Showing papers by "Gideon Koren published in 2018"

Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis.

Abstract: CONTEXT: Lactobacillus reuteri DSM17938 has shown promise in managing colic, but conflicting study results have prevented a consensus on whether it is truly effective. OBJECTIVE: Through an individual participant data meta-analysis, we sought to definitively determine if L reuteri DSM17938 effectively reduces crying and/or fussing time in infants with colic and whether effects vary by feeding type. DATA SOURCES: We searched online databases (PubMed, Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Database of Abstracts of Reviews of Effects, and Cochrane), e-abstracts, and clinical trial registries. STUDY SELECTION: These were double-blind randomized controlled trials (published by June 2017) of L reuteri DSM17398 versus a placebo, delivered orally to infants with colic, with outcomes of infant crying and/or fussing duration and treatment success at 21 days. DATA EXTRACTION: We collected individual participant raw data from included studies modeled simultaneously in multilevel generalized linear mixed-effects regression models. RESULTS: Four double-blind trials involving 345 infants with colic (174 probiotic and 171 placebo) were included. The probiotic group averaged less crying and/or fussing time than the placebo group at all time points (day 21 adjusted mean difference in change from baseline [minutes] −25.4 [95% confidence interval (CI): −47.3 to −3.5]). The probiotic group was almost twice as likely as the placebo group to experience treatment success at all time points (day 21 adjusted incidence ratio 1.7 [95% CI: 1.4 to 2.2]). Intervention effects were dramatic in breastfed infants (number needed to treat for day 21 success 2.6 [95% CI: 2.0 to 3.6]) but were insignificant in formula-fed infants. LIMITATIONS: There were insufficient data to make conclusions for formula-fed infants with colic. CONCLUSIONS: L reuteri DSM17938 is effective and can be recommended for breastfed infants with colic. Its role in formula-fed infants with colic needs further research.

Lactobacillus reuteri to Treat Infant Colic: A Meta-analysis

Abstract: CONTEXT: Lactobacillus reuteri DSM17938 has shown promise in managing colic, but conflicting study results have prevented a consensus on whether it is truly effective OBJECTIVE: Through an individual participant data meta-analysis, we sought to definitively determine if L reuteri DSM17938 effectively reduces crying and/or fussing time in infants with colic and whether effects vary by feeding type DATA SOURCES: We searched online databases (PubMed, Medline, Embase, the Cumulative Index to Nursing and Allied Health Literature, the Database of Abstracts of Reviews of Effects, and Cochrane), e-abstracts, and clinical trial registries STUDY SELECTION: These were double-blind randomized controlled trials (published by June 2017) of L reuteri DSM17398 versus a placebo, delivered orally to infants with colic, with outcomes of infant crying and/or fussing duration and treatment success at 21 days DATA EXTRACTION: We collected individual participant raw data from included studies modeled simultaneously in multilevel generalized linear mixed-effects regression models RESULTS: Four double-blind trials involving 345 infants with colic (174 probiotic and 171 placebo) were included The probiotic group averaged less crying and/or fussing time than the placebo group at all time points (day 21 adjusted mean difference in change from baseline [minutes] −254 [95% confidence interval (CI): −473 to −35]) The probiotic group was almost twice as likely as the placebo group to experience treatment success at all time points (day 21 adjusted incidence ratio 17 [95% CI: 14 to 22]) Intervention effects were dramatic in breastfed infants (number needed to treat for day 21 success 26 [95% CI: 20 to 36]) but were insignificant in formula-fed infants LIMITATIONS: There were insufficient data to make conclusions for formula-fed infants with colic CONCLUSIONS: L reuteri DSM17938 is effective and can be recommended for breastfed infants with colic Its role in formula-fed infants with colic needs further research

Pregnancy- Associated Changes in Pharmacokinetics and their Clinical Implications.

