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Aims Current long QT syndrome (LQTS) therapy, largely based on beta-blockade, does not prevent arrhythmias in all patients; therefore, novel therapies are warranted. Pharmacological inhibition of the serum/glucocorticoid-regulated kinase 1 (SGK1-Inh) has been shown to shorten action potential duration (APD) in LQTS type 3. We aimed to investigate whether SGK1-Inh could similarly shorten APD in LQTS types 1 and 2. Methods and results Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and hiPSC-cardiac cell sheets (CCS) were obtained from LQT1 and LQT2 patients; CMs were isolated from transgenic LQT1, LQT2, and wild-type (WT) rabbits. Serum/glucocorticoid-regulated kinase 1 inhibition effects (300 nM–10 µM) on field potential durations (FPD) were investigated in hiPSC-CMs with multielectrode arrays; optical mapping was performed in LQT2 CCS. Whole-cell and perforated patch clamp recordings were performed in isolated LQT1, LQT2, and WT rabbit CMs to investigate SGK1-Inh (3 µM) effects on APD. In all LQT2 models across different species (hiPSC-CMs, hiPSC-CCS, and rabbit CMs) and independent of the disease-causing variant (KCNH2 -p.A561V/p.A614V/p.G628S/IVS9-28A/G), SGK1-Inh dose-dependently shortened FPD/APD at 0.3–10 µM (by 20–32%/25–30%/44–45%). Importantly, in LQT2 rabbit CMs, 3 µM SGK1-Inh normalized APD to its WT value. A significant FPD shortening was observed in KCNQ1 -p.R594Q hiPSC-CMs at 1/3/10 µM (by 19/26/35%) and in KCNQ1 -p.A341V hiPSC-CMs at 10 µM (by 29%). No SGK1-Inh-induced FPD/APD shortening effect was observed in LQT1 KCNQ1 -p.A341V hiPSC-CMs or KCNQ1 -p.Y315S rabbit CMs at 0.3–3 µM. Conclusion A robust SGK1-Inh-induced APD shortening was observed across different LQT2 models, species, and genetic variants but less consistently in LQT1 models. This suggests a genotype- and variant-specific beneficial effect of this novel therapeutic approach in LQTS. [ABSTRACT FROM AUTHOR]

Calcium transfer into the mitochondrial matrix during sarcoplasmic reticulum (SR) Ca2+ release is essential to boost energy production in ventricular cardiomyocytes (VCMs) and match increased metabolic demand. Mitochondria from female hearts exhibit lower mito-[Ca2+] and produce less reactive oxygen species (ROS) compared to males, without change in respiration capacity. We hypothesized that in female VCMs, more efficient electron transport chain (ETC) organization into supercomplexes offsets the deficit in mito-Ca2+ accumulation, thereby reducing ROS production and stress-induced intracellular Ca2+ mishandling. Experiments using mitochondria-targeted biosensors confirmed lower mito-ROS and mito-[Ca2+] in female rat VCMs challenged with β-adrenergic agonist isoproterenol compared to males. Biochemical studies revealed decreased mitochondria Ca2+ uniporter expression and increased supercomplex assembly in rat and human female ventricular tissues vs male. Importantly, western blot analysis showed higher expression levels of COX7RP, an estrogen-dependent supercomplex assembly factor in female heart tissues vs males. Furthermore, COX7RP was decreased in hearts from aged and ovariectomized female rats. COX7RP overexpression in male VCMs increased mitochondrial supercomplexes, reduced mito-ROS and spontaneous SR Ca2+ release in response to ISO. Conversely, shRNA-mediated knockdown of COX7RP in female VCMs reduced supercomplexes and increased mito-ROS, promoting intracellular Ca2+ mishandling. Compared to males, mitochondria in female VCMs exhibit higher ETC subunit incorporation into supercomplexes, supporting more efficient electron transport. Such organization coupled to lower levels of mito-[Ca2+] limits mito-ROS under stress conditions and lowers propensity to pro-arrhythmic spontaneous SR Ca2+ release. We conclude that sexual dimorphism in mito-Ca2+ handling and ETC organization may contribute to cardioprotection in healthy premenopausal females. [ABSTRACT FROM AUTHOR]

Purpose: The COVID-19 pandemic has led to the isolation of the population in Israel, including the elderly. The present study aimed to compare the consumption of medical services among adults over the age of 65 in Israel at the time of the first COVID-19 lockdown relative to the corresponding period the year before. Methods: We conducted a retrospective longitudinal observational quantitative research based on the Natali Healthcare Solutions Israel database of subscribers. Company subscribers over the age of 65 (N = 103,955) were included in the sample (64.5% women) in two time periods, before the COVID-19 outbreak-P1, in 2019, and during the first COVID-19 lockdown- P2 in 2020. Logistic regression was applied to examine service consumption for study variables. Results: The average number of referrals to services was lower during the COVID-19 lockdown period (M = 0.3658, SD = 0.781) compared to the corresponding period in the previous year (M = 0.5402, SD = 0.935). The average number of ambulance orders, doctor home visits and service refusals were higher when compared to the same period in the previous year. During both time periods, women (P1- M = 0.5631, SD = 0.951; P2- M = 0.3846, SD = 0.800) required significantly more (p <.000) services than men (P1- M = 0.5114, SD = 0.910; P2- M = 0.3417, SD = 0.753). Older, widowed people, living in non-Jewish/mixed localities, or in average or below average socioeconomic status localities required relatively more services to those with opposite socio-demographic traits (p <.000). Summary and conclusions: In a large sample of elderly in Israel, findings indicate a decrease in referrals to medical care during the first COVID-19 lockdown period, yet an increase in ambulance orders, doctor visits and service refusals. Socio-demographic characteristics showed a similar effect in both time periods. The period of the first COVID-19 lockdown was characterized by a higher incidence of medical service refusals as compared to the equivalent period in the previous year. [ABSTRACT FROM AUTHOR]

