externally evaluated a precision dosing tool that allows individualised dosing of vancomycin in neonates. Other than drugs used in therapeutic drug monitoring, most pharmacotherapies can not rely on continuous concentration measurements but for such drugs genetics provides a valuable source of information for individualization. Effects of many genetic variants in drug metabolism pathways are often large enough to require changes in drug prescriptions or schedules. We have applied a population-based approach in testing relations between drug related adverse effects and genomic loci, and found and validated a novel variant in CTNNA3 gene that increases adverse drug effects in patients with oxicam prescriptions. This was done by leveraging the data in Estonian Genome Center and linking these to nation-wide electronic health data registries. Computational genetics relies on quantitative methods for which the most common is the genome-wide association analysis (GWAS). A common GWAS downstream step involves time-consuming visual assessment of the association study p-values in context with other variants in genomic vicinity. In order to streamline this step, we developed, Manhattan Harvester and Cropper, that allow for automated detection of peak areas and assign scores by emulating human evaluators.https://www.ester.ee/record=b524282

Cadmium in newborns

Cadmium (Cd) is a well-known nephrotoxic environmental contaminant but there are indications that the developing nervous system might be even more sensitive to Cd than the kidneys in adults. Infants are exposed to Cd from various formulas and infant diets and the gastrointestinal Cd uptake is believed to be higher in newborns than in adults. Cd levels monitored in infant foods ranged between 0.74 and 27.0 µg/kg. Cow's milk formulas had the lowest levels and cereal-based formulas had up to 21 times higher mean levels. The mean weekly Cd exposure from the recommended formula intake was calculated to vary between 0.10 and 3.05 µg/kg body weight. Rat pups received an oral dose of 109Cd in water or four different formulas. The whole-body Cd retention was higher in the pups than previously reported in adult animals and highest in the water and in the cow's milk formula groups. The small intestinal Cd retention was high, even 9 days after exposure indicating a long absorption period in the newborns. Cd levels in kidney increased still 12 days after exposure in all diet groups. Piglets received low daily doses of Cd in water or wheat/oat/milk-based follow-up formula. The formula reduced Cd uptake in comparison to water, but the distribution of Cd to the kidneys was unexpectedly higher when Cd was given in formula than in water. Simulated infant digestion of infant foods resulted in lower solubility of Cd compared to adult digestion. In a human Caco-2 cell model, cellular Cd uptake and transport from five different infant food digests was approximately one order of magnitude lower than the solubility and varied between 4-6 % and 1-2 % of the dose, respectively. Binding of Cd to dietary fibres and phytic acid reduces intestinal Cd retention and probably explains the lower Cd bioavailability from cereal-based formulas compared to water or cow's milk formula. The exposure of Cd is higher from infant formulas than from breast milk and age-specific digestion conditions as well as composition of diets affect both the Cd solubility and bioavailability. The calculated Cd intake from recommended amount of infant formulas is below the established provisional tolerable weekly intake, which however, does not include a safety factor and is based on renal effects in adults

Evaluating Neonatal Facial Pain Expression: Is There A Primal Face Of Pain?

Pain assessment continues to be poorly managed in the clinical arena. A review of the communication process in pain assessment is carried out and the hierarchical approach often recommended in the literature -with self-report as its gold-standard, is criticized as limited and simplistic. A comprehensive approach to pain assessment is recommended and a model that conceptualizes pain assessment as a complex transaction with various patient and clinician dependant factors is proposed. Attention is then focused on the pediatric patient whose pain assessment is often dependent on nonverbal communicative action. The clinical approaches to pain assessment in this population -mainly the use of behavioral/observational pain scales and facial pain scales, are explored. The primal face of pain (PFP) is identified and proposed theoretically as an important link in the function of facial pain scales. Finally, the existence of the PFP is investigated in a sample of 57 neonates across differences in sex and ethnic origin while controlling for potentially confounding factors. Facial expression to a painful stimulus is measured based on the Neonatal Facial Coding System (NFCS) and applying an innovative computer-based methodology. No statistically significant differences in facial expression were found in infant display thereby supporting the existence of the PFP

Parenteral provision of micronutrients to pediatric patients: an international expert consensus paper

© 2020 The Authors. Published by Wiley. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://doi.org/10.1002/jpen.1990INTRODUCTION:Micronutrients (vitamins and trace elements) are essential to all nutrition. For children and neonates who are dependent upon nutrition support therapies for growth and development, the prescribed regimen must supply all essential components. This paper aims to facilitate interpretation of existing clinical guidelines into practical approaches for the provision of micronutrients in pediatric parenteral nutrition. METHODS:An international, interdisciplinary expert panel was convened to review recent evidence-based guidelines and published literature to develop consensus- based recommendation on practical micronutrient provision in pediatric parenteral nutrition. RESULTS:The guidelines and evidence have been interpreted as answers to 10 commonly asked questions around the practical principles for provision and monitoring of micronutrients in pediatric patients CONCLUSION: Micronutrients are an essential part of all parenteral nutrition and should be included in the pediatric nutrition therapy care plan.Published versio

Delivering transformative action in paediatric pain: a <i>Lancet Child &amp; Adolescent Health</i> Commission

Every infant, child, and adolescent will experience pain at times throughout their life. Childhood pain ranges from acute to chronic, and includes procedural, disease-related, breakthrough, and other types of pain. Despite its ubiquity, pain is a major challenge for individuals, families, health-care professionals, and societies. As a private mental experience, pain is often hidden and can go undiscussed or ignored. Undertreated, unrecognised, or poorly managed pain in childhood leads to important and long-lasting negative consequences that continue into adulthood, including continued chronic pain, disability, and distress. This undertreatment of pain should not continue, as there are available tools, expertise, and evidence to provide better treatment for childhood pain

Text Messaging as Adjunct to Community Based Weight Management Program

Obesity ascending rates are still a public health priority. The primary aim of the study was to evaluate the effect of tailored text messages on body weight change in overweight and obese adults in a community based weight management program. A secondary aim was to detect behavioral changes in the same population. The study design was quasi-experimental with pre and posttest analysis, conducted over 12 weeks. A total of 28 participants were included in the analysis. Body weight, eating behaviors, exercise and nutrition self-efficacy, attitude toward mobile technology, social support and physical activity were assessed at baseline and at 12 weeks. Text messages were sent biweekly to the intervention but not to the control group. At 12 weeks, the intervention group had lost significant weight as compared to the control group. There was a trend toward an improvement in eating behaviors, exercise and nutrition self-efficacy in the intervention group, with no significant difference between groups. A total of 79% of participants stated that text messages helped in adopting healthy behaviors. Tailored text messages appear to enhance weight loss in a weight management program at a community setting. Large scale and long term intervention studies are needed to confirm these findings