Abstract: To critically review pregnancy-induced pharmacokinetic changes and their clinical application. Structured review of Pubmed, MBASE and published books. For many drugs, advanced pregnancy is associated with lower maternal serum concentrations. As most drug concentrations are not measured routinely, such changes are not evident to the clinician. Moreover, even for drug concentrations measured clinically, one cannot interpret lower total drug levels as evidence of lower fraction of free drug, which is the pharmacologically- active component, due to lower protein binding of many drugs in late pregnancy. Higher fractions of free drug will lead to higher rate of hepatic metabolism, especially for high extraction medications, leading to lower total drug concentrations.. Pregnancy- induced larger volume of distribution will lead to lower peak of drugs and hence may impact the achievement therapeutic levels. To further complicate matters, the adherence of many women decreases during pregnancy, mostly due to fears of adverse fetal effects. These dynamic and complex processes make changes in recommendations for dose schedule very challenging and in many cases not practical. Indeed, there are presently no pregnancy- targeted dose schedules, similar to existing dose changes, for example, in renal failure. Similar to the recent increased attention given to pharmacokinetic changes in pregnancy, well designed studies should compare dose-effect relationships in women receiving medications in different stages of pregnancy, to women receiving the same drug before, and/or after pregnancy. Whenever possible, women with chronic conditions can serve as their own controls and decrease the uncertainty created by inter- patient variability. Measuring drug effects in parallel to drug concentrations, will allow pharmacokinetic- pharmacodynamic modelling, leading to evidence-based decisions regarding changes in dose schedules during gestation.

The role of the placenta in drug transport and fetal drug exposure.

Abstract: Introduction: It was assumed for decades that the human placenta serves as a barrier, protecting the fetus from exposure to xenobiotics circulating in the mother. The thalidomide disaster completely reversed this concept. The study of the human placenta is therefore critical to understanding the mechanisms by which xenobiotics reach the fetus and exert their effects.Areas covered: This review describes mechanisms by which drugs interact with the human placenta, and experimental methods to study these interactions in humans.We have selected three areas of current clinical interest, where the placenta exhibits critical role in drug transport: The ABC transporters, the placental handling of cancer therapeutic drugs and the interaction between the placenta and immunoglobulins.Expert commentary: The optimal model to predict drug transfer and transport from the mother to the fetus is the isolated human placental lobule perfused in vitro. Unlike subcellular preparations or tissue homogenates, data obtain...

Mechanisms linking T-wave alternans to spontaneous initiation of ventricular arrhythmias in rabbit models of long QT syndrome.

Abstract: Key points T-wave alternans (TWA) and T-wave lability (TWL) are precursors of ventricular arrhythmias in long QT syndrome; however, the mechanistic link remains to be clarified. Computer simulations show that action potential duration (APD) prolongation and slowed heart rates promote APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos can exacerbate pre-existing or induce de novo APD dispersion, which combines with enhanced ICa,L to result in premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs can directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or further exacerbate the APD dispersion to cause spontaneous initiation of ventricular arrhythmias. Experiments conducted in transgenic long QT rabbits show that PVC alternans occurs at slow heart rates, preceding spontaneous intuition of ventricular arrhythmias. Abstract T-wave alternans (TWA) and irregular beat-to-beat T-wave variability or T-wave lability (TWL), the ECG manifestations of action potential duration (APD) alternans and variability, are precursors of ventricular arrhythmias in long QT syndromes. TWA and TWL in patients tend to occur at normal heart rates and are usually potentiated by bradycardia. Whether or how TWA and TWL at normal or slow heart rates are causally linked to arrhythmogenesis remains unknown. In the present study, we used computer simulations and experiments of a transgenic rabbit model of long QT syndrome to investigate the underlying mechanisms. Computer simulations showed that APD prolongation and slowed heart rates caused early afterdepolarization-mediated APD alternans and chaos, manifesting as TWA and TWL, respectively. Regional APD alternans and chaos exacerbated pre-existing APD dispersion and, in addition, APD chaos could also induce APD dispersion de novo via chaos desynchronization. Increased APD dispersion, combined with substantially enhanced ICa,L , resulted in a tissue-scale dynamical instability that gave rise to the spontaneous occurrence of unidirectionally propagating premature ventricular complexes (PVCs) originating from the APD gradient region. These PVCs could directly degenerate into re-entrant arrhythmias without the need for an additional tissue substrate or could block the following sinus beat to result in a longer RR interval, which further exacerbated the APD dispersion giving rise to the spontaneous occurrence of ventricular arrhythmias. Slow heart rate-induced PVC alternans was observed in experiments of transgenic LQT2 rabbits under isoproterenol, which was associated with increased APD dispersion and spontaneous occurrence of ventricular arrhythmias, in agreement with the theoretical predictions.