Aims: The objective of this meta‐analysis was to determine whether maternal exposure to statins is associated with increased rates of major congenital malformations and other adverse pregnancy outcomes. Methods: PubMed/Medline, Web of Science and Reprotox® databases were searched. Cohort and case control studies with prenatal exposure to statins were included. Results: Analysis of five cohort studies and one case–control study showed no significant increase in rate of major congenital malformations when the exposed group was compared with the control ([OR 1.27; 95% CI 0.80–2.04], [aOR 1.05; 95% CI 0.84–1.31]). A significant increase in heart defect risk was detected in the statin‐exposed group when unadjusted ORs were combined (OR 2.47; 95% CI 1.36–4.49). Further analysis of the same outcome by using adjusted ORs showed no significant increase in heart defect risk in the statin‐exposed group compared with the controls (aOR 1.24; 95% CI 0.93–1.66). A significantly lower live birth rate (OR 0.60, 95% CI 0.49–0.75) and a higher spontaneous abortion rate (OR 1.36; 95% Cl 1.06–1.75) were detected in the statin‐exposed group. Conclusions: Gestational statin exposure was not associated with a significant increase in risk of major congenital malformations, heart defects and other adverse pregnancy outcomes, except spontaneous abortion and live birth rate, which may be associated with maternal comorbidity and other unadjusted risk factors. Further research focusing on particular statins is needed to draw more definitive conclusions. [ABSTRACT FROM AUTHOR]

Immigrants and second‐generation immigrants from Ethiopia in Israel are assumed to be more vulnerable to problematic risk behaviours than host culture population. The aim of this study was to assess risk and protective factors associated with multiproblem behaviours such as committing driving violations, alcohol use, drugs use and violence among Ethiopian young adult immigrants and second‐generation immigrants in Israel. This is a cross‐sectional study, based on a self‐reported anonymous structured questionnaire distributed to 383 Ethiopian emerging adults (mean age 25.3; SD = 3.27, 59.3% female). Multiple Problem Behavior Index (MPBI) was created from their responses to 21 risk behaviour variables including driving violations, alcohol use, Marijuana use and violence. Logistic regression to predict multiproblem behaviours was used. We found that unplanned leisure activity hours during weekends (adjusted odds ratio – AOR = 2.594, p <.01, 95% CI 1.332–5.052), excitement seeking (AOR = 2.122, p<.01, 95% CI 1.257–3.582), depression symptoms (AOR = 2.521, p <.01, 95% CI 1.491–4.261) and gender (AOR = 0.277, p <.001, 95% CI 0.164–0.469) were associated with MPBI. In contrast, racism, perceived discrimination, Israeli and Ethiopian identities were not significantly associated with MPBI after adjusting for gender and family status. These results suggest that in a minority of Ethiopian emerging adult immigrants similar to host culture populations, risk factors such as unplanned leisure activities, excitement seeking and depression symptoms are stronger and significant factors associated with multiproblem behaviours rather than racism, perceived discrimination or Israeli and Ethiopian identities. Resources should be allocated to produce appropriate intervention programs with planned content for leisure time, especially on weekends. [ABSTRACT FROM AUTHOR]

Aim: Long QT syndrome (LQTS) is a cardiac channelopathy predisposing to ventricular arrhythmias and sudden cardiac death. Since current therapies often fail to prevent arrhythmic events in certain LQTS subtypes, new therapeutic strategies are needed. Docosahexaenoic acid (DHA) is a polyunsaturated fatty acid, which enhances the repolarizing IKs current.Methods and Results: We investigated the effects of DHA in wild type (WT) and transgenic long QT Type 1 (LQT1; loss of IKs), LQT2 (loss of IKr), LQT5 (reduction of IKs), and LQT2-5 (loss of IKr and reduction of IKs) rabbits. In vivo ECGs were recorded at baseline and after 10 µM/kg DHA to assess changes in heart-rate corrected QT (QTc) and short-term variability of QT (STVQT). Ex vivo monophasic action potentials were recorded in Langendorff-perfused rabbit hearts, and action potential duration (APD75) and triangulation were assessed. Docosahexaenoic acid significantly shortened QTc in vivo only in WT and LQT2 rabbits, in which both α- and β-subunits of IKs-conducting channels are functionally intact. In LQT2, this led to a normalization of QTc and of its short-term variability. Docosahexaenoic acid had no effect on QTc in LQT1, LQT5, and LQT2-5. Similarly, ex vivo, DHA shortened APD75 in WT and normalized it in LQT2, and additionally decreased AP triangulation in LQT2.Conclusions: Docosahexaenoic acid exerts a genotype-specific beneficial shortening/normalizing effect on QTc and APD75 and reduces pro-arrhythmia markers STVQT and AP triangulation through activation of IKs in LQT2 rabbits but has no effects if either α- or β-subunits to IKs are functionally impaired. Docosahexaenoic acid could represent a new genotype-specific therapy in LQT2. [ABSTRACT FROM AUTHOR]

To study the pathophysiology of human cardiac diseases and to develop novel treatment strategies, complex interactions of cardiac cells on cellular, tissue and on level of the whole heart need to be considered. As in vitro cell‐based models do not depict the complexity of the human heart, animal models are used to obtain insights that can be translated to human diseases. Mice are the most commonly used animals in cardiac research. However, differences in electrophysiological and mechanical cardiac function and a different composition of electrical and contractile proteins limit the transferability of the knowledge gained. Moreover, the small heart size and fast heart rate are major disadvantages. In contrast to rodents, electrophysiological, mechanical and structural cardiac characteristics of rabbits resemble the human heart more closely, making them particularly suitable as an animal model for cardiac disease research. In this review, various methodological approaches for the generation of transgenic rabbits for cardiac disease research, such as pronuclear microinjection, the sleeping beauty transposon system and novel genome‐editing methods (ZFN and CRISPR/Cas9)will be discussed. In the second section, we will introduce the different currently available transgenic rabbit models for monogenic cardiac diseases (such as long QT syndrome, short‐QT syndrome and hypertrophic cardiomyopathy) in detail, especially in regard to their utility to increase the understanding of pathophysiological disease mechanisms and novel treatment options. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc [ABSTRACT FROM AUTHOR]

