Effects of intrauterine exposure to synthetic glucocorticoids on fetal, newborn, and infant hypothalamic-pituitary-adrenal axis function in humans : a systematic review

BACKGROUND: Synthetic glucocorticoids are commonly used in reproductive medicine. Fetal organ systems are highly sensitive to changes in the intrauterine environment, including overexposure to glucocorticoids. Structural and functional alterations resulting from such changes may persist throughout life and have been associated with diverse diseases. One system that could be particularly sensitive to fetal glucocorticoid overexposure is the hypothalamic-pituitary-adrenal (hpa) axis. Many human studies have investigated this possibility, but a systematic review to identify consistent, emergent findings is lacking. METHODS: We systematically review 49 human studies, assessing the effects of intrauterine exposure to synthetic glucocorticoids on fetal, neonate, and infant hpa function. RESULTS: Study quality varied considerably, but the main findings held true after restricting the analyses to higher-quality studies: intrauterine exposure to synthetic glucocorticoids reduces offspring hpa activity under unstimulated conditions after pain but not pharmacological challenge. Although reduced unstimulated hpa function appears to recover within the first 2 wk postpartum, blunted hpa reactivity to pain is likely to persist throughout the first 4 months of life. There is some evidence that the magnitude of the effects is correlated with the total amount of glucocorticoids administered and varies with the time interval between glucocorticoid exposure and hpa assessment. CONCLUSIONS: This systematic review has allowed the demonstration of the way in which intrauterine exposure to various regimens of synthetic glucocorticoids affects various forms of hpa function. As such, it guides future studies in terms of which variables need to be focused on in order to further strengthen the understanding of such therapy, whilst continuing to profit from its clinical benefits

A multi-factorial analysis of response to warfarin in a UK prospective cohort

Background Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. Methods A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. Results VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. Conclusion Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication

Predicting Affect Classification in Mental Status Examination Using Machine Learning Face Action Recognition System: A Pilot Study in Schizophrenia Patients

Classifying patients’ affect is a pivotal part of the mental status examination. However, this common practice is often widely inconsistent between raters. Recent advances in the field of Facial Action Recognition (FAR) have enabled the development of tools that can act to identify facial expressions from videos. In this study, we aimed to explore the potential of using machine learning techniques on FAR features extracted from videotaped semi-structured psychiatric interviews of 25 male schizophrenia inpatients (mean age 41.2 years, STD = 11.4). Five senior psychiatrists rated patients’ affect based on the videos. Then, a novel computer vision algorithm and a machine learning method were used to predict affect classification based on each psychiatrist affect rating. The algorithm is shown to have a significant predictive power for each of the human raters. We also found that the eyes facial area contributed the most to the psychiatrists’ evaluation of the patients’ affect. This study serves as a proof-of-concept for the potential of using the machine learning FAR system as a clinician-supporting tool, in an attempt to improve the consistency and reliability of mental status examination

Prevalence, Characteristics, and Prognostic Significance of HFE Gene Mutations in Type 2 Diabetes: The Fremantle Diabetes Study

OBJECTIVE—To examine the relationship between iron status, hereditary hemochromatosis (HFE) gene mutations, and clinical features and outcomes of type 2 diabetes in a well-characterized representative sample of community-based patients

How physicians perceive and utilize information from a teratogen information service: The Motherisk Program

BACKGROUND: Teratogen information services have been developed around the world to disseminate information regarding the safety of maternal exposures during pregnancy. The Motherisk Program in Toronto, Canada, fields thousands of these inquiries per year. Our primary objective was to evaluate the perception and utilization of information received from us by physicians. Our secondary objective was to examine their information seeking behavior, in particular regarding teratogen information. METHODS: A one page survey was sent to physicians who had called Motherisk for information concerning pregnancy exposures in the previous 30 days for three months. Among the questions that were asked were demographics, which included gender, years in practice, specialty, information resources, and how they utilized the information received from Motherisk. RESULTS: We received 118/200 completed questionnaires (59% response rate). The mean age of the respondents was: 42 ± 9 years, mean years of practice was: 14 ± 8 years, males: 46(38%) and females 72(62%) and 95(80%) were family physicians. 56(48%) researched their question prior to calling Motherisk, 106(91%) and passed on the information received to their patient verbatim. The top four resources for information were: 1) The CPS (PDR), 2) textbooks, 3) journals and 4) colleagues. Only 8% used the Medline for gathering information. CONCLUSIONS: Physicians feel that a teratogen information service is an important component in the management of women exposed to drugs, chemicals, radiation and infections diseases etc. during pregnancy. Despite the advent of the electronic age, a minority of the physicians in our survey elected to use electronic means to seek information