Association of In Utero Exposure to Polybrominated Diphenyl Ethers With the Risk of Hypospadias.

Abstract: Importance Polybrominated diphenyl ethers (PBDEs) are added to many consumer products as flame retardants, and their endocrine-disrupting properties are a growing health concern in pregnancy. Objective To investigate whether in utero PBDE exposure as measured in maternal hair is associated with increased risk for hypospadias. Design, Setting, and Participants In this case-control study, the setting was the urology clinic of a tertiary pediatric hospital between January 3, 2011, and April 1, 2013. Participants were children diagnosed as having hypospadias and their mothers and a control group of children without hypospadias and their mothers. Dates of data analysis were September 3, 2017, to December 28, 2017. Exposures Gestational exposure to 8 PBDEs as measured in the 3-cm segment closest to the skull of maternal hair by gas chromatography–mass spectroscopy as a proxy for in utero exposure. The mothers resided in the same household for the duration of their pregnancy. Main Outcomes and Measures Difference in total maternal hair PBDE levels between the hypospadias and control groups. Results Total PBDE levels were significantly higher among mothers of infants with hypospadias (n = 152) (total PBDE level, 51.4 pg/mg; interquartile range, 35.8-78.5 pg/mg) than among controls (n = 64) (total PBDE level, 35.8 pg/mg; interquartile range, 18.1-69.9 pg/mg) (P = .02). Of the 152 women with sufficient hair samples for analysis in the case group, 89 completed a questionnaire and were included in a multivariable analysis, and of the 64 women with sufficient hair samples for analysis in the control group, 54 completed a questionnaire and were included in a multivariable analysis. Adjusting for potential confounders, hypospadias was associated with a relative 48.2% (95% CI, 23.2%-65.4%) higher maternal level of total PBDE levels in the multivariable analysis. Conclusions and Relevance In this analysis, mothers of children with hypospadias were exposed during pregnancy to significantly higher levels of PBDEs. The results of this study suggest that level of exposure to PBDEs during gestation may have a role in the etiology of hypospadias.

Machine learning of big data in gaining insight into successful treatment of hypertension

Abstract: Despite effective medications, rates of uncontrolled hypertension remain high. Treatment protocols are largely based on randomized trials and meta-analyses of these studies. The objective of this study was to test the utility of machine learning of big data in gaining insight into the treatment of hypertension. We applied machine learning techniques such as decision trees and neural networks, to identify determinants that contribute to the success of hypertension drug treatment on a large set of patients. We also identified concomitant drugs not considered to have antihypertensive activity, which may contribute to lowering blood pressure (BP) control. Higher initial BP predicts lower success rates. Among the medication options and their combinations, treatment with beta blockers appears to be more commonly effective, which is not reflected in contemporary guidelines. Among numerous concomitant drugs taken by hypertensive patients, proton pump inhibitors (PPIs), and HMG CO-A reductase inhibitors (statins) significantly improved the success rate of hypertension. In conclusions, machine learning of big data is a novel method to identify effective antihypertensive therapy and for repurposing medications already on the market for new indications. Our results related to beta blockers, stemming from machine learning of a large and diverse set of big data, in contrast to the much narrower criteria for randomized clinic trials (RCTs), should be corroborated and affirmed by other methods, as they hold potential promise for an old class of drugs which may be presently underutilized. These previously unrecognized effects of PPIs and statins have been very recently identified as effective in lowering BP in preliminary clinical observations, lending credibility to our big data results.

Evaluation of pregnancy outcomes in patients with multiple sclerosis after fingolimod exposure.

Abstract: Background and Methods:Limited data are available on the safety of fingolimod in pregnant women. We estimated the risk of adverse pregnancy outcomes in women with multiple sclerosis (MS) exposed to...

A Universal Scaling Relation for Defining Power Spectral Bands in Mammalian Heart Rate Variability Analysis.