Cardiac arrhythmias significantly contribute to cardiovascular morbidity and mortality. The rabbit heart serves as an accepted model system for studying cardiac cell excitation and arrhythmogenicity. Accordingly, primary cultures of adult rabbit ventricular cardiomyocytes serve as a preferable model to study molecular mechanisms of human cardiac excitation. However, the use of adult rabbit cardiomyocytes is often regarded as excessively costly. Therefore, we developed and characterized a novel low-cost rabbit cardiomyocyte model, namely, 3-week-old ventricular cardiomyocytes (3wRbCMs). Ventricular myocytes were isolated from whole ventricles of 3-week-old New Zealand White rabbits of both sexes by standard enzymatic techniques. Using wheat germ agglutinin, we found a clear T-tubule structure in acutely isolated 3wRbCMs. Cells were adenovirally infected (multiplicity of infection of 10) to express Green Fluorescent Protein (GFP) and cultured for 48 h. The cells showed action potential duration (APD90 = 253 ± 24 ms) and calcium transients similar to adult rabbit cardiomyocytes. Freshly isolated and 48-h-old-cultured cells expressed critical ion channel proteins: calcium voltage-gated channel subunit alpha1 C (Cavα1c), sodium voltage-gated channel alpha subunit 5 (Nav1.5), potassium voltage-gated channel subfamily D member 3 (Kv4.3), and subfamily A member 4 (Kv1.4), and also subfamily H member 2 (RERG. Kv11.1), KvLQT1 (K7.1) protein and inward-rectifier potassium channel (Kir2.1). The cells displayed an appropriate electrophysiological phenotype, including fast sodium current (I Na), transient outward potassium current (I to), L-type calcium channel peak current (I Ca,L), rapid and slow components of the delayed rectifier potassium current (I Kr and I Ks), and inward rectifier (I K1). Although expression of the channel proteins and some currents decreased during the 48 h of culturing, we conclude that 3wRbCMs are a new, low-cost alternative to the adult-rabbit-cardiomyocytes system, which allows the investigation of molecular mechanisms of cardiac excitation on morphological, biochemical, genetic, physiological, and biophysical levels. [ABSTRACT FROM AUTHOR]

Aims: Oral contraceptives (OC)s are commonly used worldwide. In a recent study, we showed that the use of OCs is associated with an increased risk for neutropenia. We aimed to investigate the clinical implications of this finding by examining the infection rates of 4 serious infections before, during and after OCs. Methods: A retrospective cohort study using the electronic medical records of a large health organization. We selected 2 retrospective cohorts of women aged 16–40 between years 2005 and 2019. The first cohort examined infection rates during 2 years before OC use and 2 consecutive years of adherent OC use. The second cohort included women who consumed OCs adherently for 2 years and then discontinued their use for 2 consecutive years. Women's infection rates were compared by χ2 test, results were stratified by OC type and age. Results: Overall, 21 595 and 20 728 women were included in Cohorts 1 and 2 respectively. We found a statistically significant higher relative risk for infection while using OCs; the overall risk ratios (95% confidence intervals) for infection in Cohorts 1 and 2 were 1.35 (1.32–1.38) and 1.27 (1.24–1.31), respectively. The overall infection risk remained statistically significant when stratified by age. Conclusions: This study demonstrates a high statistically and clinically significant risk for all infections followed during OC consumption, which is likely to have major clinical and economic implications. These findings may have implications to millions of women worldwide and should lead to more research on the safety of the pill. [ABSTRACT FROM AUTHOR]

Introduction: Body-art, including tattoos and piercings, is steadily increasing world-wide but with relatively limited reporting of adverse outcomes. The objective of the present study was to identify correlates that would facilitate a preventative strategy to minimize adverse effects of body-art. Methods: We examined patterns of body-art, health risk and perceptions among 921 participants (54% female, mean age of 35; SD = 10.8) through in-person questionnaire. Results: A significantly lower frequency of those with body-art acknowledged that not all venues (parlors, clinics, etc.) are safe in terms of health and hygiene (84.7%t vs. 96.6%, p <.001) as compared to those without body-art. Similarly, knowledge of the need for a Ministry of Health certification was reported with lower frequency (77.2% vs. 94.5%, p <.001) among those with body-art. Those who experienced medical complications reported higher frequencies of smoking cigarettes and hookah as well as using ecstasy (MDMA). The risk of medical complication after body-art was 4 times higher in those who used ecstasy (OR = 3.97; CI 1.0–14.4; p < 0.05). In addition, it was more than 3 times higher for street or home tattooing as compared to studio or a licensed medical center (OR = 3.59; CI 1.32–9.76; p <.01), as well as almost 3 times higher among those who did not receive information before performing body-art (OR = 2.70; CI 1.05–6.92; p <.05) and who had somebody other than themselves decide on the body-art design (OR = 2.68; CI 1.00–7.19; p <.05). Conclusions: A targeted informational-preventative program should be developed, informed by the risks highlighted in this study. In addition, it would be necessary to draft policies related to regulation and enforcement in order to more effectively manage body-art service provision. The Ministry of Health should supervise and guide tattooists and practitioners regarding the health risks of body-art and offer training and raise awareness among potential clients. [ABSTRACT FROM AUTHOR]

Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, affecting up to 80% of expectant women. Measuring the severity of the condition over time is important for management decisions, as well as for research into different therapeutic modalities. Twenty years ago we described and validated the Pregnancy Unique Quantification of Emesis scale (PUQE), as a clinical and research tool. PUQE has become widely used for both ends, and has been incorporated in numerous practice guidelines worldwide. In this review we describe the inception of the tool, its rational, and its wide range of use worldwide. [ABSTRACT FROM AUTHOR]

Purpose: Fexofenadine is a well-identified in vivo probe substrate of P-glycoprotein (P-gp) and/or organic anion transporting polypeptide (OATP). This work aimed to investigate the transplacental pharmacokinetics of fexofenadine enantiomers with and without the selective P-gp inhibitor fluoxetine. Methods: The chiral transplacental pharmacokinetics of fexofenadine-fluoxetine interaction was determined using the ex vivo human placenta perfusion model (n = 4). In the Control period, racemic fexofenadine (75 ng of each enantiomer/ml) was added in the maternal circuit. In the Interaction period, racemic fluoxetine (50 ng of each enantiomer/mL) and racemic fexofenadine (75 ng of each enantiomer/mL) were added to the maternal circulation. In both periods, maternal and fetal perfusate samples were taken over 90 min. Results: The (S)-(−)- and (R)-(+)-fexofenadine fetal-to-maternal ratio values in Control and Interaction periods were similar (~0.18). The placental transfer rates were similar between (S)-(−)- and (R)-(+)-fexofenadine in both Control (0.0024 vs 0.0019 min−1) and Interaction (0.0019 vs 0.0021 min−1) periods. In both Control and Interaction periods, the enantiomeric fexofenadine ratios [R-(+)/S-(−)] were approximately 1. Conclusions: Our study showed a low extent, slow rate of non-enantioselective placental transfer of fexofenadine enantiomers, indicating a limited fetal fexofenadine exposure mediated by placental P-gp and/or OATP2B1. The fluoxetine interaction did not affect the non-enantioselective transplacental transfer of fexofenadine. The ex vivo placental perfusion model accurately predicts in vivo placental transfer of fexofenadine enantiomers with remarkably similar values (~0.17), and thus estimates the limited fetal exposure. [ABSTRACT FROM AUTHOR]