Association of warfarin dose with genes involved in its action and metabolism

We report an extensive study of variability in genes encoding proteins that are believed to be involved in the action and biotransformation of warfarin. Warfarin is a commonly prescribed anticoagulant that is difficult to use because of the wide interindividual variation in dose requirements, the narrow therapeutic range and the risk of serious bleeding. We genotyped 201 patients for polymorphisms in 29 genes in the warfarin interactive pathways and tested them for association with dose requirement. In our study, polymorphisms in or flanking the genes VKORC1, CYP2C9, CYP2C18, CYP2C19, PROC, APOE, EPHX1, CALU, GGCX and ORM1-ORM2 and haplotypes of VKORC1, CYP2C9, CYP2C8, CYP2C19, PROC, F7, GGCX, PROZ, F9, NR1I2 and ORM1-ORM2 were associated with dose (P < 0.05). VKORC1, CYP2C9, CYP2C18 and CYP2C19 were significant after experiment-wise correction for multiple testing (P < 0.000175), however, the association of CYP2C18 and CYP2C19 was fully explained by linkage disequilibrium with CYP2C9*2 and/or *3. PROC and APOE were both significantly associated with dose after correction within each gene. A multiple regression model with VKORC1, CYP2C9, PROC and the non-genetic predictors age, bodyweight, drug interactions and indication for treatment jointly accounted for 62% of variance in warfarin dose. Weaker associations observed for other genes could explain up to ∼10% additional dose variance, but require testing and validation in an independent and larger data set. Translation of this knowledge into clinical guidelines for warfarin prescription will be likely to have a major impact on the safety and efficacy of warfarin. ELECTRONIC SUPPLEMENTARY MATERIAL: Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00439-006-0260-8 and is accessible for authorized users

In-utero exposure to antihypertensive medication and neonatal and child health outcomes:A systematic review

Background: Although medication is generally avoided wherever possible during pregnancy, pharmacotherapy is required for the treatment of pregnancy associated hypertension, which remains a leading cause of maternal and fetal morbidity and mortality. The long-term effects to the child of in-utero exposure to antihypertensive agents remains largely unknown. Objective: The aim of this study was to systematically review published studies on adverse outcomes to the child associated with in-utero exposure to antihypertensive medications. Methods: OVID, Scopus, EBSCO Collections, the Cochrane Library, and Web of Science databases were searched for relevant publications published between January 1950 and October 2016 and a total of 688 potentially eligible studies were identified. Results: Following review, 47 primary studies were eligible for inclusion. The Critical Appraisal Skills Programme checklist was used to assess study quality. Five studies were of excellent quality; the remainder were either mediocre or poor. Increased risk of low birth weight, low size for gestational age, preterm birth, and congenital defects following in-utero exposure to all antihypertensive agents were identified. Two studies reported an increased risk of attention deficit hyperactivity disorder following exposure to labetalol, and an increased risk of sleep disorders following exposure to methyldopa and clonidine. Conclusion: The current systematic review demonstrates a paucity of relevant published high-quality studies. A small number of studies suggest possible increased risk of adverse child health outcomes; however, most published studies have methodological weaknesses and/or lacked statistical power thus preventing any firm conclusions being drawn

Therapeutic Dosing of Acenocoumarol: Proposal of a Population Specific Pharmacogenetic Dosing Algorithm and Its Validation in North Indians

Objectives: To develop a population specific pharmacogenetic acenocoumarol dosing algorithm for north Indian patients and show its efficiency in dosage prediction. Methods: Multiple and linear stepwise regression analyses were used to include age, sex, height, weight, body surface area, smoking status, VKORC1-1639 G.A, CYP4F2 1347 G.A, CYP2C9*2,*3 and GGCX 12970 C.G polymorphisms as variables to generate dosing algorithms. The new dosing models were compared with already reported algorithms and also with the clinical data for various performance measures. Odds ratios for association of genotypes with drug sensitive and resistant groups were calculated. Results: The pharmacogenetic dosing algorithm generated by multiple regression analysis explains 41.4 % (p-value,0.001) of dosage variation. Validation of the new algorithm showed its predictive ability to be better than the already established algorithms based on similar variables. Its validity in our population is reflected by increased sensitivity, specificity, accuracy and decreased rates of over- and under- estimation in comparison to clinical data. The VKORC1-1639 G.A polymorphism was found to be strongly associated with acenocoumarol sensitivity according to recessive model. Conclusions: We have proposed an efficient north India specific pharmacogenetic acenocoumarol dosing algorithm whic

Prediction of phenprocoumon maintenance dose and phenprocoumon plasma concentration by genetic and non-genetic parameters

International audienc