Abstract: Background: Power spectral density (PSD) analysis of the heartbeat intervals in the three main frequency bands (very low frequency (VLF), low frequency (LF) and high frequency (HF)) provides a quantitative noninvasive tool for assessing the function of the cardiovascular control system In humans, these frequency bands were standardized following years of empirical evidence However, no quantitative approach has justified the frequency cutoffs of these bands and how they might be adapted to other mammals Defining mammal-specific frequency bands is necessary if the PSD analysis of the HR is to be used as a proxy for measuring the autonomic nervous system activity in animal models Methods: We first describe the distribution of prominent frequency peaks found in the normalized PSD of mammalian data using a Gaussian mixture model while assuming three components corresponding to the traditional VLF, LF and HF bands We trained the algorithm on a database of human electrocardiogram recordings (n=18) and validated it on databases of dogs (n=17) and mice (n = 7) Finally, we tested it to predict the bands for rabbits (n=4) for the first time Results: Double-logarithmic analysis demonstrates a scaling law between the GMM-identified cutoff frequencies and the typical heart rate (HRm): f_(VLF-LF)=00037∙〖HR〗_m^058,f_(LF-HF)=00017∙〖HR〗_m^101 and f_(〖HF〗_up )=00128 ∙〖HR〗_m^086 We found that the band cutoff frequencies and Gaussian mean scale with a power law of 1/4 or 1/8 of the typical body mass (BMm), thus revealing allometric power laws Conclusions: Our automated data-driven approach allowed us to define the frequency bands in PSD analysis of beat-to-beat time series from different mammals The scaling law between the band frequency cutoffs and the HRm can be used to approximate the PSD bands in other mammals

Effect of Lidocaine-Prilocaine Cream (EMLA®) on Pain of Intramuscular Fluzone® Injection

Abstract: The efficacy of lidocaine-prilocaine cream (EMLA® — Eutectic mixture of Local Anesthetics) in alleviating the pain of intramuscular injections was investigated in a randomized, double-blind, placebo-controlled, parallel group trial. EMLA® or placebo cream was applied to the arms of 60 adult volunteers before receiving influenza virus vaccine (Fluzone®). Twenty-nine subjects received approximately 2.5 g of EMLA® cream and 31 subjects received approximately 2.5 g of an inert placebo cream under occlusion for 60-90 minutes. The cream was then removed and each subject received one 0.5 mL intramuscular injection of influenza virus vaccine using a 22 gauge one inch needle. Pain of needle puncture and pain of injection were both assessed by the subjects using a visual analog scale. EMLA® was associated with decreased needle puncture pain (p < 0.0002) and decreased pain of injection when compared to placebo (p = 0.0139). There was a significant correlation between scores of needle puncture pain and injection pain. Mild skin pallor was a common skin reaction from EMILA®· While the efficacy of EMLA® to alleviate pain of venipuncture is well documented, this is the first study to show the efficacy of EMLA ® for intramuscular injections. RESUME Une etude randomisee a double insu, en controle parallele avec placebo a permis d'evaluer la capacite de la Lidocaine-Prilocaine (creme EMLA® — melange eutectique d'anesthesiques locaux) a soulager la douleur causee par les injections intramusculaires. On a applique la creme EMLA® ou un placebo sur le bras de 60 volontaires adultes avant de leur injecter un vaccin viral contre la grippe (Fluzone®). Vingt-neuf (29) sujets ont ete traites avec la creme EMLA® et 31 avec le placebo. Tous ont recu une application d'environ 2,5 g de creme sous un pansement occlusif pendant 60 a 90 minutes. Apres l'elimination de la creme, on leur a injecte 0,5 mL de vaccin par voie intramusculaire au moyen d'une aiguille calibre 22 d'un pouce. Les sujets ont evalue la douleur causee par l’insertion de l'aiguille et par l'injection au moyen d'une echelle visuelle analogique. Comparativement au placebo, la creme EMLA® a attenue la douleur associee a l'insertion de l’aiguille (p < 0.0002) et a l’injection (P = 0,0139). On a note une correlation significative entre les cotes se rapportant a la douleur provoquee par l'insertion de l'aiguille et celles relatives a la douleur causee par l'injection. L'apparition d'une legere pâleur fut une reaction cutanee courante a l'application de la creme EMLA®. Il est bien etabli que cette derniere soulage la douleur due a la ponction veineuse, mais la presente etude est la premieree a demontrer son efficacite en cas d'injection intramusculaire.