Hypothalamic-Pituitary-Adrenal (HPA) axis activity is related to negative mental health outcomes, including depression. Most developmental research uses salivary cortisol to index HPA activity; however, hair cortisol concentrations (HCCs) reflect cortisol production over extended periods of time. While HCCs have been linked to adult depression, their relationship to the development of children's depressive symptoms is unclear. We assessed HCCs in 60 seven-year-old community-dwelling girls who were followed up one year later. In broader models, girls' age 7 HCCs were positively associated with age 8 depressive symptoms at a trend level, indicating that HCCs may be related to mental health early in development. [ABSTRACT FROM AUTHOR]

Background: Opioid use disorder (OUD) affects an estimated 16 million people worldwide. The diagnosis of OUD is commonly delayed or missed altogether. We aimed to test the utility of machine learning in creating a prediction model and algorithm for early diagnosis of OUD. Subjects and methods: We analyzed data gathered in a commercial claim database from January 1, 2006, to December 31, 2018 of 10 million medical insurance claims from 550 000 patient records. We compiled 436 predictor candidates, divided to six feature groups - demographics, chronic conditions, diagnosis and procedures features, medication features, medical costs, and episode counts. We employed the Word2Vec algorithm and the Gradient Boosting trees algorithm for the analysis. Results: The c-statistic for the model was 0.959, with a sensitivity of 0.85 and specificity of 0.882. Positive Predictive Value (PPV) was 0.362 and Negative Predictive Value (NPV) was 0.998. Significant differences between positive OUD- and negative OUD- controls were in the mean annual amount of opioid use days, number of overlaps in opioid prescriptions per year, mean annual opioid prescriptions, and annual benzodiazepine and muscle relaxant prescriptions. Notable differences were the count of intervertebral disc disorder-related complaints per year, post laminectomy syndrome diagnosed per year, and pain disorders diagnosis per year. Significant differences were also found in the episodes and costs categories. Conclusions: The new algorithm offers a mean 14.4 months reduction in time to diagnosis of OUD, at potential saving in further morbidity, medical cost, addictions and mortality. [ABSTRACT FROM AUTHOR]

The medications used in assisted reproduction are given before and during early pregnancy, and hence, they may potentially result in adverse fetal effects. In this review we present an updated account of their fetal safety and discuss methodological challenges in interpretation of existing data. The fetal safety/risks of clomiphene citrate, aromatase inhibitors, metformin, gonadotropins and progestins are discussed. We searched PubMed, EMBASE, Cochrane, Google, and Google Scholar from inception to 30 April 2020 for publications pertinent to our topic. There are several major challenges in studying fetal safety of medications used in assisted reproduction. The fact is that the rates of congenital malformations among infertile women giving birth spontaneously is higher than the rates among healthy women conceiving spontaneously. In most clinical studies of assisted reproduction, the primary endpoint is the success in inducing pregnancy, neglecting to report pregnancy outcome and adverse neonatal event. As an example for this reality, it has been estimated that between 1977 and 2005 around 10 million pregnancies were treated with dydrogesterone (DYD), yet till 2019 only very few studies, with a total sample size of less than 600 were reported with regards to fetal safety. [ABSTRACT FROM AUTHOR]

Background and Purpose: Reliable prediction of pro-arrhythmic side effects of novel drug candidates is still a major challenge. Although drug-induced pro-arrhythmia occurs primarily in patients with pre-existing repolarisation disturbances, healthy animals are employed for pro-arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss-of-function mutations of human HERG (HERG-G628S, loss of IKr ; LQT2), KCNE1 (KCNE1-G52R, decreased IKs ; LQT5), or both transgenes (LQT2-5) in the heart.Experimental Approach: Effects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild-type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff-perfused hearts.Key Results: LQTS models reflect patients with clinically "silent" (LQT5) or "manifest" (LQT2 and LQT2-5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr -blocking (LQT5) or IK1 /IKs -blocking (LQT2 and LQT2-5) properties of drugs compared to healthy WT animals. Impaired QT-shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2-5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT.Conclusion and Implications: LQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2-5), their combined use could provide more reliable and more thorough prediction of (multichannel-based) pro-arrhythmic potential of novel drug candidates. [ABSTRACT FROM AUTHOR]