Deviations from Typical Developmental Trajectories Detectable at 9 Months of Age in Low Risk Children Later Diagnosed with Autism Spectrum Disorder

Abstract: This study was designed to track the developmental trajectory, during the first 24 months of life, of 335 low-risk infants later diagnosed with Autism Spectrum Disorder and identify early deviations observed in routine Well Care checkups. We compared their achievements to typically developing children and to children later diagnosed with non-autistic developmental impairments. The results show that in the first 6 months, the children with autism showed normal acquisition of milestones, whereas by 9 months of age they began to fail the language/communication, as well as motor items when compared to typical and delayed non-autistic children. Regular check-up visits may be useful in detecting early failure in achieving milestones, leading to earlier referral for further evaluation and treatment.

No. 274-Management of Varicella Infection (Chickenpox) in Pregnancy

Abstract: Objective To review the existing data regarding varicella zoster virus infection (chickenpox) in pregnancy, interventions to reduce maternal complications and fetal infection, and antepartum and peripartum management . Methods The maternal and fetal outcomes in varicella zoster infection were reviewed, as well as the benefit of the different treatment modalities in altering maternal and fetal sequelae. Evidence Medline was searched for articles and clinical guidelines published in English between January 1970 and November 2010. Values The quality of evidence was rated using the criteria described in the Report of the Canadian Task Force on Preventive Health Care. Recommendations for practice were ranked according to the method described in that report (Table). Recommendations 1.Varicella immunization is recommended for all non-immune women as part of pre-pregnancy and postpartum care (II-3B). 2.Varicella vaccination should not be administered in pregnancy. However, termination of pregnancy should not be advised because of inadvertent vaccination during pregnancy (II-3D). 3.The antenatal varicella immunity status of all pregnant women should be documented by history of previous infection, varicella vaccination, or varicella zoster immunoglobulin G serology (III-C). 4.All non-immune pregnant women should be informed of the risk of varicella infection to themselves and their fetuses. They should be instructed to seek medical help following any contact with a person who may have been contagious (II-3B). 5.In the case of a possible exposure to varicella in a pregnant woman with unknown immune status, serum testing should be performed. If the serum results are negative or unavailable within 96 hours from exposure, varicella zoster immunoglobulin should be administered (III-C). 6.Women who develop varicella infection in pregnancy need to be made aware of the potential adverse maternal and fetal sequelae, the risk of transmission to the fetus, and the options available for prenatal diagnosis (II-3C). 7.Detailed ultrasound and appropriate follow-up is recommended for all women who develop varicella in pregnancy to screen for fetal consequences of infection (III-B). 8.Women with significant (e.g., pneumonitis) varicella infection in pregnancy should be treated with oral antiviral agents (e.g., acyclovir 800 mg 5 times daily). In cases of progression to varicella pneumonitis, maternal admission to hospital should be seriously considered. Intravenous acyclovir can be considered for severe complications in pregnancy (oral forms have poor bioavailability). The dose is usually 10 to 15 mg/kg of BW or 500 mg/m2 IV every 8 h for 5 to 10 days for varicella pneumonitis, and it should be started within 24 to 72 h of the onset of rash (III-C). 9.Neonatal health care providers should be informed of peripartum varicella exposure in order to optimize early neonatal care with varicella zoster immunoglobulin and immunization (III-C). Varicella zoster immunoglobulin should be administered to neonates whenever the onset of maternal disease is between 5 days before and 2 days after delivery (III-C).

Transient Outward K+ Current (Ito) Underlies the Right Ventricular Initiation of Polymorphic Ventricular Tachycardia in a Transgenic Rabbit Model of Long-QT Syndrome Type 1

Abstract: Background:Sudden death in long-QT syndrome type 1 (LQT1), an inherited disease caused by loss-of-function mutations in KCNQ1, is triggered by early afterdepolarizations (EADs) that initiate polymo...

A cost-effectiveness analysis of maternal CYP2D6 genetic testing to guide treatment for postpartum pain and avert infant adverse events.

Abstract: Mothers with a CYP2D6 ultrarapid metabolizer phenotype may expose their infants to risk of adverse events when taking codeine while breastfeeding, by producing more of the active metabolite, morphine. Pharmacogenetic testing may be a valuable tool to identify such mothers, but testing can be costly. The objective of the study was to determine the incremental costs of genotyping to avert neonatal adverse events during maternal pharmacotherapy. A cost-effectiveness analysis, using a decision model, was performed with a hypothetical cohort of prenatal subjects. Parameter estimates, costs and ranges for sensitivity analyses were ascertained from the literature and expert opinion. Sensitivity analyses were conducted to assess the robustness of the results. Probabilistic sensitivity analysis revealed an incremental cost-effectiveness (ICER) of $10 433 (Canadian dollars) for genotyping compared to no genotyping per adverse event averted. Results were sensitive to hospital admission costs. The ICER was lower when evaluating only subjects having caesarean deliveries or those from ethnic populations known to have a high prevalence of ultra-rapid metabolizers. Although genotyping to guide pharmacotherapy was not cost saving, the cost to avert an infant adverse event may represent good value for money in specific populations. With a growing demand for personalized medicine, these findings are relevant for decision makers, clinicians and patients.

Environmental exposures and fetal growth: the Haifa pregnancy cohort study.

Abstract: The developing fetus is susceptible to environmental insults. Studying the effects of environmental exposures on fetal growth is essential for understanding the causal pathway between prenatal exposures and pregnancy outcomes. Here we describe the Haifa Pregnancy Cohort Study (HPCS) and discuss challenges and opportunities in applying “big data” paradigm. Maccabi Healthcare Services (MHS), is the second largest Israeli health maintenance organization (HMO) providing care services to two million beneficiaries. The HPCS cohort potentially includes ~750,000 newborns born between 1998 and 2017. We will estimate daily exposures to air pollutants, temperature and greenness, using satellite-based data and models. We hypothesize that residents of Haifa have higher exposures to environmental pollutants and that in pregnant women this higher exposure is associated with poorer fetal growth. We will evaluate outcomes such as birth-weight, head-circumference and gestational age at birth. We will adjust for pregnancy complications such as pre-eclampsia and gestational diabetes and parental variables, such as maternal weight, age and smoking habits as potential confounders. In addition, we will conduct a multi-tiered field study, nested within this population, among 150 pregnant women residing in two geographical regions-one in the polluted Haifa area, and one in a relatively unpolluted area in central Israel. Blood and urinary samples will be collected, as well as personal and indoor exposure to air pollution. Evaluating environmental exposures of pregnant women and assessing in utero growth over the course of the pregnancy during different exposure windows, is of great scientific and public health interest. Recent advances in data collection and analysis pose great promise to provide insights into contribution of environment to the health of the developing fetus, but also pose major challenges and pitfalls, such as data management, proper statistical framework and integration of data in the population-based study and selectiveness in the nested field study. Yet the continuing follow-up of the study cohort, integrating data from different services, health-promotion, and eventually, application later in real life of our main promises. Our study aims to meet these challenges and to provide evidence of the environmental exposures associated with fetal growth.

Dose-Dependent Teratology in Humans: Clinical Implications for Prevention.

Abstract: Since the inception of clinical teratology, the vast majority of scientific work has focused on identification of drugs and environmental agents causing malformations in humans as a dichotomous variable (i.e. yes or no), as well as the relative and absolute risks of such occurrences. Generally, the dose dependency of such events has not been investigated. With the establishment of large pregnancy databases, dose-dependence relationships are being uncovered for increasing numbers of medications, including valproic acid, carbamazepine, phenobarbital, lamotrigine, topiramate, and lithium. In this review we discuss newly recognized dose-dependent human teratogens and the implications to counseling and clinical management of pregnant women. The option of limiting the dose below a teratogenic threshold for women who may need these drugs may be important in managing such pregnancies. Similarly, in women that were exposed before they realized they had conceived, this new knowledge may lead to significant improvement in risk assessment. A common denominator of all studies calculating dose-dependent teratogenicity in humans is their use of total daily drug dose. None of these studies have standardized their calculations for women's body weight. It is quite possible that the teratogenic dose threshold may be below the clinically effective dose levels for specific women, and hence such information needs to be considered and applied individually. With large administrative databases now reporting on drug safety in pregnancy, more accurate data will likely emerge on dose dependency of human teratogens, and these will likely increase the accuracy of risk assessment.