Key points: Small‐conductance Ca2+‐activated K+ (SK) channels expressed in ventricular myocytes are dormant in health, yet become functional in cardiac disease.SK channels are voltage independent and their gating is controlled by intracellular [Ca2+] in a biphasic manner. Submicromolar [Ca2+] activates the channel via constitutively‐bound calmodulin, whereas higher [Ca2+] exerts inhibitory effect during depolarization.Using a rat model of cardiac hypertrophy induced by thoracic aortic banding, we found that functional upregulation of SK2 channels in hypertrophic rat ventricular cardiomyocytes is driven by protein kinase A (PKA) phosphorylation. Using site‐directed mutagenesis, we identified serine‐465 as the site conferring PKA‐dependent effects on SK2 channel function.PKA phosphorylation attenuates ISK rectification by reducing the Ca2+/voltage‐dependent inhibition of SK channels without changing their sensitivity to activating submicromolar [Ca2+]i.This mechanism underlies the functional recruitment of SK channels not only in cardiac disease, but also in normal physiology, contributing to repolarization under conditions of enhanced adrenergic drive. Small‐conductance Ca2+‐activated K+ (SK) channels expressed in ventricular myocytes (VMs) are dormant in health, yet become functional in cardiac disease. We aimed to test the hypothesis that post‐translational modification of SK channels under conditions accompanied by enhanced adrenergic drive plays a central role in disease‐related activation of the channels. We investigated this phenomenon using a rat model of hypertrophy induced by thoracic aortic banding (TAB). Western blot analysis using anti‐pan‐serine/threonine antibodies demonstrated enhanced phosphorylation of immunoprecipitated SK2 channels in VMs from TAB rats vs. Shams, which was reversible by incubation of the VMs with PKA inhibitor H89 (1 μmol L–1). Patch clamped VMs under basal conditions from TABs but not Shams exhibited outward current sensitive to the specific SK inhibitor apamin (100 nmol L–1), which was eliminated by inhibition of PKA (1 μmol L–1). Beta‐adrenergic stimulation (isoproterenol, 100 nmol L–1) evoked ISK in VMs from Shams, resulting in shortening of action potentials in VMs and ex vivo optically mapped Sham hearts. Using adenoviral gene transfer, wild‐type and mutant SK2 channels were overexpressed in adult rat VMs, revealing serine‐465 as the site that elicits PKA‐dependent phosphorylation effects on SK2 channel function. Concurrent confocal Ca2+ imaging experiments established that PKA phosphorylation lessens rectification of ISK via reduction Ca2+/voltage‐dependent inhibition of the channels at high [Ca2+] without affecting their sensitivity to activation by Ca2+ in the submicromolar range. In conclusion, upregulation of SK channels in diseased VMs is mediated by hyperadrenergic drive in cardiac hypertrophy, with functional effects on the channel conferred by PKA‐dependent phosphorylation at serine‐465. Key points: Small‐conductance Ca2+‐activated K+ (SK) channels expressed in ventricular myocytes are dormant in health, yet become functional in cardiac disease.SK channels are voltage independent and their gating is controlled by intracellular [Ca2+] in a biphasic manner. Submicromolar [Ca2+] activates the channel via constitutively‐bound calmodulin, whereas higher [Ca2+] exerts inhibitory effect during depolarization.Using a rat model of cardiac hypertrophy induced by thoracic aortic banding, we found that functional upregulation of SK2 channels in hypertrophic rat ventricular cardiomyocytes is driven by protein kinase A (PKA) phosphorylation. Using site‐directed mutagenesis, we identified serine‐465 as the site conferring PKA‐dependent effects on SK2 channel function.PKA phosphorylation attenuates ISK rectification by reducing the Ca2+/voltage‐dependent inhibition of SK channels without changing their sensitivity to activating submicromolar [Ca2+]i.This mechanism underlies the functional recruitment of SK channels not only in cardiac disease, but also in normal physiology, contributing to repolarization under conditions of enhanced adrenergic drive. [ABSTRACT FROM AUTHOR]

Drug-induced proarrhythmia constitutes a potentially lethal side effect of various drugs. Most often, this proarrhythmia is mechanistically linked to the drug's potential to interact with repolarizing cardiac ion channels causing a prolongation of the QT interval in the ECG. Despite sophisticated screening approaches during drug development, reliable prediction of proarrhythmia remains very challenging. Although drug-induced long-QT-related proarrhythmia is often favored by conditions or diseases that impair the individual's repolarization reserve, most cellular, tissue, and whole animal model systems used for drug safety screening are based on normal, healthy models. In recent years, several transgenic rabbit models for different types of long QT syndromes (LQTS) with differences in the extent of impairment in repolarization reserve have been generated. These might be useful for screening/prediction of a drug's potential for long-QT-related proarrhythmia, particularly as different repolarizing cardiac ion channels are impaired in the different models. In this review, we summarize the electrophysiological characteristics of the available transgenic LQTS rabbit models, and the pharmacological proof-of-principle studies that have been performed with these models—highlighting the advantages and disadvantages of LQTS models for proarrhythmia research. In the end, we give an outlook on potential future directions and novel models. [ABSTRACT FROM AUTHOR]

Background: Throat pain is a common complaint in the ambulatory setting. Diagnosis of group A Streptococcus is made with a culture, molecular test or a rapid antigen detection test from the tonsils or the posterior pharyngeal wall, while other areas of the oral cavity are considered unacceptable. The purpose of the study is to compare cultures from the tonsils or posterior pharyngeal wall (throat) with cultures from the oral cavity (mouth). Methods: A prospective study conducted in ambulatory care. Eleven family physicians collected 2 swabs (throat and mouth) from 200 consecutive patients who complaint about throat pain. Inclusion criteria were throat pain and Centor Criteria > 2. Exclusion criteria were tonsillectomy and age (< 3 or > 65 years old). Participants were later divided into two groups – pediatrics (3–18 years old) and adults (19–65 year old). Sensitivity and specificity of mouth culture were calculated, with throat culture considered the reference gold standard. Results: Between November 2017 and March 2019, 200 swabs were collected (101 adults and 99 children). In the adult group sensitivity of mouth culture was 72.1% (95% Confidence Interval [CI] 59.9–82.3%) and specificity was 100% (95% CI 92.7–89.4%-100%). In the pediatric group sensitivity of mouth culture was 78.3% (95% CI 65.8–87.9%) and specificity was 100% (95% CI 92.5–100%). Conclusion: Our study demonstrated higher sensitivity of mouth culture for GAS than previously published. This finding suggests that areas of the oral cavity that were considered as unacceptable sites for culture of GAS pharyngitis may be considered as acceptable swabbing sites. Trial registration: Trial registration: ClinicalTrials.gov, ID NCT03137823. Registered 3 May 2017. [ABSTRACT FROM AUTHOR]

Cardiovascular malformations form the largest group of congenital anomalies, typically quoted at 0.8% of all live births. Several medicinal drugs have been proven to cause cardiovascular malformations. We discuss here the risks of the major known medications, including lithium, valproic acid, ondansetron, methylphenidate, topiramate, and the newly recognised dydrogesterone. In contrast, we discuss the controversial and debated effects of selective serotonin reuptake inhibitors (SSR) and selective serotonin norepinephrine reuptake inhibitors (SNRI). Subsequently we describe the principles of counselling pregnant women and those planning pregnancy, who are exposed to these drugs. [ABSTRACT FROM AUTHOR]

The increasing medicinal use of cannabis during recent years has largely overlooked children and pregnant women due to litigious and ethical concerns. However, over the last few years medicine has observed increasing numbers of children treated with cannabis for autism spectrum disorder (ASD) and fetal alcohol spectrum disorder (FASD), and pregnant women treated for hyperemesis gravidarum (HG). This review provides an account of major findings discovered through this research. Specifically, cannabis may offer therapeutic advantages to behavioral symptoms of autism spectrum disorder and fetal alcohol spectrum disorder, and to the severe nausea and vomiting in hyperemesis gravidarum. The use of medical cannabis in children and pregnant women should be further discussed and researched in this patient population. [ABSTRACT FROM AUTHOR]