Clinical implications of selective serotonin reuptake inhibitors-selective serotonin norepinephrine reuptake inhibitors pharmacogenetics during pregnancy and lactation.

Abstract: Depression occurs during pregnancy in 3.9-12.8% of the women. The different serotonin reuptake inhibitors (SRIs) are metabolized in the liver by CYP450 enzymes. CYP2D6 metabolizes paroxetine, fluoxetine, duloxetine and venlafaxine, while CYP2C19 deactivates citalopram and escitalopram. Polymorphisms in these enzymes change the metabolic clearance and levels of these drugs. Higher metabolism of most SRIs in late pregnancy results in lower maternal levels, which could result in decreased efficacy. Very few studies have addressed the potential interaction between pregnancy-induced increase in 2D6 metabolism and specific genotypes of the women, suggesting that ultra-rapid and extensive metabolizers exhibit lower serum concentrations than the other slower genotypes. Preliminary studies suggest that some genotypes of the serotonin transporter (SLC6A4) promoter are associated and are linked to adverse effects in infants with SRI exposure during pregnancy. Presently, there are no clear clinical implications of SRI pharmacogenetic status in pregnancy and lactation. In late pregnancy, women may exhibit lower steady state concentrations of these drugs, necessitating increased doses but these are presently guided clinically and not through genotyping. Much more work is needed to define whether SRI genotype has clinical implications and predictive value for either mother or offspring.

Sea water desalination: A newly discovered cause of iodine deficiency.

Abstract: It has been only 50 years since Basil Hetzel (deceased February 2017) first demonstrated in Papua New Guinea that endemic goiter and cretinism were attributable to an iodinedeficient diet and that iodine supplementation would entirely prevent these conditions and their significant brain damage in unborn children. His pioneering work and his establishment of the International Council for the Control of Iodine Deficiency Disorders (ICCIDD) in 1986 have developed the scientific understanding and public awareness of iodine deficiency disorders (IDD), leading the World Health Assembly in 1990 to declare IDD as a global public health problem and to set a goal for its elimination (WHO, 1990). The Iodine Global Network (IGN), the successor of the ICCIDD, has recently reported population iodine surveys with studies of school-aged children in 143 of 198 countries (IGN, 2017). Based on median urinary iodine concentrations (UIC), none showed severe iodine deficiency (<20 lg/L). Two countries (Angola and Madagascar) showed levels in the moderate iodine deficiency range (20–49 lg/L), and 18 showed levels in the mild iodine deficiency range (50–99 lg/L). Thus, the studies indicate iodine sufficiency in 123 countries. Iodine sufficiency in the general population (including school-aged children) is defined by a median level of 100 lg/L of UIC. While this is an extraordinary, yet unsung, public health success, there is no room for complacency. While the worldwide iodine situation seems to be reaching sufficiency for school-aged children, it is not for pregnant women. The iodine needs of pregnant women ( 150 lg/L) exceed those of the general population ( 100 lg/L) (IGN, 2017). The worldwide data for pregnant women is deficient, and the current data indicate wide spread maternal iodine insufficiency. National (or subnational) surveys of pregnant women are known for only 69 nations, about one-third of the 198 countries (IGN, 2017). Of those, most (39 of 695 57%) have median urinary iodine levels in the insufficient range (<150 lg/L). Severely low levels are reported for the Ukraine (13 lg/L), Morocco (31 lg/L), and New Zealand (38 lg/L). Moderate levels of iodine insufficiency are reported for 18 countries, ranging from 61 lg/L for Israel to 99 lg/L for the United Kingdom. Mild levels of iodine insufficiency (100–149 lg/L) were reported for another 18 countries. The case of Israel highlights an interesting situation in which a new contributory cause of iodine insufficiency has been identified. Israel has not had an IDD prevention program, neither a universal salt iodization (USI) nor a urinary iodine monitoring program. Historically, Israel has not been known to have a significant iodine problem. Benbassat et al. (2004) reported a median urinary iodine level for pregnant women of 143 lg/ L and for nonpregnant adults of 137 lg/L. Furthermore, the 2003 Israeli National Health Interview Study (INHIS-1) found only a 2.9% prevalence of use of prescriptions for thyroid conditions among Israeli adults (Ovadia et al., 2013). In contrast, Ovadia et al. (2013) noted that the second (2010) Israeli National Health Interview Survey (INHIS-2) showed a medication use prevalence of 4.7%, an apparent 60% increase from the first survey (Ovadia et al., 2013). They conducted a study in Ashkelon, where a large sea water desalination plant was built, demonstrating a high (76%) prevalence of elevated thyroglobulin (Tg> 10 lIU/mL). They demonstrated that this iodine deficiency was due to a low iodine dietary intake and raised the concern of low iodine water intake. They pointed out that during this period three of the world’s largest seawater reverse osmosis (SWRO) plants were built in Israel and supplied drinking water to an increasing proportion of the Israeli population. The SWRO process removes all iodine and other micronutrients from the drinking water, and they suggested that deiodized water might be a significant contributor to iodine deficiency in Israel. The same authors conducted in 2016 the first Israeli National Iodine Survey among both school-aged children and pregnant women (Ovadia et al., 2017). The more than 1,000 spot urine specimens from each group represented a national sample of the population by district and ethnic group. Samples were collected at a centralized national laboratory that covered more than two million people, about 25% of the Israeli population, and were analyzed at the Human Nutrition Laboratory at ETH Zurich. The median (IQR) UIC was 83 (52–127) lg/L for school-aged children, compared to a WHO adequacy of 100 lg/L, and 61 (36–97) for pregnant women, compared to a WHO adequacy of 150–249 lg/L.

Selective serotonin reuptake inhibitor use in pregnant women; pharmacogenetics, drug-drug interactions and adverse effects.

Abstract: Introduction: Possible negative effects of selective serotonin reuptake inhibitors (SSRIs) in pregnancy relate to congenital anomalies, negative perinatal events and neurodevelopmental outcome. Man...

Hypothyroidism in Young Children Following Exposure to Iodinated Contrast Media: An Observational Study and a Review of the Literature.

Abstract: While it is well documented that exposure to iodinated contrast media (ICM) can interfere with thyroid function in adults, much less is known about the incidence and risk factors associated with ICM induced hypothyroidism in young children. Using a computerized database we identified 843 children who were exposed to ICM between 1998 and 2015. The incidence rate of ICM induced hypothyroidism per 1000 person-years was 9.66 (95% CI: 4.17-19.04). When compared to the rest of the cohort, children with hypothyroidism were more likely to be younger, weigh less and to have undergone cardio-angiography. These results are supported by findings described in the literature review. The risk of ICM- induced hypothyroidism needs to be considered especially in young children with low weight, undergoing cardio-angiography examinations. Systematic monitoring of thyroid function should be conducted in this focused patient population to avoid potential adverse consequences on child development.

Preventing Inappropriate Hydroxyurea Dosing in Children by Introducing a Child-Appropriate Preparation

Abstract: Hydroxyurea (HU) is the only FDA- approved disease- modifying drug for sickle cell disease, by inducing the production of fetal hemoglobin and thus decreasing the sickling of red blood cells. Till recently HU was available only in adult doses of 1000 mg. This meant that to aim at the standard dose of 20 mg/kg/d, most young children had to be overdosed, or the doses had to be fluctuated daily to achieve the aimed mean dose. Because adherence improves with unchanged daily dose, and due to the more than 10 fold variability in HU pharmacokinetics in children, there was an urgent need for a pediatric formulation of HU. This issue has been solved with FDA approval of the French-originated orphan HU, Siklos, a preparation of 50 and 100 mg, which prevents the risk of inappropriate dosing in children.