Aims: The goal of the current study was to assess the risk for major congenital malformations following first‐trimester exposure to amoxicillin, or amoxicillin and clavulanic acid (ACA). Methods: A population‐based retrospective cohort study was conducted, by linking 4 computerized databases: maternal and infant hospitalization records, drug dispensing database of Clalit Health Services in Israel and data concerning pregnancy terminations. Multivariate negative‐binomial regression was used to assess the risk for major malformations following first‐trimester exposure, adjusted for mother's age, ethnicity (Bedouin vs Jewish), parity, diabetes mellitus, lack of perinatal care, and the year of birth. Results: The study included 101 615 pregnancies, of which 6919 (6.8%) were exposed to amoxicillin: 1045 (1.0%) to amoxicillin only and 6041 (5.9%) to ACA. No significant association was found, in the univariate and multivariate analyses, between first‐trimester exposure to amoxicillin or ACA and major malformations in general (crude relative risk, 1.05 95% confidence interval 0.95–1.16; adjusted relative risk 1.09, 95% confidence interval 0.98–1.20), or for major malformations according to organ systems. No dose–response relationship was found between exposure in terms of the defined daily dose and major malformations. Conclusion: Exposure to amoxicillin and ACA during the first trimester of pregnancy was not associated with an increased risk of major congenital malformations. [ABSTRACT FROM AUTHOR]

Despite effective medications, rates of uncontrolled glucose levels in type 2 diabetes remain high. We aimed to test the utility of machine learning applied to big data in identifying the potential role of concomitant drugs not taken for diabetes which may contribute to lowering blood glucose. Success in controlling blood glucose was defined as achieving HgA1c levels < 6.5% after 90-365 days following diagnosis and initiating treatment. Among numerous concomitant drugs taken by type 2 diabetic patients, alpha 1 (α1)-adrenoceptor antagonist drugs were the only group of medications that significantly improved the success rate of glucose control. Searching the published literature, this effect of α1-adrenoceptor antagonists has been shown in animal models, where this class of medications appears to induce insulin secretion. In conclusion, machine learning of big data is a novel method to identify effective antidiabetic effects for potential repurposable medications already on the market for other indications. Because these α1-adrenoceptor antagonists are widely used in men for treating benign prostate hyperplasia (BPH) at age groups exhibiting increased rates of type 2 diabetes, this finding is of potential clinical significance. [ABSTRACT FROM AUTHOR]

Background: Perinatal depression is a common problem that affects about 18% of women worldwide, though the heterogeneity between countries is great. The aims of this study were to assess the prevalence of perinatal depressive symptoms in a national sample of women in Israel, and to investigate associations of these symptoms with demographic, medical and lifestyle factors. Methods: The study included all members of Maccabi Health Services, the second largest health maintenance organization in Israel, who filled the Edinburgh Postnatal Depression Scale (EPDS) during 2015–2016. Crude odds ratios (ORs) and adjusted ORs (aORs) are presented for associations of sociodemographic, medical and lifestyle factors with perinatal depressive symptoms, according to a score ≥ 10 on the EPDS. Results: Of 27,520 women who filled the EPDS, 1346 (4.9%) met the criteria for perinatal depression. In a logistic regression analysis we found the following factors associated with perinatal depression: the use of antidepressant medications (aOR = 2.34, 95% CI 1.94–2.82, P < 0.001 and aOR = 3.44; 95% CI 2.99–3.97, P < 0.001 for ≤3 months and > 3 months respectively), a diagnosis of chronic diabetes mellitus (aOR = 2.04; 95% CI 1.22–3.43, P = 0.007), Arab background (aOR = 2.28; 95% CI 1.82–2.86, P < 0.001), current and past smoking (aOR = 1.62; 95% CI 1.35–1.94, P < 0.001 and aOR = 1.36; 95% CI 1.05–1.76, P = 0.021, respectively), and anaemia (aOR = 1.17; 95% CI 1.04–1.32, P = 0.011). Orthodox Jewish affiliation and residence in the periphery of the country were associated with lower perinatal depression (aOR = 0.48; 95% CI 0.36–0.63, P < 0.001 and aOR = 0.72; 95% CI 0.57–0.92, P = 0.007, respectively). Conclusions: The prevalence of perinatal depression in this study was 4.9%. Perinatal depression was associated with a number of demographic, medical and lifestyle factors, including the use of antidepressant medication, chronic diabetes mellitus, Arab background, current or past smoking, and anaemia. These risk factors may help identify women at risk of perinatal depression. [ABSTRACT FROM AUTHOR]

Fetal Alcohol Spectrum Disorder (FASD) describes the wide range of adverse physical, behavioral and cognitive effects resulting from ethanol exposure during embryonic and fetal development. Identification of children suffering from FASD is often difficult, as abuse of ethanol during pregnancy is a heavily stigmatized behavior that receives little prenatal screening attention in routine care. Over the last 3 decades, measurement of the ethanol metabolites fatty acid ethyl esters (FAEE) has emerged as a useful tool to detect in the neonatal period fetal alcohol exposure starting from mid gestation. This review aims at updating clinicians and researchers on the validity and utility of this biological marker in two aspects: The association with adverse fetal outcomes and in generating population estimates of fetal alcohol exposure. [ABSTRACT FROM AUTHOR]

Aim: Aging in humans is associated with a 10–40-fold greater incidence of sudden cardiac death from malignant tachyarrhythmia. We have reported that thiol oxidation of ryanodine receptors (RyR2s) by mitochondria-derived reactive oxygen species (mito-ROS) contributes to defective Ca2+ homeostasis in cardiomyocytes (CMs) from aging rabbit hearts. However, mechanisms responsible for the increase in mito-ROS in the aging heart remain poorly understood. Here we test the hypothesis that age-associated decrease in autophagy is a major contributor to enhanced mito-ROS production and thereby pro-arrhythmic disturbances in Ca2+ homeostasis. Methods and Results: Ventricular tissues from aged rabbits displayed significant downregulation of proteins involved in mitochondrial autophagy compared with tissues from young controls. Blocking autophagy with chloroquine increased total ROS production in primary rabbit CMs and mito-ROS production in HL-1 CMs. Furthermore, chloroquine treatment of HL-1 cells depolarized mitochondrial membrane potential (Δψm) to 50% that of controls. Blocking autophagy significantly increased oxidation of RyR2, resulting in enhanced propensity to pro-arrhythmic spontaneous Ca2+ release under β-adrenergic stimulation. Aberrant Ca2+ release was abolished by treatment with the mito-ROS scavenger mito-TEMPO. Importantly, the autophagy enhancer Torin1 and ATG7 overexpression reduced the rate of mito-ROS production and restored both Δψm and defective Ca2+ handling in CMs derived from aged rabbit hearts. Conclusion: Decreased autophagy is a major cause of increased mito-ROS production in the aging heart. Our data suggest that promoting autophagy may reduce pathologic mito-ROS during normal aging and reduce pro-arrhythmic spontaneous Ca2+ release via oxidized RyR2s. [ABSTRACT FROM AUTHOR]

Background: Oral contraceptives (OCs) are one of the most commonly used classes of drugs worldwide. A case of neutropenia and associated infections in a young woman using OCs that settled after discontinuation and reappeared upon re-challenge, has led us to investigate a potential association between oral contraceptives and neutropenia. Objectives: To compare rates of neutropenia among women receiving OCs to a matched control group of women not exposed to the "pill". Patients and Methods: In this population-based cohort study we used a large computerized database of a health fund, comparing women prescribed OCs and a control group not using the pill. We selected a cohort of 51,394 OC users aged 16–40 years who purchased their first monthly pack of OCs between 2010 and 2018. Controls included all non-pregnant women aged 16–40 years for whom OC was not dispensed (n = 140,932). Neutrophil count before and during OC were compared. Results: Prior to OC exposure, 1.3% of the women were neutropenic, compared to 1.6% after exposure to OC (RR 1.22; 95% CI 1.1–1.35). Mean neutrophil count changed from 3.87 × 103 to 3.82 × 103 mm3 (p < 0.001). In the control group (n = 140,932) no difference was seen in the proportion of neutropenic women between the first complete blood count (1.7%) compared to the second (1.8%) count (p = 0.305). In all severity levels, neutropenia was significantly more common in the OC group. The relative risk was higher for severe (RR 1.63) than for mild neutropenia (RR 1.13) (p = 0.034 for trend). Conclusions: There is a significant increase in the proportion of neutropenic women after initiating OCs. More research is needed in order to evaluate the effect of neutropenia in this group of women. [ABSTRACT FROM AUTHOR]

Introduction: With the majority of elderly persons consuming multiple drugs, inappropriate drug use is a major issue in geriatric medicine. Areas covered: We reviewed PubMed, Embase, and Cochrane from inception to 1 May 2019 for potentially inappropriate use of medications, polypharmacy, and age-dependent changes in pharmacokinetics and pharmacodynamics. We selected to highlight new aspects that have emerged in recent years: appropriate monitoring of drug adherence and the introduction of Big Data analysis in advancing geriatric pharmacology. Expert opinion: There are major gaps in the pharmacological treatment of the elderly. Most drugs were designed and tested in adults, with no pharmacokinetic and pharmacodynamic data on changes in old age. This void must be corrected through systematic and well-designed research programs. Potentially inappropriate use of medications (PIM) in the elderly is a serious issue in advanced age. Analysis of PIM shows relatively low predictive value in real life medicine. Most physicians continue to prescribe to the elderly medicines which should not be given at all, or not combined. Polypharmacy is a complex issue in old age, and in many cases treating physicians are not conducting critical assessment of the need for numerous medications. [ABSTRACT FROM AUTHOR]

Introduction: Opioids constitute a cornerstone of pain relief treatment. However, opioid safety during pregnancy has not been well established. Recent studies reported an association between in utero opioid exposure and spina bifida. Methods: In order to further evaluate the association of opioids exposure during pregnancy with adverse pregnancy outcomes, we conducted a large historical cohort by linking four databases: medications dispensations, births, pregnancy terminations for medical reasons and infant hospitalizations during the years of 1999–2009. Confounders that were controlled for included maternal age, ethnicity, maternal diabetes, smoking status, parity, obesity, year and folic acid intake. A secondary analysis for total major malformations and for spina bifida was performed using propensity score matching for first trimester exposure. Results: Of the 101,586 women included in the study, 3003 were dispensed opioids during the first trimester. Intrauterine exposure to opioids was not associated with overall major malformations (adjusted odds ratio (aOR) 0.97, 95% CI 0.83–1.13), cardiovascular malformations (aOR = 0.89, 95% CI 0.70–1.13) other malformations by systems or spina bifida in particular. However, the risk for spina bifida among newborns and abortuses who were exposed to codeine was four times higher than that of the unexposed (aOR = 4.42, 95% CI 1.60–12.23). This association remained significant in a secondary analysis using propensity score matching. Third trimester exposure to opioids was not associated with low birth weight (aOR = 1.08, 95% CI 0.77–1.52), perinatal death (aOR = 1.38, 95% CI 0.64–2.99) and other adverse pregnancy outcomes. Conclusions: These findings suggest that opioids exposure (as a homogenous group) is not a significant risk factor for overall major malformations. Exposure to codeine during the first trimester was found to be associated with increased risk of spina bifida. However, this finding was based on a small number of cases and need to be verified in future work. [ABSTRACT FROM AUTHOR]

Aims: Women with long QT syndrome 2 (LQT2) have a particularly high postpartal risk for lethal arrhythmias. We aimed at investigating whether oxytocin and prolactin contribute to this risk by affecting repolarization.Methods and Results: In female transgenic LQT2 rabbits (HERG-G628S, loss of IKr), hormone effects on QT/action potential duration (APD) were assessed (0.2-200 ng/L). Hormone effects (200 ng/L) on ion currents and cellular APD were determined in transfected cells and LQT2 cardiomyocytes. Hormone effects on ion channels were assessed with qPCR and western blot. Experimental data were incorporated into in silico models to determine the pro-arrhythmic potential. Oxytocin prolonged QTc and steepened QT/RR-slope in vivo and prolonged ex vivo APD75 in LQT2 hearts. Prolactin prolonged APD75 at high concentrations. As underlying mechanisms, we identified an oxytocin- and prolactin-induced acute reduction of IKs-tail and IKs-steady (-25.5%, oxytocin; -13.3%, prolactin, P < 0.05) in CHO-cells and LQT2-cardiomyocytes. IKr currents were not altered. This oxytocin-/prolactin-induced IKs reduction caused APD90 prolongation (+11.9%/+13%, P < 0.05) in the context of reduced/absent IKr in LQT2 cardiomyocytes. Hormones had no effect on IK1 and ICa,L in cardiomyocytes. Protein and mRNA levels of CACNA1C/Cav1.2 and RyR2 were enhanced by oxytocin and prolactin. Incorporating these hormone effects into computational models resulted in reduced repolarization reserve and increased propensity to pro-arrhythmic permanent depolarization, lack of capture and early afterdepolarizations formation.Conclusions: Postpartum hormones oxytocin and prolactin prolong QT/APD in LQT2 by reducing IKs and by increasing Cav1.2 and RyR2 expression/transcription, thereby contributing to the increased postpartal arrhythmic risk in LQT2. [ABSTRACT FROM AUTHOR]

There are several methods to treat vitamin B12 deficiency (VB12d): intramuscular (IM), oral, sublingual (SL), and intranasal vitamin B12 (VB12) preparations. Large studies comparing the efficacy of SL vs. IM supplements are lacking. The aim of the present study was to compare the efficacy of SL versus the standard IM administration of VB12 in restoring B12 levels. This was a retrospective analysis of data from the computerized pharmacy records of Maccabi Health Service (MHS). Data were recorded for all patients older than 18 years of age who were prescribed VB12 during January 2014–December 2017. The main outcome was the change in levels of serum vitamin B12 (sVB12) after treatment. Overall, there were 4281 patients treated with VB12 supplements. Of them, 830 (19.3%) patients were treated with VB12 IM injections and 3451 (80.7%) with SL tablets. The mean ± SD difference between sVB12 levels before and after administration of VB12 supplements was significantly higher in the SL group vs. IM injection group (252 ± 223 vs. 218 ± 184 ng/L, p < 0.001). SL VB12 significantly increased the odds ratio (OR) for an increase of sVB12 levels, compared to the IM group, OR 1.85, CI 95% 1.5–2.3, p < 0.001. This is the largest study that documents therapy with SL preparations of VB12 sufficient and even superior to the IM route. The SL overcomes the challenges of IM injections and should be the first line option for patients with VB12d. [ABSTRACT FROM AUTHOR]

The health risks of cigarette smoking have been reported to increase continuously, while it is estimated to be responsible for the death toll of more than seven million people globally each year. In an effort to reduce the risk involved in cigarette smoking, nicotine-free inhalators have been developed as smoking-cessation aids. To evaluate the feasibility of nicotine-free inhalators in such respect, we investigated the composition of volatile organic compounds (VOCs) released from the consumption of nicotine-free inhalators of which major components include natural essential oils and traditional Chinese medicinal herbs. Vapor samples from nicotine-free inhalators were generated and collected for analysis using an e-cigarette auto-sampler. The vapor samples were captured onto a multi-bed sorbent tube sampler and a 2,4-dinitrophenylhydrazine (DNPH) cartridge for the quantitative analysis with the aid of thermal desorption-gas chromatography/mass spectrometry and high-performance liquid chromatography, respectively. A total of 29 VOCs were determined in vapor samples at concentrations below 0.2 ppm. Concentrations of (+)-isomenthone and acrolein slightly exceeded the derived no-effect level (DNEL) or sensory irritation level. However, VOCs were below the concentration exposure limit, according to the Occupational Safety and Health Administration (OSHA). According to our study, most of the aroma compounds and VOCs released from nicotine-free inhalator were lower than the DNEL or sensory irritation level. Consequently, it is found that nicotine-free inhalators could be safe to use in reference to toxic guidelines for inhalation exposure. However, if the use of nicotine-free inhalators is over prolonged period, it can also increase the risk of exposure to potentially toxic compounds. [ABSTRACT FROM AUTHOR]

Background: Most patients with Parkinson's disease exhibit intracellular accumulation of the α-synuclein protein encoded by the α-synuclein gene. It was recently shown that β2-adrenoreceptor agonists downregulate this gene, decreasing the apparent risk of Parkinson's disease by up to 40%. In contrast, exposure to β-blocking drugs increases production of the α-synuclein protein. Objective: The aim of this study was to examine whether chronic exposure to β-blockers is associated with an increased risk for Parkinson's disease. Patients and Methods: From the electronic charts of Maccabi Health Services, we identified all patients receiving their first β-blocker treatment between 1998 and 2004, and followed them up, for a diagnosis of Parkinson's disease, between 2005 and 2016. We calculated the morbidity hazard of Parkinson's disease diagnosis in users of β-blockers compared with non-users, as well as users of angiotensin-converting enzyme (ACE) inhibitors for hypertension, after adjusting for sex, age, weight, smoking status, cholesterol levels and use of statins, employing the Cox proportional hazard model. We also conducted a Kaplan–Meier survival analysis. Results: Overall, 145,098 patients received β-blockers, and 1,187,151 patients did not. The adjusted hazard ratio for Parkinson's disease among β-blocker users was 1.51 (95% confidence interval 1.28–1.77; p < 0.0001). In contrast, the Parkinson's disease morbidity hazard for patients receiving ACE inhibitors was no different than for the general population. The morbidity risk showed the effect of cumulative dose response with low threshold levels. Conclusions: Chronic use of β-blockers confers a time- and dose-dependent increased risk for Parkinson's disease. In view of the available alternatives for β-blockers, their chronic use should be carefully reconsidered. [ABSTRACT FROM AUTHOR]

Background and Objective: Young children may be accidentally exposed to adult dose forms of medications, some of which can be fatal, even with a single dose. As numerous new medications have been introduced, we herein update a 2004 list of potentially toxic drugs that can be lethal for toddlers when taking one adult dose unit.Methods: We reviewed all medications available in North America and identified their reported fatal doses per kilogram in children, or in adults if no pediatric data were available. For each drug we identified the largest dose unit available on the market and calculated how many dose units would be fatal to a 10 kg toddler.Results: Since 2004, the list of potentially fatal drugs for toddlers has doubled and now includes new anticoagulants, a phosphodiesterase-5 inhibitor, new antiepileptic drugs, antidiabetic medications, drugs for multiple sclerosis, and second-generation antipsychotic drugs, among others.Conclusion: With the development of potent new medications, an increasing number of drugs are dangerous upon accidental exposure to toddlers and young children. The present 2018 list of documented fatal drugs has doubled compared with 2004, and special labeling of these medications is urgently needed to avoid such calamities. [ABSTRACT FROM AUTHOR]